research questions breast cancer

Cochrane Breast Cancer

Top 10 breast cancer topics needing a cochrane systematic review.

Deciding which research topics to focus on in medicine and health depends on many factors. These factors can include the currency of a topic, feedback from people providing or receiving care, and the priorities of funders.

In late 2019, the Cochrane Breast Cancer Group (part of Cochrane’s Cancer Network) conducted a formal priority-setting exercise to help decide which review topics were most needed in the Cochrane Library. The Group did this by circulating a survey listing 25 new or existing review topics to a diverse group of individuals who are part of the international breast cancer community. The survey asked individuals to rank their top 10 topics from the list. Read details about the aims and methods used for this priority-setting exercise, which adhered to the standards outlined in Cochrane’s priority setting guidance note .

What were the top 10 review topics?

Read about the ranking of the 25 new or existing review topics .

What is next?

Support to author teams For the top 10 topics, the Cochrane Breast Cancer Group will prioritise these topics during the editorial and peer-review process.

For all breast cancer review topics registered with Cochrane, the Cochrane Breast Cancer Group continues to work on these topics with author teams as these remain important topics. There will be no noticeable change in the support provided to author teams.

Future topics The Cochrane Breast Cancer Group is open to receiving new topic ideas. If you have suggestions for new topics that are not currently covered in the Cochrane Library, please send your idea to [email protected] .

Repeating this priority-setting exercise The priority-setting exercise may be repeated every 3 years, depending on resources.

Who responded to the survey?

The survey was circulated to over 800 individuals. Of the 199 people who responded, 90 people (45%) provided complete responses. The respondents were doctors (59%), researchers (18%) and people who had received treatment or currently receiving treatment for breast cancer (14%). Most respondents were from the UK, followed by the USA, Argentina, and India.

How did we calculate the ranking for each review topic?

The average ranking was calculated for each topic. This method is commonly used to determine ranking scores from surveys. This approach considers the number of counts for each ranking on a topic, the weighting of each rank (where a ranking of 1 gets the most weight) and the total number of counts. 

[Cover image: foliage of the Yew tree. Taxanes, a class of chemotherapy drugs, were originally derived from the Yew tree]

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Breast Cancer Treatments: Updates and New Challenges

Anna burguin.

1 Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada; [email protected]

2 Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada; [email protected]

Caroline Diorio

3 Department of Preventive and Social Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada

Francine Durocher

Associated data.

The study did not report any data.

Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence, a deeper understanding of the development of new treatments that are more specific and effective in treating each BC subgroup is key. New approaches have recently emerged such as immunotherapy, conjugated antibodies, and targeting other metabolic pathways. This review summarizes current BC treatments and explores the new treatment strategies from a personalized therapy perspective and the resulting challenges.

1. Introduction

Breast cancer (BC) is the most frequent cancer and the second cause of death by cancer in women worldwide. According to Cancer Statistics 2020, BC represents 30% of female cancers with 276,480 estimated new cases and more than 42,000 estimated deaths in 2020 [ 1 ].

Invasive BC can be divided into four principal molecular subtypes by immunohistological technique based on the expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) [ 2 ]. Luminal A BC (ER+ and/or PR+, and HER2-) represents around 60% of BC and is associated with a good prognosis [ 3 ]. Luminal B BC (ER+ and/or PR+, and HER2+) represents 30% of BC and is associated with high ki67 (>14%), a proliferation marker, and a poor prognosis [ 4 ]. HER2 BC (ER-, PR-, and HER2+) represents 10% of BC and is also associated with a poor prognosis [ 5 ]. Lastly, triple-negative BC (TNBC) (ER-, PR-, and HER2-) represents 15–20% of BC and is associated with more aggressivity and worse prognosis compared to other BC molecular subtypes and often occurs in younger women [ 6 ]. Characteristics of BC by molecular subtypes are described in Figure 1 .

Characteristics of breast cancer molecular subtypes. ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; TNBC: triple-negative breast cancer. a . Frequency derived from Al-thoubaity et al. [ 12 ] and Hergueta-Redondo et al. [ 13 ]. b . Grade derived from Engstrom et al. [ 14 ]. c . Prognosis derived from Hennigs et al. [ 15 ] and Fragomeni et al. [ 16 ]. d . The 5–year survival rate derived from the latest survival statistics of SEER [ 7 ].

The 5-year relative BC-specific survival rate of BC is encouraging with 90.3% for all subtypes and stages. However, for metastatic BC the 5-year relative cancer-specific survival rate is still low: 29% regardless of subtype and can drop to 12% for metastatic TNBC [ 7 ]. This clearly indicates that strategies of treatment for metastatic BC patients are not effective enough to ensure a good survival rate. Thus, it is crucial to find new solutions for the treatment of metastatic BC and especially TNBC.

Treatment choice is based on the grade, stage, and BC molecular subtype to have the most personalized, safe, and efficient therapy. The grade describes the appearance of tumor cells compared to normal cells. It includes tubule differentiation, nuclear pleomorphism, and the mitotic count [ 8 ]. The stage is used to classify the extent of cancer in the body and is defined using the TNM system comprising tumor size, lymph node status, and the presence of metastases [ 9 ]. For non-metastatic BC, the strategic therapy involves removing the tumor by complete or breast-conserving surgery with preoperative (neoadjuvant) or postoperative (adjuvant) radiotherapy and systemic therapy including chemotherapy, and targeted therapy. Targeted therapy comprises endocrine therapy for hormone receptor-positive (HR+) BC and anti-HER2 therapy for HER2+ BC. Unfortunately, there is no available targeted therapy for the TNBC subtype. For metastatic BC the priority is to contain tumor spread as this type of BC remains incurable. The same systemic therapies are used to treat metastatic BC [ 10 ].

Challenges in the treatment of BC including dealing with treatment resistance and recurrence. Indeed, 30% of early-stage BC have recurrent disease, mostly metastases [ 11 ]. Thus, it is crucial to develop new strategic therapies to treat each BC subgroup effectively.

This review will summarize current treatments for invasive BC, the underlying resistance mechanisms and explore new treatment strategies focusing on personalized therapy and the resulting challenges.

2. Common Treatments for All Breast Cancer Subtypes

In addition to surgery, radiotherapy and chemotherapy are used routinely to treat all BC subtypes [ 17 ].

2.1. Surgery

The most standard breast surgery approaches are either total excision of the breast (mastectomy), usually followed by breast reconstruction, or breast-conserving surgery (lumpectomy). Lumpectomy entails the excision of the breast tumor with a margin of surrounding normal tissue. The recommended margins status is defined as “no ink on tumor”, meaning no remaining tumor cells at the tissue edge [ 18 ]. Studies show that total mastectomy and lumpectomy plus irradiation are equivalent regarding relapse-free and overall survival (OS) [ 19 ]. Contraindications for breast-conserving surgery include the presence of diffuse microcalcifications (suspicious or malignant-appearing), disease that cannot be incorporated by local excision with satisfactory cosmetic result, and ATM (ataxia-telangiesctasia mutated) mutation (biallelic inactivation) [ 18 ].

The surgery to remove axillary lymph nodes is useful to determine cancerous cell spread and for therapeutic purposes. For instance, axillary lymph node dissection (ALND) can improve survival rated by removing remaining tumor cells. ALND used to be the goal standard for removing positive lymph nodes. However, clinical trials showed that sentinel lymph node biopsy (SLNB) had the same effect as ALND regarding disease-free survival (DFS) and OS [ 20 ]. Other clinical trials demonstrated that ALND was not necessary for all patients with positive lymph nodes. Moreover, most patients who receive radiation and systemic treatment after SLNB have negative lymph nodes as these treatments are sufficient in eliminating residual tumor cells [ 21 ].

2.2. Radiotherapy

Radiation therapy has been used to treat cancer since Röngten discovered the X-ray in 1895 [ 22 ]. High-energy radiations are applied to the whole breast or a portion of the breast (after breast-conservative surgery), chest wall (after mastectomy), and regional lymph nodes [ 23 ]. A meta-analysis showed that radiation following conservative surgery offered more benefits to patients with higher-risk BC while patients with small, low-grade tumors could forego radiation therapy [ 24 ]. Postmastectomy radiation to the chest wall in patients with positive lymph nodes is associated with decreased recurrence risk and BC mortality compared to patients with negative lymph nodes [ 25 ]. A radiation boost to the regional node radiation treatment can be incorporated after mastectomy for patients at higher risk for recurrence [ 26 ]. This additional radiation boost to regional nodes following mastectomy is associated with improved (DFS) but is also associated with an increase in radiation toxicities such as pneumonitis and lymphedema [ 27 ]. Radiotherapy can be administered concurrently with personalized therapy (anti-HER2 therapy or endocrine therapy).

As one of the major side effects of radiotherapy is cardiotoxicity, it is critical to minimize exposure to the heart and lungs [ 28 ]. Additional techniques can be used to reduce the radiation exposure to the heart, lungs, and normal tissue such as prone positioning, respiratory control, or intensity-modulated radiotherapy [ 29 ].

Advanced invasive BC can exhibit radiation therapy resistance [ 30 ]. The hypoxic tumor microenvironment, which lacks oxygen, leads to increased cell proliferation, apoptosis resistance, and radiotherapy resistance [ 31 ]. The major player of this resistance is the HIF-1α (hypoxia-inducible factor 1 alpha) protein [ 32 ]. Indeed, HIF-1α overexpression is caused by low oxygen levels within the microenvironment and promotes the maintenance of hypoxia by allowing tumoral cells to survive in a hypoxic microenvironment [ 33 , 34 , 35 ]. Cancer stem cells (CSC) could also have a role in radiation therapy resistance [ 36 ]. CSC can self-renew and initiate subpopulations of differential progeny, and a hypoxic microenvironment is ideal for CSC survival and proliferation [ 37 , 38 ].

Radiation therapy is used to treat all BC subtypes, but its implication is more important for TNBC, as there is no personalized therapy for this subtype. It has been shown that radiotherapy benefits TNBC patients both after conserving surgery and mastectomy [ 39 ].

2.3. Chemotherapy

BC chemotherapy comprises several families of cytotoxic drugs, including alkylating agents, antimetabolites and tubulin inhibitors [ 40 ]. Cyclophosphamide is a nitrogen mustard alkylating agent causing breakage of the DNA strands [ 41 ]. The mechanism of action for anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) includes DNA intercalation, thereby inhibiting macromolecular biosynthesis [ 42 ]. Taxanes, including docetaxel and paclitaxel, bind to microtubules and prevent their disassembly, leading to cell cycle arrest and apoptosis [ 43 ].

Chemotherapy can be administered in the neoadjuvant or adjuvant setting and for metastatic BC treatment.

2.3.1. Neoadjuvant Chemotherapy (NAC)

Neoadjuvant chemotherapy was initially administered for non-metastatic but inoperable BC, defined as unreachable tumors [ 44 ]. Then, chemotherapy was used before the surgery for operable tumors to facilitate breast conservation [ 45 ].

Studies demonstrated that chemotherapy administered before surgery is as effective as administered after surgery [ 46 , 47 , 48 ]. The NSABP-B-18 trial compared the effects of doxorubicin and cyclophosphamide administered either postoperatively or preoperatively. This trial showed that NAC reduces the rate of axillary metastases in node-negative BC patients [ 48 ].

Some patients fail to achieve pathologic complete response after a full course of NAC. Unfortunately, there is no consensus regarding the treatment strategy to follow for patients with residual disease after surgery [ 49 , 50 ]. The BC subtype plays an important role in the response to NAC. Indeed, TNBC and HER2+ BC are more likely to be sensitive to chemotherapy. Hence, NAC is a good strategy to maximize pathologic complete response in these BC subtypes [ 45 ].

2.3.2. Adjuvant Chemotherapy

Adjuvant chemotherapy is administered to BC patients with lymph nodes metastases or a high risk of recurrence [ 51 ]. The standard chemotherapy treatment comprises an anthracycline and a taxane. The two most common regimens are cyclophosphamide and doxorubicin for four cycles followed by paclitaxel for four cycles. Then patients are given the previous combination of therapies followed by either weekly paclitaxel for 12 weeks, or docetaxel every 3 weeks for four cycles [ 52 , 53 ].

Like neoadjuvant therapy, patients with HR-negative BC receive more benefits from adjuvant therapy (i.e., reduction of BC recurrence and mortality) than HR+ BC patients [ 54 ]. However, for patients with HR+, node-negative BC associated with a high Oncotype recurrence score (≥31), calculated from the expression of 16 BC-related genes and 5 reference genes, adjuvant chemotherapy reduces the risk of recurrence [ 55 ]. The TAILORx clinical trial showed that HR+ BC patients with a low Oncotype recurrence score do not benefit from chemotherapy alone [ 56 ].

According to the molecular BC subtype, chemotherapy can be administered with targeted therapies. Patients with HR+ BC should receive endocrine therapy after chemotherapy is completed, and HER2+ BC patients should receive trastuzumab combined with chemotherapy [ 57 ]. For TNBC patients, front-line therapy includes a combination of taxane and anthracycline [ 58 ].

One of the major drawbacks of chemotherapy is its side effects. The early side effects (0–6 months of treatment) involve fatigue, alopecia, cytopenia (reduction in the number of normal blood cells), muscle pain, neurocognitive dysfunction, and chemo-induced peripheral neuropathy. The chronic or late side effects (after 6 months of treatment) include cardiomyopathy, second cancers, early menopause, sterility, and psychosocial impacts [ 59 ].

As mentioned previously in this review, chemotherapy is composed of taxanes, anthracyclines and cyclophosphamide. Each of these molecules can lead to resistance in BC patients [ 60 ].

One mechanism of resistance is by overexpressing p-glycoprotein, an ATP-binding cassette (ABC) family member, which confers resistance to anthracycline and taxanes [ 61 ]. Breast cancer resistance protein (BCRP), another ABC family member, induces resistance to anthracycline but not taxanes when overexpressed [ 62 ]. Microtubule alterations can also lead to taxane resistance. The overexpression of β-tubulin III induces paclitaxel resistance [ 63 ]. Moreover, mutations in microtubule-associated proteins (MAPs) affect microtubule dynamics and improve taxane resistance [ 64 ]. Multiple enzymes are known to be involved in the cyclophosphamide detoxification, leading to its resistance. For example, aldehyde dehydrogenase upregulation detoxifies aldophosphamide a type of cyclophosphamide, and mutations in glutathione S-transferases, enzymes involved in drug-metabolizing conjugation reactions, can also affect cyclophosphamide detoxification [ 65 , 66 ].

Surgery, radiotherapy, and chemotherapy are complementary strategies in the treatment of BC patients. However, they are not sufficient to effectively treat all BC molecular subtypes, as they do not have the same response to radiotherapy or chemotherapy. Thus, personalized therapies are essential in the process for BC treatment.

3. Current Personalized Treatments for Breast Cancer: Strengths and Weaknesses

The current strategies of treatment are principally based on the tumor progression and BC molecular subtypes in order to offer the most personalized treatment for BC patients. The algorithm of BC treatment is represented in Figure 2 .

Breast cancer treatment flow diagram. ( A ). Early-stage breast cancer. ( B ). Metastatic/advanced breast cancer. a Neoadjuvant chemotherapy for HR+ BC patients is not systematic. It is mainly administered to luminal B BC patients and/or elder BC patients. HR+: hormone receptors positive; HER2+: human epidermal growth factor receptor 2 positive; TNBC: triple-negative breast cancer; AIs: aromatase inhibitors; T-DM1: trastuzumab-emtansine.

3.1. Endocrine Therapy

Endocrine therapy is the main strategy to treat HR positive invasive BC. The purpose of this therapy is to target the ER directly (selective estrogen receptors modulators and degraders) or the estrogen synthesis (aromatase inhibitors) [ 67 ]. The most common types of endocrine therapy are selective estrogen receptor modulators (SERMs), selective modulators estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs) [ 68 ]. Endocrine therapy mechanism of action and resistance are described in Figure 3 .

Endocrine therapy mechanisms of action and resistance. The left part of the figure shows the mechanism of endocrine therapy through aromatase inhibitors, tamoxifen, and fulvestrant. The right part of the figure describes the mechanisms of resistance to endocrine therapy through the epigenetic modifications, the increase of coactivators and cell cycle actors, and the activation of other signaling pathways. Estrogens can go through the plasma membrane by a. diffusion as they are small non-polar lipid soluble molecules; b. binding to membrane ER initiating the activation of Ras/Raf/MAPK and PI3K/Akt signaling pathways which are blocked by tamoxifen. 1: inhibition of ER dimerization; 2: blockage of nucleus access; 3: ER degradation. ER: estrogen receptor; AIB1: amplified in breast cancer 1; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HER: human epidermal receptors; EGF: epidermal growth factor; HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; Me: methylation; Ac: acetylation.

3.1.1. Selective Estrogen Receptor Modulators (SERMs)

SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, are antiestrogens that compete with estrogen by binding to the ER. This binding changes the conformation of the ER ligand-binding domain, and once ER is translocated to the nucleus, it blocks co-factor recruitment and subsequent genes transcription involved in cell cycle progression (cyclin D1), cell proliferation (like IGF-1), or cell migration (collagenase) [ 69 , 70 ].

The most used SERMs is tamoxifen, approved by the US Food and Drugs Administration (FDA) in 1977. It is an adjuvant therapy orally administered for 5 to 10 years according to tumor aggressivity. Tamoxifen adjuvant treatment reduces recurrence risk by 50% for the first 5 years and 30% for the next 5 years [ 71 ]. Tamoxifen is given to either premenopausal or postmenopausal patients. However, for high-risk premenopausal patients, adding ovarian suppression is more effective than tamoxifen alone [ 72 ]. Tamoxifen can also be administered as neoadjuvant treatment, especially for elderly BC patients [ 73 ]. However, studies have demonstrated no difference in OS for ER+ BC patients when neoadjuvant tamoxifen is compared to surgery [ 74 , 75 ].

Other SERMs have since been developed, such as toremifene approved by the FDA in 1997 [ 76 ]. Studies comparing the effect of toremifene and tamoxifen in premenopausal patients with ER+ advanced BC have shown that toremifene efficacy and safety are similar to tamoxifen [ 77 , 78 ]. Bazedoxifene and raloxifene are administered as prevention treatment to postmenopausal patients at high risk of developing invasive BC and for preventing osteoporosis [ 79 , 80 , 81 ].

The most frequent adverse events of SERMs are hot flushes, nausea, vomiting, vaginal bleeding/discharges, and increased risk of thromboembolic events [ 82 ]. Of note, about 40% of HR+ BC patients will develop resistance to SERMs [ 83 ]. SERMs resistance can occur by the loss of ER expression or functions. Epigenetic modifications such as hypermethylation of CpG islands or histone deacetylation can lead to transcriptional repression of ER [ 84 ]. Another potential mechanism for ER expression loss is the overpopulation of ER-negative cells in heterogenous ER+ tumors [ 85 ]. Mutations in the ligand-binding domain of ER gene ( ESR1 ) inhibit the binding of estrogen to the ER leading to the abolition of downstream signaling. Moreover, abnormal splicing can lead to truncated, nonfunctional ER protein [ 86 , 87 ]. Another explanation for SERMs resistance is the abnormal expression of ER coregulators [ 88 ]. Coregulators are very important in the ER pathway as they can increase or decrease ER activity depending on incoming signals [ 89 ]. The most studied coregulator involved in SERMs resistance is the AIB1 (Amplified in breast cancer 1) coactivator protein, often overexpressed in resistant breast tumors [ 90 ]. In particular, in ER+ cells that overexpress HER2, there is a crosstalk between HER2 and AIB1. HER2 induces phosphorylation of AIB1 leading to evasion and subsequent activation of the ER signaling pathway even though it is inhibited by SERMs [ 91 ]

3.1.2. Selective Estrogen Receptor Degraders (SERDs)

To counteract the large proportion of tamoxifen-resistant tumors, a new type of therapeutic agents with a different mechanism of action has been developed: SERDs. In contrast to SERMs, SERDs completely block the ER signaling pathway.

Fulvestrant is the main SERD administered. It was discovered by Wakeling and collaborators in 1987 and demonstrated pure anti-estrogen activity [ 92 ]. Fulvestrant binds to ER with a higher affinity than tamoxifen. Once it binds to the ER, it inhibits receptor dimerization and then blocks ER translocation to the nucleus leading to its degradation [ 93 , 94 , 95 ].

Fulvestrant is administered by intramuscular injections, and common adverse effects are nausea, pain, and headaches [ 96 ]. Fulvestrant is approved to treat postmenopausal and premenopausal patients with ovarian function suppression, with ER+ advanced or metastatic BC on prior endocrine therapy [ 97 ]. More recently (in 2017), fulvestrant was approved as first-line monotherapy for advanced ER+ breast cancer [ 98 ]. According to the 2021 NCCN guidelines, fulvestrant combined with endocrine therapy or CDK4/6 inhibitors is one of the preferred regimens for second-line therapy in ER+ advanced or metastatic BC [ 99 ]. The combination of fulvestrant with other endocrine therapies has not shown any advantages over fulvestrant used in monotherapy [ 100 , 101 ]. Clinical studies have shown benefits from fulvestrant when administered in higher doses to patients with ESR1 -mutated advanced BC [ 102 , 103 ]. Indeed, ESR1 mutations occur in nearly 20% of cases of ER+ BC [ 86 ].

However, fulvestrant can lead to resistance by different mechanisms. For example, by upregulating the PI3K (phosphatidylinositol 3-kinase), mTOR (mammalian target of rapamycin) and Ras-ERK (extracellular signal-regulated kinase) signaling pathways. PI3K/Akt/mTOR is a downstream signaling pathway of ER activation and plays an important role in antiestrogen therapy resistance [ 104 ]. PI3K pathway activation can occur independently of ER by binding to the epidermal growth factor (EGF) [ 105 ]. Moreover, it has been shown that Akt overexpression leads to fulvestrant resistance [ 106 ]. IGF-1R activation (insulin-like growth factor 1 receptor) may be another mechanism of resistance to fulvestrant. IGF-1R expression is involved in cell survival and promotes metastatic cell proliferation. The interaction between IGF-1R and ER initiates the activation of IGF-1R/MAPK (mitogen-activated protein kinase) and IGF-1R/PI3K signaling leading to antiestrogen resistance [ 107 ].

3.1.3. Aromatase Inhibitors (AIs)

Aromatase is a cytochrome P50 enzyme involved in the synthesis of androgens and estrogens [ 108 ]. Aromatase is found in the breast, uterus, and other estrogen-sensitive tissues in specific levels depending on menopausal status [ 109 , 110 ]. Aromatase expression is increased in breast tumors and associated with high estrogen levels. Therefore, high expression of aromatase promotes ER+ tumor proliferation [ 111 ].

Aromatase inhibitors (AIs) block aromatase enzyme activity, leading to the inhibition of estrogen synthesis. Current AIs can be classified into two categories: steroidal AIs and non-steroidal AIs [ 112 ]. Exemestane, a steroidal AI, has a steroid-like structure similar to androstenedione, which is the aromatase substrate. Exemestane irreversibly binds to the aromatase substrate-binding site leading to its inactivation [ 113 ]. Non-steroidal AIs include letrozole and anastrozole. They both bind non-covalently and competitively to the aromatase substrate-binding site and prevent the binding of androgens by saturating the binding site [ 112 ].

AIs are an oral treatment administered only to postmenopausal women (including patients that become postmenopausal following ovarian suppression). It is administered alone or in combination with tamoxifen as adjuvant therapy for HR+ BC patients [ 114 , 115 , 116 , 117 ]. AIs can be administered for 5 years or 2–3 years if followed by tamoxifen and up to 5 years after previous tamoxifen or AI treatment. For advanced or metastatic HR+ BC, AIs can be delivered as first-line and second-line therapy. Patients who become postmenopausal after or during the 5 years of tamoxifen treatment can receive AIs, such as letrozole, as an extended treatment strategy [ 118 , 119 ].

Estrogens have protective effects on the cardiovascular system by regulating serum lipids concentrations and increasing vasodilatation [ 120 ]. Hence, AIs might increase the risk of developing cardiovascular diseases by reducing estrogen levels in the blood [ 121 ]. Other adverse effects of AIs include hot flushes, vaginal dryness, fatigue, and osteoporosis [ 122 ]. ER+ tumors can acquire AI resistance. Some mechanisms of AI resistance are similar to those conferring SERM or SERD resistance, such as ESR1 mutations, epigenetic modifications, and PI3K pathway upregulation [ 123 ]. However, other mechanisms of action are involved in AI resistance. For example, the upregulation of cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6-retinoblastoma (CDK6-RB) pathways can lead to an estrogen-dependent cell progression [ 124 ]. Clinical studies have shown better benefits from CDK4-CDK6 inhibitors in combination with AIs compared to AIs alone [ 125 , 126 ].

Endocrine therapy is a well-established treatment strategy for HR+ tumors. Over the last decades, SERMs, SERDs and AIs have been proven as safe and effective personalized therapy for HR+ BC patients, and these therapeutic strategies have shown continued improvements. However, the main drawback of endocrine therapy is acquired or de novo resistance [ 127 ]. Hence, it is essential to develop new therapeutic agents that use different modes of action to treat HR+ BC more efficiently.

3.2. Anti-HER2 Therapy

The overexpression of HER2 is associated with worse survival outcome compared to HR-positive/HER2-negative BC [ 128 , 129 ]. Hence, therapies targeting HER2 are essential to treat HER2-positive BC. The current anti-HER2 therapies comprise antibodies that target specific HER2 epitopes, tyrosine kinase inhibitors (TKIs) and, more recently, antibody-drug conjugates (ADCs) [ 130 ]. Anti-HER2 mechanisms of action and resistance are described in Figure 4 .

Anti-HER2 therapy mechanisms of action and resistance. The left part of the figure describes the mechanism of action of anti-HER2 therapy through anti-HER2 antibody (trastuzumab and pertuzumab), tyrosine kinase inhibitors (lapatinib and nerotinib), and trastuzumab-emtansine (T-DM1). The right part of the figure describes the mechanism of resistance to anti-HER2 therapy through constitutive active p95 HER2 fragment, activation of other signaling pathways, and rapid recycling of HER2-T-DM1. ADCC: antibody-dependent cellular cytotoxicity; HER2: human epidermal growth factor receptor 2; EGF: epidermal growth factor, HB-EGF: heparin-binding EGF-like growth factor; TGF-α: transforming growth factor alpha; T-DM1: trastuzumab-emtansine; IGF-1R: insulin growth factor receptor 1; IGF: insulin growth factor; HGF: hepatocyte growth factor; MEK/MAPK: mitogen activated protein kinase; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; PTEN: phosphatase and tensin homolog.

3.2.1. Antibodies Targeting HER2

The first developed HER2-targeted antibody, trastuzumab (Herceptin), was approved by the FDA in 1998 [ 131 , 132 ]. Trastuzumab targets subdomain IV of the HER2 extracellular domain. However, the mechanism underlying trastuzumab’s therapeutic effect is not well understood. Multiple studies have reported hypotheses to explain trastuzumab’s mechanism of action. For instance, trastuzumab may inhibit the formation of the HER2-HER3 heterodimer, known to be the most oncogenic pair in the HER family [ 133 ]. It could also inhibit the formation of the active p95 HER2 fragment by preventing cleavage of the HER2 extracellular domain [ 134 ]. An indirect antitumor effect could be activating antibody-dependent cellular cytotoxicity (ADCC) by engaging with Fc receptors on immune effector cells [ 135 ].

Initially, trastuzumab was approved for administration in metastatic HER2+ BC, increasing the clinical benefits of first-line chemotherapy [ 132 ]. Trastuzumab has also demonstrated its efficacy and safety in early-stage HER2+ BC. It is given as neoadjuvant or adjuvant therapy in combination with other anti-HER2 treatments and/or with chemotherapy [ 136 , 137 , 138 ]. The recommended dose for intravenous trastuzumab is 4 mg/kg followed by 2 mg/kg weekly for 1 year in the adjuvant setting for early-stage HER2+ BC and until disease-free progression for metastatic HER2+ BC [ 139 ].

Pertuzumab (Perjeta) is another antibody that targets the HER2 extracellular domain but binds to subdomain II. Once it binds to HER2, pertuzumab prevents HER2 heterodimerization with other HER family members, leading to inhibition of downstream signaling pathways [ 140 ]. Like trastuzumab, one of pertuzumab’s indirect antitumor effects is activating the ADCC pathway [ 141 ]. Multiple clinical trials have shown that pertuzumab, combined with trastuzumab and chemotherapy, improved OS in metastatic HER2+ BC patients compared to trastuzumab and chemotherapy alone [ 142 , 143 , 144 , 145 ]. The benefits of pertuzumab have also been shown in early-stage HER2+ BC, as pertuzumab can be used in the neoadjuvant or adjuvant setting combined with trastuzumab and chemotherapy [ 146 , 147 , 148 , 149 ]. Pertuzumab is administered in fixed doses of 840 mg followed by 420 mg every three weeks [ 150 ].

Despite the major positive impacts of trastuzumab and pertuzumab in HER2+ BC treatment, only one-third of BC patients with HER2+ tumors benefit from anti-HER2 antibodies [ 151 ]. One of the hypotheses explaining this resistance concerns structural modifications of HER2, which hinder antibody binding. Alternative splicing can lead to a truncated isoform lacking the extracellular domain, thus forming a constitutive active p95 HER2 fragment [ 152 ]. The overexpression of other tyrosine kinases can bypass the signaling pathways mediated by HER2. It has been shown that cells overexpressing IGF-1R overcome cell cycle arrest by increasing CDK2 kinase activity [ 153 ]. Moreover, the overexpression of c-Met (a hepatic growth factor receptor) synergizes with HER2 signaling to confer resistance to anti-HER2 antibodies. Indeed, c-Met physically interacts with HER2, and c-Met depletion renders cells more sensitive to trastuzumab [ 154 , 155 ]. Another hypothesis for anti-HER2 antibody resistance is intracellular alterations in HER2 downstream signaling pathways. HER2 activates PI3K/Akt signaling, and PTEN (phosphatase and tensin homolog) is a well-known inhibitor of this pathway [ 156 ]. Tumors with a loss of PTEN function and/or constitutive activation of PI3K due to alteration mutations achieve worse therapeutic outcomes with trastuzumab [ 157 , 158 ].

3.2.2. Tyrosine Kinase Inhibitors (TKIs)

Since tumors may be resistant to anti-HER2 antibodies, new approaches have been developed. TKIs such as lapatinib, neratinib, or pyrotinib are small molecules that compete with ATP at the catalytic domain of the receptor to prevent tyrosine phosphorylation and HER2 downstream signaling [ 159 ].

Lapatinib is a dual EGFR/HER2 TKI blocking both HER1 and HER2 activation [ 160 ]. In metastatic BC, clinical trials have shown that lapatinib offers more benefits than chemotherapy alone [ 161 , 162 , 163 ]. The effects of lapatinib in the neoadjuvant/adjuvant setting have also been evaluated. As a neoadjuvant treatment, lapatinib plus trastuzumab combined with chemotherapy were more efficient than chemotherapy combined with lapatinib or trastuzumab alone [ 164 ]. Lapatinib as adjuvant treatment showed modest antitumor efficacy compared to placebo in a randomized, controlled, and multicenter phase III trial (TEACH) [ 165 ]. For luminal B (ER/PR+; HER2+) advanced or metastatic BC, lapatinib can be administered in combination with AIs.

Neratinib is an irreversible TKI targeting HER1, HER2, and HER4 [ 166 ]. The FDA approved Neratinib in 2017 as an extended adjuvant treatment for patients with HER2+ early-stage BC and combination with trastuzumab in the adjuvant setting [ 167 , 168 ]. Neratinib can be delivered in combination with capecitabine as a third-line and beyond therapy for HER2+ advanced or metastatic BC.

More recently, pyrotinib, a new generation TKI targeting HER1, HER2 and HER4, has been developed [ 169 ]. Pyrotinib is still under clinical trials to prove its efficacy and safety [ 170 ]. However, in 2018, the Chinese State Drug Administration approved pyrotinib in combination with or after chemotherapy treatment for patients with HER2+ advanced or metastatic BC [ 171 ].

Despite the recent development of TKI treatments, patients can still exhibit intrinsic or acquired resistance to these agents. Three mechanisms of action have been hypothesized: (1) activation of compensatory pathways, (2) HER2 tyrosine kinase domain mutation, and (3) other gene amplification [ 172 ]. For instance, activation of the PI3K/Akt pathway and FOXO3A (Forkhead transcription factor) by the upregulation of HER3 can lead to lapatinib resistance [ 173 ]. Other tyrosine kinases can be involved, such as c-Met, also known to be implicated in trastuzumab resistance. C-Met induces the activation of PI3K/Akt signaling in lapatinib-resistant BC [ 174 ]. Mutations in the HER2 tyrosine kinase domain lead to the constitutive activation of HER2 by substituting individual amino acids [ 175 ]. Lastly, it has been shown that the amplification of the NIBP (TRAPPC9, Trafficking Protein Particle Complex 9) gene occurs in HER2+ lapatinib-resistant tumors. The inhibition of NIBP makes resistant cells sensitive to lapatinib [ 176 ].

3.2.3. Trastuzumab-Emtansine (T-DM1)

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC), which is a conjugate of trastuzumab and a cytotoxic molecule, DM1, a derivative of maytansine [ 177 ]. T-DM1 binds to HER2 with the trastuzumab part. The formed complex is then internalized for degradation, releasing DM1 metabolites into the cytoplasm. DM1 then inhibits microtubule assembly causing cell death [ 178 , 179 ]. Thus, T-DM1 consists of the antitumor effects of trastuzumab and those associated with DM1 metabolites [ 180 ].

Three phase III clinical trials have evaluated the safety and efficacy of T-DM1 for HER2+ metastatic BC [ 181 , 182 , 183 ]. They have shown that T-DM1 improves OS and DFS of HER2+ metastatic BC patients compared to lapatinib in combination with trastuzumab or chemotherapy [ 181 , 182 , 183 ]. T-DM1 as neoadjuvant treatment has less efficacy compared with trastuzumab or pertuzumab with chemotherapy [ 146 ]. This suggests that T-DM1 should not be administered as a neoadjuvant treatment but as a first-line or second-line therapy for HER2+ metastatic BC. The 2021 NCCN guidelines recommend using T-DM1 as second-line therapy for HER2+ advanced or metastatic BC [ 99 ].

The mechanism of action of T-DM1 involves those related to trastuzumab and DM1, so the observed resistance to T-DM1 could come from interference in one or both constituents [ 184 ]. The mechanism of T-DM1 resistance has been hypothesized to involve (1) the loss of trastuzumab mediated activity, (2) the dysfunctional intracellular trafficking of T-DM1, and (3) the impairment of DM1 mediated cytotoxicity [ 185 ].

As previously described in this review, the reduction of trastuzumab effects can occur by reduced HER2 expression, dysregulation of PI3K signaling, or the activation of alternative tyrosine kinase receptors [ 153 , 154 , 156 , 186 ]. The alteration of HER2-T-DM1 complex internalization can go through a rapid recycling of HER2 to the plasma membrane leading to the inhibition of DM1 metabolism released into the cytoplasm [ 187 ]. The internalization of the HER2-T-DM1 complex occurs through the formation of lysosomes. These vesicles enclose lysosomal enzymes involved in HER2-T-DM1 complex degradation. In T-DM1-resistant tumors, the level of lysosomal enzymes is inhibited [ 188 , 189 ]. T-DM1 also disrupts microtubule assembly causing incomplete spindle formation resulting in mitotic catastrophe and apoptosis [ 190 ]. Cells resistant to T-DM1 can avoid this process by reducing the induction of Cyclin-B1, an enzyme essential for cell cycle progression [ 191 ].

HER2+ BC are aggressive and associated with poor prognosis and metastasis, and recurrences. Anti-HER2 therapy has greatly improved the management of HER2+ BC. However, 25% of early-stage HER2+ BC patients will have a recurrence after the initial anti-HER2 treatment [ 192 ]. The emergence of new therapeutic agents specific for HER2+ BC provides new hope to treat this particularly aggressive BC subtype.

3.3. PARP Inhibitors

The prevalence of BRCA (Breast Cancer genes) mutations in TNBC patients is approximately 20% [ 193 ]. BRCA1 and BRCA2 are proteins involved in the DNA damage response to repair DNA lesions [ 194 ]. Mutations in BRCA 1/2 genes are associated with an increased risk of breast and ovarian cancers [ 195 ].

PARP (poly-(ADP-ribose) polymerase protein) proteins are also involved in the DNA damage response as they recruit DNA repair proteins, such as BRCA1 and BRCA2, to the damage site [ 196 ]. PARP inhibitors (PARPi) were developed to inhibit DNA repair in BRCA-mutated BC since cells defective in BRCA functions cannot repair DNA damage when PARP is inhibited [ 197 ]. The principal PARPis currently in clinical development are olaparib, talazoparib, veliparib, and rucaparib [ 198 ]. PARP inhibitors mechanisms of action and resistance are described in Figure 5 .

PARP inhibitors mechanisms of action and resistance. The left part of the figure describes the mechanism of PARP inhibitors in the context of BRCA mutated breast cancer. The right part of the figure describes the mechanism of resistance to PARP inhibitors through secondary intragenic mutations restoring BRCA proteins functions and the decrease of the recruitment of nucleases (MUS81 or MRE11) to protect the replication fork. PARP: poly-(ADP-ribose) polymerase protein; PARPi: PARP inhibitors; BRCA: breast cancer protein; MUS81: methyl methanesulfonate ultraviolet sensitive gene clone 81; MRE11: meiotic recombination 11.

3.3.1. Olaparib

Olaparib is the first FDA-approved PARPi for the treatment of BRCA -mutated BC [ 199 ]. Phase I and phase II trials evaluating the effects of olaparib monotherapy in germline BRCA-mutated (gBRCAm) BC proved its clinical benefits by improving progression-free survival (PFS) [ 200 , 201 , 202 , 203 ]. The phase III, randomized, open-label, OlympiAD trial compared olaparib monotherapy vs. standard chemotherapy in patients with BRCA mutated HER2-negative BC. This trial showed that olaparib has better efficacy and tolerability than standard chemotherapy for this group of patients [ 204 ]. Olaparib has also been tested in combination with chemotherapy. A phase I study evaluated the effects of olaparib in combination with paclitaxel in unselected TNBC patients [ 205 ]. The overall response rate (ORR) for these patients was 37%. Two phase I studies evaluating the combination of olaparib with cisplatin or carboplatin in gBRCAm BC patients showed improved ORR [ 206 , 207 ].

3.3.2. Talazoparib

Talazoparib has the highest PARP-DNA trapping efficiency among the PARPis [ 208 ]. A phase II trial testing the effects of talazoparib on gBRCAm early-stage BC showed decreased tumor size in all patients included [ 209 ]. Other phase I and II trials with gBRCAm BC patients receiving talazoparib confirmed the efficiency of this PARPi [ 210 , 211 ]. The EMBRACA study, an open-label phase III trial, compared talazoparib monotherapy to chemotherapy in gBRCAm, HER2-negative BC patients [ 212 ]. PFS and ORR were improved with talazoparib compared to chemotherapy alone.

3.3.3. Veliparib

Veliparib has been mostly evaluated in combination with chemotherapy. For example, the phase II multicenter I-SPY2 trial tested the combination of veliparib and neoadjuvant chemotherapy in unselected TNBC patients [ 213 ]. The predicted complete response rate (pCR) was 51% with veliparib and chemotherapy vs. 26% in the control arm (chemotherapy alone). The phase II BROCADE study evaluated the combination of veliparib with carboplatin and paclitaxel in gBRCAm BC patients [ 214 ]. The ORR was improved with the combination of veliparib and chemotherapy compared to chemotherapy alone. Lastly, the phase III BRIGHTNESS study evaluated the addition of veliparib to carboplatin in the standard neoadjuvant chemotherapy setting [ 211 ]. The addition of veliparib showed no further benefit to chemotherapy.

3.3.4. Rucaparib

Rucaparib is the second PARPi that has been FDA approved for gBRCAm BC patients [ 215 ]. Intravenous rucaparib was tested in a phase II trial of gBRCAm BC patients [ 216 ]. Stable disease, meaning no tumor development, was reported in 44% of patients. Rucaparib was also tested in combination with chemotherapy in unselected TNBC patients [ 217 ]. This phase I study showed that rucaparib could be safely used in combination with chemotherapy. The phase II, a randomized BRE09-146 trial, evaluated rucaparib in combination with cisplatin vs. cisplatin alone in gBRCAm patients with residual disease following neoadjuvant therapy [ 218 ]. DFS was similar in the two arms, as low-dose rucaparib did not affect cisplatin toxicity. However, the rucaparib dose may not have been sufficient to inhibit PARP activity.

Tumor cells can become resistant to PARPi by different mechanisms [ 219 ].

First, secondary intragenic mutations that restore BRCA proteins functions can lead to PARPi resistance [ 220 ]. These genetic events can lead to the expression of nearly full-length proteins or full-length wild-type proteins with complete restored functions [ 221 ]. This has been reported mostly in ovarian cancer patients, and it has also been demonstrated in BC cell line models [ 222 ]. Tumor cells with missense mutations conserving the N-terminal and C-terminal domains of BRCA proteins also lead to poor PARPi response [ 223 ]. Another mechanism of action leading to PARPi resistance is decreased expression of PARP enzymes. Indeed, tumor cells with low PARP1 expression acquire resistance to veliparib [ 224 ].

In addition, tumor cells can find alternative mechanisms to protect the replication fork. It has been shown that PARPi-resistant cells can reduce the recruitment of the MRE11 (meiotic recombination 11) nuclease to the damage site, leading to the protection of the fork by blocking its access [ 225 ]. Another study has shown that BRCA2 -mutated tumors acquired PARPi resistance by reducing the recruitment of the MUS81 (methyl methanesulfonate ultraviolet sensitive gene clone 81) nuclease to protect the replication fork [ 226 ].

Chemotherapy has been the pioneer treatment strategy for TNBC for decades. The development of PARPis has been a major improvement in the treatment of TNBC and, more specifically, gBRCAm TNBC, as they have shown more benefits over chemotherapy [ 227 ]. However, TNBC is a heterogenous BC subtype, and PARPis cannot treat all TNBCs as it is administered only for gBRCAm TNBC [ 228 ]. Therefore, it is necessary to develop specific targeted therapies to treat each TNBC subtype.

4. New Strategies and Challenges for Breast Cancer Treatment

4.1. emerging therapies for hr-positive breast cancer.

As mentioned in Section 3.1 , the major mechanisms of action of current endocrine therapy resistance occur via (1) the mTOR/PI3K/Akt signaling pathway and (2) the actors of the cell cycle progression CDK4/6. Therefore, emerging therapies for HR+ BC mainly target these pathways to bypass estrogen-independent cell survival [ 229 ]. The most recent completed clinical trials on emerging therapies for HR+ BC are presented in Table 1 .

Most recent completed clinical trial on emerging therapies for HR-positive breast cancer.

HR+: hormone receptors positive; HER2-: human epidermal growth factor receptor 2 negative; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; pCR: pathologic complete response; HR: hazard ratio.

4.1.1. mTOR/PI3K/AKT Pathway Inhibitors

The mTOR/PI3K/Akt pathway inhibitors can be divided into different categories according to the target in the pathway. Specific inhibitors have been developed to target all or specific isoforms of PI3K, mTORC1 and Akt [ 251 ].

Pan-Pi3K Inhibitors

Pan-PI3K inhibitors target all PI3K isoforms resulting in significant off-target effects. The main pan-PI3K inhibitors are buparlisib and pictilisib [ 252 ]. Multiple clinical trials have tested the effects of pan-PI3K inhibitors in luminal BC.

The phase III randomized double-blinded BELLE-2 trial compared buparlisib combined with fulvestrant, to fulvestrant monotherapy in luminal A advanced or metastatic BC patients [ 230 ]. The results of this trial showed a modest improvement in PFS when buparlisib was added to fulvestrant. Another phase III clinical trial (BELLE-3) studied the effects of buparlisib plus fulvestrant in luminal A advanced or metastatic BC patients with no benefits from endocrine therapy [ 231 ]. Though PFS was significantly improved with buparlisib, there were severe adverse effects such as hyperglycemia, dyspnea, or pleural effusion. Lastly, the phase II/III BELLE-4 clinical trial evaluated buparlisib plus paclitaxel in HER2-negative locally advanced or metastatic BC patients [ 232 ]. The addition of buparlisib to paclitaxel did not improve PFS in these patients. Thus, further studies on buparlisib in HR+ BC were not conducted. The phase II randomized, double-blinded FERGI clinical trial analyzed the effects of pictilisib plus fulvestrant in luminal A BC patients resistant to AI [ 233 ]. The addition of pictilisib to fulvestrant did not improve PFS. Moreover, severe adverse effects occurred when the dose of pictilisib was increased. These results were confirmed for pictilisib plus paclitaxel, as the phase II PEGGY study showed no benefit from pictilisib in PI3K-mutated HER2-negative BC patients [ 234 ].

Hence, pan-PI3K inhibitors are not optimal to treat HR+ BC due to their toxicity and lack of efficacy.

Isoform-Specific PI3K Inhibitors

To sort out issues related to off-target effects and toxicities with pan-PI3K inhibitors, isoform-specific PI3K inhibitors have been developed. These isoform-specific PI3K inhibitors can specifically target the PI3K p110α, p110β, p110δ, and p110γ isoforms [ 252 ]. Multiple clinical trials have tested the effects of isoform-specific PI3K inhibitors.

PI3K p110α is the most commonly mutated isoform in BC [ 253 ]. Alpelisib is the first FDA-approved PI3K p110α isoform inhibitor. A phase Ib clinical trial tested the effects of alpelisib and letrozole in patients with ER+ metastatic BC refractory to endocrine therapy [ 235 ]. The clinical benefit of the alpselisib and letrozole combination was higher for patients with PI3K-mutated BC, but clinical activity was still observed in patients with non-mutated tumors. The phase III randomized SOLAR-1 clinical trial compared the effects of alpelisib plus fulvestrant to fulvestrant alone in luminal A advanced BC patients who received no benefits from prior endocrine therapy [ 236 ]. The addition of alpelisib improved PFS for patients with PI3K-mutated BC.

Taselisib targets the PI3K p110α, p110γ and p110δ isoforms [ 254 ]. Taselisib was tested in the SANDPIPER study, a phase III randomized clinical trial, in combination with fulvestrant in patients with ER+ metastatic BC resistant to AIs [ 238 ]. Although the addition of taselisib slightly improved PFS, further clinical trials with taselisib were interrupted since high rates of severe adverse events were detected.

mTORC1 Inhibitors

mTORC1 inhibitors, such as everolimus, block the mTORC1 dependent phosphorylation of s6k1 [ 255 ]. The BOLERO-2 phase III randomized clinical trial investigated the effects of exemestane with or without everolimus in AI-resistant ER+ metastatic BC patients [ 240 ]. The combination of everolimus and exemestane improved PFS. The TAMRAD phase II randomized open-label study compared the effects of tamoxifen with or without everolimus in AI-resistant luminal A BC patients [ 241 ]. This study showed an improvement in overall survival (OS) when everolimus was given in combination with tamoxifen. The findings of these two clinical trials led to FDA approval of everolimus. More recently, the PrE0102 phase II randomized clinical trial showed that the addition of everolimus to fulvestrant improved PFS of patients with AI-resistant ER+ BC compared to fulvestrant alone [ 242 ].

Akt Inhibitors

Akt inhibitors target all Akt isoforms as Akt 1, 2, and 3 isoforms share very similar structures [ 256 ]. Capivasertib is the principal Akt inhibitor under investigation in different clinical trials. The FAKTION phase II multi-centered randomized clinical trial compared the effects of capivasertib plus fulvestrant to fulvestrant plus placebo in AI-resistant luminal A advanced BC patients [ 243 ]. PFS was significantly improved with the combination of capivasertib and fulvestrant in comparison with the placebo arm.

The AKT1 E17K activating mutation is the most common in Akt and occurs in approximately 7% of ER+ metastatic BC. This mutation in the Akt lipid-binding pocket leads to constitutive Akt activation by modifying its localization to the membrane [ 257 ]. A phase I study analyzed the effects of capivasertib alone or in combination with fulvestrant in a cohort of patients with AKT1 E17K mutation ER+ metastatic BC [ 244 ]. Capivasertib, in combination with fulvestrant, demonstrated clinically meaningful activity and better tolerability compared to capivasertib alone.

4.1.2. CDK4/6 Inhibitors

There are currently three CDK4/6 inhibitors approved to treat HR+/HER2- metastatic BC: palbociclib, ribociclib, and abemaciclib. They can be administered as first-line treatment combined with AIs or as second-line treatment combined with fulvestrant [ 258 ].

First-Line Treatment

Palbociclib, a highly selective CDK4/6 inhibitor, is the first FDA-approved CDK4/6 inhibitor as first-line treatment combined with AIs for metastatic or advanced HR+ BC patients [ 259 ].

PALOMA-1 is an open-label, randomized phase II study that evaluated the effects of palbociclib in combination with letrozole vs. letrozole alone as first-line treatment for HR+ advanced BC patients [ 126 ]. The addition of palbociclib to letrozole significantly improved PFS in HR+ BC patients. A phase III study was performed (PALOMA-2) to confirm these findings and expand the efficacy and safety of palbociclib, [ 245 ]. This double-blinded clinical trial tested the combination of palbociclib and letrozole in postmenopausal BC patients without prior systemic therapy for advanced BC. The addition of palbociclib to letrozole significantly improved PFS and ORR.

Ribociclib is the second FDA-approved CDK4/6 inhibitor for first-line treatment in postmenopausal advanced BC patients in combination with AIs [ 260 ]. The phase III MONALEESA-2 clinical trial results showed improved PFS and ORR with the combination of ribociclib and letrozole in HR+ metastatic BC patients. The clinical benefits and manageable tolerability observed with ribociclib and letrozole are maintained with longer follow-up compared to letrozole alone [ 247 ].

Abemaciclib has been tested in the phase III randomized double-blinded MONARCH-3 study [ 250 ]. HR+ advanced BC patients with no prior systemic therapy received abemaciclib plus anastrozole or letrozole or AIs plus placebo in the control arm. PFS and ORR were significantly improved with the combination of abemaciclib and AIs.

Second-Line Treatment

As second-line treatment, palbociclib can be given in combination with fulvestrant in advanced or metastatic BC patients with disease progression after endocrine therapy [ 261 ]. This was confirmed in the phase III multi-centered randomized double-blinded PALOMA-3 trial [ 246 ]. BC patients who received palbociclib plus fulvestrant had significantly longer PFS compared to fulvestrant plus placebo.

The phase III MONALEESA-3 study tested the effects of ribociclib plus fulvestrant in patients with HR+ advanced BC who received prior endocrine therapy in the advanced setting [ 248 ]. The PFS and ORR were significantly improved when ribociclib was added to fulvestrant. Thus, ribociclib plus fulvestrant can be considered as second-line treatment for these BC patients.

Abemaciclib has been recently approved in combination with fulvestrant for HR+ advanced or metastatic BC patients with disease progression after endocrine therapy. This was based on the results of the phase III, double-blinded MONARCH 2 study [ 249 ]. The combination of abemaciclib and fulvestrant demonstrated a significant improvement of PFS and ORR compared to fulvestrant plus placebo in HR+ metastatic BC patients who experienced relapse or progression after prior endocrine therapy.

mTOR/PI3K/Akt inhibitors and CDK4/6 inhibitors show great promise for advanced HR+ BC resistant to endocrine therapy. To leverage the potential of these two types of therapies, some preclinical studies have evaluated a triple therapy combination including PI3K inhibitors, CDK4/6 inhibitors, and endocrine therapy (see the summarized table at the end of the manuscript) [ 262 ].

4.2. New Strategic Therapies for HER2-Positive Breast Cancer

As mentioned in Section 3.2 , HER2+ BC is currently treated with specific HER2 targeting antibodies or tyrosine kinase inhibitors (TKIs), and more recently, with TDM-1, an antibody-drug conjugate. These treatments have greatly improved HER2+ BC survival. However, 25% of HER2+ BC patients will still develop resistance to anti-HER2 treatment. Hence, new therapeutic strategies are emerging, such as new antibodies targeting HER2, new TKIs, vaccines, and PI3K/mTOR and CDK4/6 inhibitors [ 263 ]. The most recent completed clinical trials on new strategies for HER2+ BC treatment are gathered in Table 2 .

Most recent completed clinical trials on emerging therapies for HER2+ breast cancer.

HER2+: human epidermal growth factor receptor 2 positive; ER+: estrogen receptor positive; HLA2/3: human leucocyte antigen 2/3; MBC: metastatic breast cancer; BC: breast cancer; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; DFS: disease-free survival OS: overall survival GM-CSF: granulocyte macrophage colony-stimulated factor; HR: hazard ratio.

4.2.1. New Antibodies

Novel types of antibodies have been developed to target HER2+ BC more efficiently. They can be divided into three categories: antibody-drug conjugates (ADC), modified antibodies, and bispecific antibodies.

Antibody-Drug Conjugates (ADC)

ADCs are the combination of a specific monoclonal antibody and a cytotoxic drug that is released in the antigen-expressing cells [ 280 ]. The most common ADC is TDM-1, and the promising results with TDM-1 have led to the development of new ADCs.

Trastuzumab-deruxtecan (DS-8201a) is a HER2-targeting antibody (trastuzumab) linked to a DNA topoisomerase I inhibitor (deruxtecan) [ 281 ]. A phase I study demonstrated that DS-8201a had antitumor activity even with HER2 low-expressing tumors [ 282 ]. These results led to phase II and phase III clinical trials. The DESTINY-Breast01 clinical trial is an open-labeled, single-group, multicentered phase II study [ 264 ] was evaluated in HER2+ metastatic BC patients who received prior TDM-1 treatment. DS-8201a showed durable antitumor activity for these patients. Two phase III clinical trials are currently evaluating DS-8201a. DESTINY-Breast02 (ClinicalTrials.gov identifier: NCT03523585) is comparing DS-8201a to standard treatment (lapatinib or trastuzumab) in HER2+ metastatic BC patients previously treated with TDM-1. The DESTINY-Breast03 (ClinicalTrials.gov identifier: NCT03529110) trial is evaluating the effects of DS-8201a vs. TDM-1 in HER2+ metastatic BC patients with prior trastuzumab and taxane treatment.

Trastuzumab-duocarmycin (SYD985) is a HER-2 targeting antibody (trastuzumab) conjugate with a cleavable linker-duocarmycin payload that causes irreversible alkylation of the DNA in tumor cells leading to cell death [ 283 ]. A dose-escalation phase I study evaluated the effects of SYD85 in BC patients with variable HER2 status and refractory to standard cancer treatment [ 284 ]. Trastuzumab-duocarmycin showed clinical activity in heavily pretreated HER2+ metastatic BC patients, including TDM-1 resistant and HER2-low BC patients. After these promising results, a phase I expansion cohort study was performed on the same type of patients (heavily pretreated HER2+ or HER2-low BC patients) [ 265 ]. This study confirmed previous results on the efficacy of STD985. A phase III clinical trial (TULIP-ClinicalTrials.gov identifier: NCT03262935) is ongoing to compare SYD985 to the treatment chosen by the physician in HER2+ metastatic BC patients. Other ADCs are under clinical trials to test their safety and activity for HER2+ advanced BC patients. RC48 is an anti-HER2 antibody conjugated with monomethyl auristatin E that demonstrated promising efficacy and a manageable safety profile in an open-labeled, multicentered phase II study (ClinicalTrials.gov identifier: NCT02881138) [ 248 ]. PF06804103 conjugates an anti-HER2 monoclonal antibody and the cytotoxic agent, Aur0101. In a phase I study (ClinicalTrials.gov identifier: NCT03284723), PF06804103 showed manageable toxicity and promising antitumor activity [ 249 ]. XMT1522 showed encouraging results in a dose-escalation phase I study (ClinicalTrials.gov identifier: NCT02952729) [ 250 ]. MEDI4276, which targets two different HER2 epitopes and is linked to a microtubule inhibitor, showed promising clinical activity in a phase I study (ClinicalTrials.gov identifier: NCT02576548) [ 254 ] (see the summarized table at the end of the manuscript).

Chimeric Antibody

Margetuxumab (MGAH22) is a human/mouse chimeric IgG1 targeting HER2 monoclonal antibody. It is based on trastuzumab as it binds to the same epitope (subdomain IV or HER2 extracellular domain) but with an enhanced Fcγ domain. The substitution of five amino acids into the IgG1 Fc domain increases CD16A affinity, a receptor found on macrophages and natural-killer cells, and decreases CD32B affinity, leading to increased antibody-dependent cell-mediated cytotoxicity (ADCC) [ 285 ]. A phase I study evaluated margetuximab toxicity and tumor activity on HER2+ BC patients for whom no standard treatment was available [ 266 ]. This study showed promising single-agent activity of margetuximab as well as good tolerability. The phase III randomized open-labeled SOPHIA clinical trial (ClinicalTrials.gov Identifier: NCT02492711) compared margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in pretreated HER2+ advanced BC patients [ 286 ]. The combination of margetuximab and chemotherapy significantly improved the PFS of patients compared to trastuzumab plus chemotherapy. This study is still under investigation to collect data on OS (see the summarized table at the end of the manuscript).

Bispecific Antibodies

Bispecific antibodies (BsAbs) can target two different epitopes in the same or different receptors by combining the functionality of two monoclonal antibodies [ 287 ]. MCLA-128 targets both HER2 and HER3 and have an enhanced ADCC activity [ 288 ]. A phase I/II study evaluated the safety, tolerability, and antitumor activity of MCLA-128 in patients with pretreated HER2+ metastatic BC.

Preliminary results showed encouraging clinical benefits of MCLA-128. An open-labeled, multicentered phase II study (ClinicalTrials.gov identifier: NCT03321981) is ongoing to evaluate the effects of MCLA-128 in combination with trastuzumab and chemotherapy in HER2+ metastatic BC patients.

ZW25 is a BsAb biparatopic that binds the IV and II subdomains of the HER2 extracellular domain, the binding epitopes of trastuzumab and pertuzumab, respectively [ 289 ]. The efficacy of ZW25 was evaluated in a phase I study given alone or in combination with chemotherapy in patients with advanced or metastatic HER2+ BC. The results of this study showed promising antitumor activity, and no-dose limiting was observed.

T-cell bispecific antibodies (TCBs) are another type of BsAbs recently developed. TCBs target the CD3-chain of the T-cell receptor and tumor-specific antigens, resulting in lymphocyte activation and tumor cell death [ 290 ].

GBR1302 targets both HER2 and CD3 receptors and directs T-cells to HER2+ tumor cells. A phase II study (ClinicalTrials.gov identifier: NCT03983395) is ongoing to determine the safety profile of the GBR1302 single agent in previously treated HER2+ metastatic BC. PRS-343 targets HER2 and the immune receptor CD137, a member of the tumor necrosis factor receptor family. Two clinical trials are investigating the effects of PRS-343 monotherapy (ClinicalTrials.gov identifier: NCT03330561) or in combination with other treatments (ClinicalTrials.gov identifier: NCT03650348) (see the summarized table at the end of the manuscript).

4.2.2. HER2-Derived Peptide Vaccines

One of the strategies of immunotherapy is activating the patient’s immune system to kill cancer cells. Vaccination is an emerging approach to induce a tumor-specific immune response by targeting tumor-associated antigens, such as HER2 [ 291 ]. HER2-derived peptide vaccines comprise different parts of the HER2 molecule, such as E75 (extracellular domain), GP2 (transmembrane domain), and AE37 (intracellular domain) [ 292 ].

E75 (HER2/neu 369–377: KIFGSLAFL) has high affinity for HLA2 and HLA3 (human leucocyte antigen) that can stimulate T-cells against HER2 overexpressing tumor cells [ 293 ]. The efficacy of the E75 vaccine to prevent BC recurrence has been evaluated in a phase I/II study, in which high-risk HER2+ HLA2/3+ BC patients received the E75 vaccine [ 269 ]. The results demonstrated the safety and clinical efficacy of the vaccine as PFS was improved in the E75-vaccinated group compared to the unvaccinated group. Other clinical trials are currently investigating the efficacy of the E75 vaccine on HER2+ BC (see he summarized table at the end of the manuscript).

GP2 (654-662: IISAVVGIL) is a subdominant epitope with poor affinity for HLA2 [ 294 ]. A phase I trial evaluating the effects of a GP2 vaccine in disease-free BC patients showed that it was safe and tolerable with HER2-specific immune response [ 295 ]. The GP2 vaccine has been tested in a randomized, open-labeled phase II study to prevent BC recurrence. The patients that received the GP2 vaccine had HER2+ and HLA2+ BC and were disease-free with a high risk of recurrence at the time of the study [ 270 ]. The results demonstrated that the GP2 vaccine was safe and clinically beneficial for patients with HER2+ BC who received the full vaccine series.

AE37 (Ii-key hybrid of MHC II peptide AE36 (HER2/neu 776–790)) can stimulate CD8+ and CD4+ cells. A randomized, single-blinded phase II study evaluated the effects of an AE37 vaccine to prevent BC recurrence. Patients with a high risk of recurrence and HER2+ BC received the AE37 vaccine [ 271 ]. The vaccination demonstrated no benefit in the overall intention-to-treat analysis, a method that considers the randomized treatment to avoid bias happening after the randomization [ 296 ]. However, the study showed that the AE37 vaccine was safe, and results suggested that it could be effective for HER2-low BC, such as TNBC.

4.2.3. New Tyrosine Kinase Inhibitors (TKIs)

As previously described in this review (see Section 3.2.2 Tyrosine kinase inhibitors (TKIs)), TKIs are small molecules targeting the HER2 intracellular catalytic domain [ 159 ]. New TKIs have been developed with better efficacy and less toxicity in the treatment of HER2+ metastatic BC, such as tucatinib and poziotinib.

Tucatinib is a TKI with high selectivity for HER2, leading to less EGFR-related toxicities, common with other HER TKIs [ 297 ]. A phase I dose-escalation trial evaluated the combination of tucatinib and trastuzumab in BC patients with progressive HER2+ brain metastases [ 298 ]. This study showed preliminary evidence of tucatinib efficacy and tolerability in these patients. Tucatinib was also tested in combination with TDM-1 in a phase Ib trial in HER2+ metastatic BC patients with heavy pre-treatment [ 299 ]. The combination of tucatinib and TDM-1 showed acceptable toxicity and antitumor activity in these patients. Tucatinib was FDA approved in combination with trastuzumab and capecitabine for patients with advanced or metastatic HER2+ BC who received prior anti-HER2 in the metastatic setting [ 300 ]. This was based on the results of the phase II HER2CLIMB clinical trial, where HER2+ metastatic BC patients received tucatinib or placebo in combination with trastuzumab and capecitabine [ 267 ]. The addition of tucatinib to trastuzumab and capecitabine improved PFS and OS of heavily pretreated HER2+ metastatic BC patients.

Poziotinib is a pan-HER kinase inhibitor that irreversibly inhibits the HER family members’ kinase activity [ 301 ]. A phase I study evaluated the efficacy and tolerability of poziotinib in advanced solid tumors. The results showed encouraging antitumor activity against different types of HER2+ cancers as poziotinib was safe and well-tolerated by the patients [ 302 ]. The phase II NOV120101-203 study evaluated the safety and efficacy of poziotinib monotherapy in heavily pretreated HER2+ metastatic BC patients [ 268 ]. Poziotinib showed meaningful activity in these patients with no severe toxicities.

4.2.4. mTOR/PI3K Inhibitors and CDK4/6 Inhibitors

As mentioned in the previous Section 4.1 , mTOR/PI3K inhibitors and CDK4/6 inhibitors have been evaluated as potential new strategic therapies for HR+ BC resistant to endocrine therapy. The mTOR/PI3K signaling pathway and CDK4/6 also play a role in the mechanisms leading to treatment resistance in HER2+ BC [ 303 ]. Thus, targeting them with mTOR/PI3K and CDK4/6 inhibitors is also being investigated in HER2+ BC subtype.

mTOR/PI3K Inhibitors

Alpelisib and taselisib are PI3K isoform-specific inhibitors that were also evaluated in HR+ BC [ 235 , 236 , 238 , 253 , 254 ]. A phase I study evaluated alpelisib in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PI3KCA mutant HER2+ metastatic BC [ 272 ]. Unfortunately, the results of this study were limited by high gastrointestinal toxicity. Another phase I study tested alpelisib in combination with TDM-1 in HER2+ metastatic BC patients pretreated with trastuzumab [ 273 ]. The combination of alpelisib and TDM-1 demonstrated tolerability and antitumor activity in trastuzumab-resistant HER2+ metastatic BC patients. Taselisib is being tested in an ongoing phase Ib dose-escalation trial in combination with anti-HER2 therapies (trastuzumab, pertuzumab and TDM-1) in HER2+ advanced BC patients (ClinicalTrials.gov identifier: NCT02390427).

Copanlisib is a highly selective and potent pan-class I PI3K inhibitor [ 304 ]. A phase Ib (PantHER) study evaluated the tolerability and activity of copanlisib in combination with trastuzumab in heavily pretreated HER2+ metastatic BC patients [ 274 ]. The combination of copanlisib and trastuzumab was safe and tolerable. Preliminary evidence of tumor stability was observed in these patients.

Everolimus is a mTORC1 inhibitor also tested in HR+ BC [ 240 , 241 , 242 ]. Everolimus was tested in phase III clinical trials, in combination with trastuzumab and docetaxel (BOLERO-1), or in combination with trastuzumab and vinorelbine (BOLERO-3) in trastuzumab-resistant advanced HER2+ BC [ 275 , 276 ]. Unfortunately, results showed an increase of adverse effects with everolimus. Moreover, the BOLERO-1 clinical trial showed no improvement in PFS with the combination of trastuzumab and everolimus. By contrast, PFS was significantly longer when everolimus was added to vinorelbine in BOLERO-3. A study analyzing the molecular alterations found in patients in the BOLERO-1 and BOLERO-3 clinical trials demonstrated that HER2+ BC patients could derive more benefit from everolimus if the tumors had PI3KCA mutations, PTEN loss or a hyperactive PI3K pathway [ 305 ].

CDK4/6 Inhibitors

Palbociclib, ribociclib and abemaciclib are CDK4/6 inhibitors that have been FDA approved to treat HR+ BC as first-line treatments [ 247 , 250 , 259 ]. They have also been evaluated in multiple clinical trials for advanced HER2+ BC. Palbociclib has been tested in combination with trastuzumab in the phase II SOLTI-1303 PATRICIA clinical trial in heavily pretreated advanced HER2+ BC patients [ 277 ]. Palbociclib combined with trastuzumab demonstrated safety and encouraging survival outcomes in these patients. Palbociclib has also been evaluated in combination with TDM-1 in HER2+ advanced BC patients pretreated with trastuzumab and taxane therapy [ 306 ]. The results of this phase I/Ib study showed safety, tolerability, and antitumor activity in these patients.

Ribociclib was evaluated in a phase Ib/II trial in combination with trastuzumab to treat advanced HER2+ BC patients previously treated with multiple anti-HER2 therapies [ 278 ]. The combination of ribociclib and trastuzumab was safe, but there was limited activity in heavily pretreated patients. The conclusions of this study suggest that CDK4/6 inhibitor/anti-HER2 combination should be administered in patients with few previous therapies.

Abemaciclib has been tested in the phase II randomized open-labeled MonarcHER trial in combination with trastuzumab with or without fulvestrant vs. trastuzumab with standard chemotherapy in HR+/HER2+ BC patients [ 279 ]. The combination of abemaciclib, trastuzumab, and fulvestrant significantly improved PFS in these patients, with a tolerable safety profile.

There are multiple ongoing clinical trials for advanced HER2+ BC testing the combination of palbociclib, trastuzumab, pertuzumab, and anastrozole (ClinicalTrials.gov identifier: NCT03304080); or palbociclib and trastuzumab plus letrozole (ClinicalTrials.gov identifier: NCT03054363). Preliminary results are expected around July 2021 and March 2022, respectively (see he summarized table at the end of the manuscript).

A great proportion of HER2+ BC patients develop resistance to traditional anti-HER2 therapies, and 40–50% of patients with advanced HER2+ BC develop brain metastases [ 307 ]. Thus, developing new therapies to overcome resistance is essential. The therapeutic strategies that have been described in this section provide new hope for HER2+ BC patients, especially for advanced or metastatic HER2+ BC patients.

4.3. Emerging Therapies for Triple Negative Breast Cancer (TNBC)

TNBC is the most aggressive BC subtype. The fact that TNBC lacks ER and PR expression and does not overexpress HER2, combined with its high heterogeneity, has contributed to the difficulties in developing efficient therapies [ 308 ]. Thus, multiple strategic therapies have been developed to treat all TNBC subtypes. These include conjugated antibodies, targeted therapy, and immunotherapy. An overview of the most recent and completed clinical trials on emerging therapies for TNBC is presented in Table 3 .

Most recent completed clinical trials on emerging therapies for TNBC.

TNBC: triple negative breast cancer; HER2: human epidermal growth factor receptor; HR: hormonal receptor; MBC: metastatic breast cancer; BC: breast cancer; AR: androgen receptor; PPV: personalized peptide vaccine; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; IDFS: invasive disease-free survival; OS: overall survival; TTP: time to progression; pCR: pathologic complete response; HR: hazard ratio.

4.3.1. Antibodies-Drug Conjugates (ADC)

Antibody drug conjugates (ADCs) deliver a cytotoxic drug into the tumor cell by the specific binding of an antibody to a surface molecule [ 280 ]. Multiple ADCs have been investigated in TNBC such as sacituzumab govitecan, ladiratuzumab vedotin, or trastuzumab deruxtecan.

Sacituzumab govitecan combines an antibody targeting trophoblast antigen 2 (Trop-2) and a topoisomerase I inhibitor SN-38 [ 334 ]. Trop-2, a CA 2+ signal transducer, is expressed in 90% of TNBCs and is associated with poor prognosis [ 335 , 336 ]. A single-arm, multicentered phase I/II study evaluated sacituzumab govitecan in heavily pretreated metastatic TNBC patients [ 336 , 337 ]. The efficacy and safety of scituzumab govitecan was shown in these patients, as it was associated with durable objective response. Based on these results, a randomized phase III trial (ASCENT) tested sacituzumab govitecan compared to single-agent chemotherapy chosen by the physician in patients with relapsed or refractory metastatic TNBC [ 309 ]. Sacituzumab govitecan significantly improved PFS and OS of metastatic TNBC patients compared to chemotherapy.

Ladiratuzumab vedotin is composed of a monoclonal antibody targeting the zinc transporter LIV-1 and a potent microtubule disrupting agent, monoethyl auristatin E (MMAE) [ 338 ]. LIV-1 is a transmembrane protein with potent zinc transporter and metalloproteinase activity, expressed in more than 70% of metastatic TNBC tumors [ 339 ]. All clinical trials investigating ladiratuzumab vedotin are still ongoing. A dose-escalation phase I study is evaluating the safety and efficacy of ladiratuzumab vedotin in heavily pretreated metastatic TNBC patients (ClinicalTrials.gov identifier: NCT01969643). Preliminary results showed encouraging antitumor activity and tolerability of ladiratuzumab vedotin with an objective response rate of 32% [ 340 ]. The estimated study completion date is June 2023. Two phase Ib/II trials are testing ladiratuzumab vedotin in combination with immunotherapy agents in metastatic TNBC patients, such as pembrolizumab (ClinicalTrials.gov Identifier: NCT03310957) with expected preliminary results in February 2022, or in combination with multiple immunotherapy-based treatments (ClinicalTrials.gov Identifier: NCT03424005) with expected preliminary results in January 2023.

Trastuzumab deruxtecan is an ADC developed as a treatment for metastatic HER2+ BC patients. Its mechanism of action is described in Section 3.2 . Even though trastuzumab deruxtecan was developed to treat HER2+ BC, it showed antitumor activity in HER2-low tumors in a phase I study [ 282 ]. Based on these results, an ongoing open-labeled, multicentered phase III study (ClinicalTrials.gov Identifier: NCT03734029) is recruiting patients with HER2-low metastatic BC to test trastuzumab deruxtecan vs. standard treatment chosen by the physician. Preliminary results are expected in January 2023 (see Table 4 ).

Ongoing clinical trials on emerging therapies for BC treatment for all BC molecular subtypes.

TNBC: triple negative breast cancer; HER2: human epidermal growth factor receptor 2; ER: estrogen receptor; MBC: metastatic breast cancer; BC: breast cancer; HR: hormonal receptor; PFS: progression free survival; CBR: clinical benefit rate; ORR: objective response rate; DFS: disease-free survival; OS: overall survival; TTP: time to progression. pCR: pathologic complete response; GM-CSF: granulocyte macrophage colony-stimulated factor; DLT: dose-limiting toxicities; MTD: maximum tolerated dose; TTF: time to treatment failure; TTR: time to treatment response; iDFS: invasive disease-free survival; RFS: recurrence free survival; DDFS: distant disease-free survival; iEFS: invasive events-free survival; CR: clinical response; DoCB: duration of clinical benefit; SD: stable disease; DoR: duration of response; IAEs: incidence of adverse events; TDR: treatment discontinuation rate; PR: partial response; DCR: disease control rate; HR: hazard ratio.

4.3.2. Targeted Therapies

Targeted therapy is the current standard of care to treat HR+ and HER2+ BC, but it cannot be administered to patients with TNBC as these tumors lack the expression of these biomarkers. Hence, the next logical step is to identify biomarkers associated with TNBC to develop specific targeted therapies. Several emerging targeted therapies are being clinically trialed with limited or mixed results.

VEGF and EGFR Inhibitors

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are overexpressed in most TNBC patients [ 341 , 342 ]. Bevacizumab and cetuximab are antibodies developed to specifically target VEGF and EGFR, respectively. Unfortunately, clinical trials studying the effects of these antibodies in TNBC patients demonstrated limited results. The phase III, randomized BEATRICE study evaluating adjuvant bevacizumab-continuing therapy in TNBC demonstrated no significant benefit in OS [ 310 ]. A phase II trial evaluating the impact of adding bevacizumab or cisplatin to neoadjuvant chemotherapy to stage II to III TNBC concluded that further investigation of bevacizumab in this setting was unlikely [ 311 ].

The phase II randomized TBCRC 001 trial testing the combination of cetuximab and carboplatin in stage IV TNBC showed a response in fewer than 20% of patients [ 312 ]. Another randomized phase II study compared the effects of cetuximab plus cisplatin to cisplatin alone in metastatic TNBC patients. Adding cetuximab to cisplatin prolonged PFS and OS, warranting further investigation of cetuximab in TNBC [ 313 ]. Based on these results, bevacizumab is not recommended for the treatment of TNBC.

mTOR/PI3K/AKT Inhibitors

mTOR/PI3K/Akt signaling pathway is an important target involving all BC subtypes. Inhibitors of mTOR, PI3K, and Akt have been tested in HR+ and HER2+ BC patients and have also been tested in TNBC patients. The mTOR inhibitor everolimus has been tested in a randomized phase II trial in combination with chemotherapy vs. chemotherapy alone in stage II/III TNBC patients [ 314 ]. Unfortunately, the addition of everolimus was associated with more adverse effects, without improving pCR or clinical response. A phase I study testing the combination of everolimus and eribulin in metastatic TNBC patients showed that this combination was safe, but the efficacy was modest [ 343 ].

The Akt inhibitor ipatasertib has been tested in combination with paclitaxel (vs. placebo) for metastatic TNBC patients in the phase II multicentered double-blinded randomized LOTUS trial [ 315 ]. The results showed improved PFS when patients received ipatasertib. Another phase II double-blinded randomized trial, FAIRLANE, testing neoadjuvant ipatasertib plus paclitaxel for early TNBC, showed no clinically or statistically significant improvement in the pCR rate, but ipatasertib’s antitumor effect was more pronounced in patients with PI3K/AKT1/PTEN-altered tumors [ 316 ]. Capivasertib, another Akt inhibitor, has been tested in combination with paclitaxel (vs. placebo), first-line therapy for metastatic TNBC patients in the phase II double-blinded randomized PAKT trial [ 317 ]. The addition of capivasertib to paclitaxel significantly improved PFS and OS, with better benefits for patients with PI3K/AKT1/PTEN-altered tumors.

Androgen Receptor Inhibitors

The androgen receptor (AR) is a steroidal hormonal receptor that belongs to the nuclear receptor family and is expressed in 10% to 50% of TNBC tumors [ 344 ]. Tumors expressing AR have better prognosis but are less responsive to chemotherapy [ 345 ]. Multiple clinical trials have tested AR inhibitors in TNBC [ 318 , 319 , 320 ].

Bicalutamide, an AR agonist, was tested in a phase II study in patients with AR+, HR- metastatic BC [ 318 ]. The results showed promising efficacy and safety for these patients.

Enzalutamide, a nonsteroidal antiandrogen, has been tested in a phase II study in patients with locally advanced or metastatic AR+ TNBC [ 319 ]. Enzalutamide demonstrated significant clinical activity and tolerability, warranting further investigation.

Abiraterone, a selective inhibitor of CYP17, has been evaluated in combination with prednisone in AR+ locally advanced or metastatic TNBC patients [ 320 ]. This combination was beneficial for 20% of the patients.

Several clinical trials are currently testing AR inhibitors alone or combined with other treatments for TNBC patients; expecting results between 2022 and 2027 (see Table 4 ).

4.3.3. Immunotherapy

Targeted antibodies.

The immune system plays a crucial role in BC development and progression. Tumor cells can escape the immune system by regulating T-cell activity leading to the inhibition of immune response [ 346 , 347 ]. Two principal biomarkers found in TNBC are associated with this bypass: the programmed cell death protein receptor (PD-1) and its ligand PDL-1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) [ 348 ].

PD-1 is an immune checkpoint receptor expressed on the surface of activated T-cells. PDL-1, its ligand, is expressed on the surface of dendritic cells or macrophages. The interaction of PD-1 and PDL-1 inhibits T-cell response [ 349 ]. CTLA-4 is expressed on T-cells and inhibits T-cell activation by binding to CD80/CD86, leading to decreased immune response [ 350 ].

Atezolizumab, an anti-PDL-1 antibody, has demonstrated safety and efficacy in a phase I study for metastatic TNBC patients [ 351 ]. Based on these results, atezolizumab was tested in combination with nab-paclitaxel for unresectable locally advanced or metastatic TNBC in the phase III double-blinded placebo-controlled randomized Impassion130 study [ 321 ]. Atezolizumab plus nab-paclitaxel prolonged PFS and OS in both the intention-to-treat population and PDL1+ subgroup. Another double-blinded, randomized phase III study (Impassion031) compared atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy vs. placebo for early-stage TNBC [ 322 ]. This combination significantly improved pCR with an acceptable safety profile.

Durvalumab, another anti-PDL-1 antibody, has been tested in combination with an anthracycline taxane-based neoadjuvant therapy for early TNBC in the randomized phase II GeparNuevo study [ 323 ]. This combination increased pCR rate, particularly in patients pretreated with durvalumab monotherapy before chemotherapy. Another randomized phase II study, SAFIRO BREAST-IMMUNO, compared durvalumab to maintenance chemotherapy in a cohort including TNBC patients [ 324 ]. Results showed that durvalumab, as a single agent therapy, could improve outcomes in TNBC patients. A phase I study tested durvalumab in combination with multiple TNBC therapies: PARP inhibitor olaparib and VEGFR1-3 inhibitor cediranib for patients with recurrent cancers including TNBC [ 325 ]. This combination was well tolerated and showed preliminary antitumor activity in all of these patients.

The safety and efficacy of avelumab, another anti-PDL-1 antibody, was evaluated in the phase Ib JAVELIN study in patients with locally advanced or metastatic BC, including TNBC [ 326 ]. Avelumab showed an acceptable safety profile and clinical activity, particularly in tumors expressing PDL-1.

Pembrolizumab is an anti-PD-1 antibody that has been tested in multiple clinical trials. The phase Ib KEYNOTE-012 study demonstrated the safety and efficacy of pembrolizumab on advanced TNBC patients [ 352 ]. Based on these results, the phase II KEYNOTE-086 study evaluated pembrolizumab monotherapy for pretreated or non-pretreated metastatic TNBC patients [ 327 , 353 ]. Pembrolizumab monotherapy showed a manageable safety profile and durable antitumor activity for both pretreated and non-pretreated subgroups. The randomized open-labeled phase III KEYNOTE-119 trial compared pembrolizumab monotherapy to standard chemotherapy in metastatic TNBC [ 354 ]. Pembrolizumab monotherapy did not significantly improve OS compared to chemotherapy in these patients. These findings suggest that pembrolizumab should be investigated in a combinational approach rather than in monotherapy. Based on these results, pembrolizumab was tested in combination with chemotherapy (vs. placebo) for pretreated locally recurrent or metastatic TNBC patients in the phase III double-blinded randomized KEYNOTE-355 trial [ 328 ]. The combination of pembrolizumab plus chemotherapy significantly and clinically improved PFS compared to chemotherapy plus placebo. Pembrolizumab has also been evaluated for early TNBC as neoadjuvant therapy in combination with chemotherapy (vs. placebo) in the phase III KEYNOTE-522 trial [ 329 ]. The combination of pembrolizumab plus chemotherapy significantly improved pCR rate in these patients compared to placebo plus chemotherapy.

Tremelimumab is an anti-CTLA-4 antibody. A dose-escalation phase I study evaluating the safety and efficacy of tremelimumab in patients with metastatic BC showed good tolerability [ 330 ].

Vaccination is an emerging approach to prevent recurrence in high-risk BC patients. As mentioned earlier, TNBC is the most aggressive BC subtype with a higher risk of distant recurrence [ 331 ]. Thus, developing vaccines to prevent recurrence in TNBC patients is of great interest.

Takahashi et al. have developed a novel regimen of personalized peptide vaccination (PPV) based on the patient’s immune system to select vaccine antigens from a pool of peptide candidates [ 332 ]. They performed a phase II study where metastatic recurrent BC patients with prior chemotherapy and/or hormonal therapies received a series of personalized vaccines. This vaccination demonstrated safety, possible clinical benefit, and immune response, especially for TNBC patients [ 332 ]. A multicentered, randomized, double-blinded phase III study analyzed the effects of sialyl-TN keyhole limpet hemocyanin (STn-KLH) on metastatic BC patients [ 333 ]. STn-KLH consists of a synthetic STn, an epitope expressed in BC and associated with aggressive and metastatic tumors, and a high molecular weight protein carrier KLH [ 355 ]. Stn-KLH demonstrated good tolerability, but no benefits in time to progression (TTP) or survival were found. Thus, this vaccination is not recommended for metastatic BC patients [ 333 ].

PVX-410 is a multiple peptide vaccine that activates T-cell to target tumor cells and was developed to treat myeloma. A phase Ib/II study demonstrated the safety and immunogenicity in myeloma patients [ 356 ]. Based on these results, a PVX-410 vaccine is currently being tested to treat TNBC in multiple clinical trials (see Table 4 ).

Finding new treatments for TNBC is an ongoing challenge. The therapeutic strategies that have been described in this section offer great hope to treat TNBC patients. However, because TNBC is highly heterogeneous, it is difficult to find a single treatment efficient for all TNBC subtypes [ 228 ].

5. Conclusions

This review clearly demonstrates that the treatment of BC is complex and is constantly evolving with a large number of ongoing clinical trials on emerging therapies. Indeed, the BC molecular subtype will determine the personalized therapeutic approach, such as targeted treatments like endocrine therapy for HR+ BC or anti-HER2 therapy for HER2+ BC. These therapies have demonstrated their safety and efficacy in treating BC over the years. However, it is essential to go beyond these conventional treatments as BC is a complex disease and not all patients can benefit from personalized treatment. One of the major challenges in BC treatment is finding effective therapies to treat TNBC patients since conventional targeted therapies cannot be administered for this specific BC subtype, which has the worst survival outcomes.

Another important issue in BC treatment is the acquisition of treatment resistance. This is a common phenomenon for either endocrine therapy, anti-HER2 therapy, and chemotherapy.

Hence, understanding the mechanisms underlying drug resistance is a good strategy to develop novel treatments for BC. For example, the mTOR/PI3K/Akt pathway is involved in the mechanism of resistance in all BC molecular subtypes, and thus developing specific inhibitors targeting this pathway is a promising BC treatment approach.

Acknowledgments

The authors would also like to thank team members from the C.D. and F.D. research groups for their valuable assistance.

Abbreviation

Author Contributions

A.B. conceptualized and drafted the manuscript. F.D. and C.D. supervised the project. All authors did critical revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

This work was supported by the “Fond de recherche du Québec–Santé (FRQS)” associated with the Canadian Tumor Repository Network (CTRNet). Caroline Diorio is a senior Research Scholar from the FRSQ. Anna Burguin holds a Bourse d’excellence en recherche sur le cancer du sein—Faculté de médecine-Université Laval.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer

The incidence of discordant clinical and genomic risk in patients with invasive lobular or ductal carcinoma of the breast: a National Cancer Database Study

Introduction.

Breast cancer is the most frequently diagnosed cancer with one in eight woman being diagnosed in their lifetime 1 . Invasive breast cancers exhibit different histological subtypes with the majority (~75–80%) being carcinoma of no special type (NST), previously referred to as invasive ductal carcinoma (IDC). Invasive lobular breast cancer (ILC) is the most common special type, representing 10–15% of all breast cancers 2 . The hallmark of ILC is loss of E-cadherin, resulting in discohesive cells and alteration of tumor cellular morphology. These are the foundation for the histopathological diagnosis 3 . The diagnosis of ILC remains challenging in part due to the existence of different ILC subtypes and a lack of consistency of diagnostic methodology 4 . Recent studies have shown that interobserver agreement in diagnosis of ILC can be increased with the use of E-cadherin immunohistochemistry (IHC) as a diagnostic marker 5 , and although efforts to improve this have recently been published ( https://pubmed.ncbi.nlm.nih.gov/38641322/ ), at this point in time there are no guidelines recommending its use. The pathognomonic feature of ILC is genetic inactivation of CDH1 6 . Compared to patients with NST, patients with ILC are older, and at the time of diagnosis tumors are mostly estrogen receptor-positive, larger, and of higher stage, likely due to limitations of imaging modalities for detection of lobular tumors 7 . Patients with ILC suffer more frequently from late recurrences (often to less common sites such as the gastrointestinal and urogenital tract) than patients with NST, resulting in worse long-term outcome despite fewer high-risk patients being identified by molecular profiling 8 . There are limited studies comparing response to chemotherapy, but collectively they suggest decreased efficacy in patients with ILC 9 , 10 . Despite the increasing realization of unique biology, etiology, and progression of ILC, ILC is understudied relative to other breast cancers, and there are no treatment guidelines specifically for ILC 7 , however some clinical trials specific for or enriching for patients with ILC are currently being performed.

Here we undertook a worldwide survey, which included the three major stakeholders – breast cancer clinicians/researchers, laboratory-based researchers, and the community including patients and patient advocates. Using this survey, we analyzed the current understanding of ILC and identified consensus research questions on ILC, which can provide the foundation for future collaborative studies.

Demographics and characteristics of survey respondents

In total, 1714 individuals were contacted by email with a 39% response rate and for these responses there was a 95% completion rate in taking the survey. Subsequent additional targeted recruitment and outreach via social media especially Twitter (now X) and Facebook resulted in an additional 1,166 respondents starting the survey. In total, 1774 participants answered at least one question and 1310 finished the survey. Of the survey respondents, 688 asked to be included as having contributed to the survey, and they are listed (Supplementary Data File 1 ).

Respondents resided in 66 countries (Supplementary Data File 2 ) covering all continents except Antarctica (Fig. 1A ). The top three countries based on number of respondents were the US (47.65%), UK (9.66%) and Ireland (6.55%).

A A world map showing the percentage by country of respondents to the survey, and the top ten countries with numbers of respondents. World map was generated using https://github.com/geopandas/geopandas . B Overall number of physicians, lab- based researchers, and breast cancer patients, with advocates being indicated. C Physicians are separated by clinical specialty.

Respondents self-identified as breast cancer physicians/researchers ( N  = 413), as basic (laboratory-based) researchers ( N  = 376), and breast cancer patients ( N  = 1121) of whom 288 (26.1%) indicated membership in advocacy groups (Fig. 1B ). Some respondents belonged to more than one category - 28 clinicians and 17 laboratory-based researchers were also breast cancer patients. There was also overlap between the breast cancer clinicians/researchers and the laboratory-based researcher, with 195 (47.2%) identifying as clinicians with a research lab.

The majority of the breast cancer physicians were medical oncologists (46.5%) and surgeons (22.5%) followed by representation from pathology (12.3%), radiation oncology (4.1%), gynecology (1.0%) and others (5.6%), which included palliative care, patient navigators, clinical oncology, geneticist, family medicine, nuclear medicine and more (Fig. 1C ). Most of the clinicians practice in academia (60.6%), followed by private practice (17.4%), and governmental institutions (16.9%). There was an equal distribution of experience: 1–10 years (24.0%), 11–20 years (32.6%), 21–30 years 22.7%), and 31 years and more (19.6%). The majority of physicians treated 11-50 (42.8%) and 51–100 (26.8%) patients per month.

The majority of self-identified laboratory-based researchers work in academic institutions (80.7%), and others in private (9.4%) and governmental (6.7%) institutions. There was a roughly equal distribution of researchers working (50.9%) vs. not working on lobular (49.1%) breast cancer, and 80% of those working on ILC have previously received funding for their work on ILC from a wide range of funders (Supplementary Data File 3 ). The majority of researchers have been working for 1–10 years (35.7%), followed by 11–20 years (29.7%), 21–30 years (23.7%), 31 years (7.8%) and more (19.6%), and less than 1 year (3.6%).

There were 1121 respondents that indicated that they have or have had breast cancer or in situ carcinoma, called “patients” hence forth. At the time of response to the survey, 62.5% had breast cancer but were currently without evidence of disease, 25.4% were in active treatment for breast cancer, and 19.1% had indicated that their disease had recurred with 8.1% being local and 11.1% being distant recurrences. Lobular breast cancer was the most common histology (63.1%), followed by LCIS (13.6%), DCIS (6.8%), NST (6.3%), mixed ductal/lobular (5.3%) and others/unknown (4.9%). The average age for diagnosis was 52.3 years.

Of the 1121 patients who responded, 288 (26.1%) indicated membership in advocacy groups. Of the total number of respondents to the survey, 403 (23.1% of all respondents) belonged to one or more of 170 different advocacy groups, support groups, and other foundations (Supplementary Data File 4 ).

Current understanding of lobular breast cancer by clinicians, and communication with patients

The majority of physicians were confident in describing the differences between ILC and NST (Fig. 2A ), and there was no significant difference between medical oncologists, surgeons and other specialties. Only 4% were not all confident, or slightly confident (12%) about the differences. Physicians indicated that knowledge of histology was seen as very/extremely important (73%) (Fig. 2B ), and this again was not different between the different specialties The majority of physicians stated that knowledge of histology affected their treatment decisions a lot (51%) or a moderate amount (32%), with surgeons (60%) and others (59%) using histology information significantly more than medical oncologists (40%). Very few physicians (4.5%) felt that knowing histology was not at all or only slightly important. The majority of physicians (57%) indicated that there either was no data, that they did not know, or that they were unsure if there were clinical trials and outcome data supporting unique treatments for ILC. Refining treatment guidelines specifically for lobular breast cancer was seen as valuable for treating patients with ILC in the future by 76% of physicians, for a number of reasons outlined in Supplementary Text File 2 .

A Responses by clinicians about confidence in describing differences between ILC and NST. B Importance of knowledge of histology for physicians. C Patients’ responses on communication with physicians. ”Other” refers to “ I was not offered personalized therapy because my physician explained that the treatment is no different for ductal than for lobular ”.

We asked how patients perceived the knowledge of and specifically, the communication about ILC-specific features by physicians. Many patients (52%) thought that their health care providers did not explain unique features of ILC (Fig. 2C ). “Personalized therapy based on histological diagnosis” was discussed with 21% of patients, while it was not discussed with 42%. For 28% of patients, the physicians explained that there was no difference in treatment for NST and ILC. Discussions about potential personalized therapies were held mostly with medical oncologists (89%), followed by surgeons (72%). There were an equal number of radiation oncologists who “definitely did not/probably not” (50%) and who “definitely did/probably did” (50%) discuss ILC-personalized therapy. Most physicians (71%) did not mention that ILC can metastasize to unique places and did not discuss what symptoms, including unusual symptoms, of recurrence the patients should report in the future (78%). For all these communication-related questions, there were differences between countries, with health care providers in the US more frequently being perceived as explaining ILC specific features compared to other countries (Supplementary Data File 5 ).

Finally, we asked which other ILC-related topics the patients wished they have had a chance to discuss with their physicians. The most common was a discussion of the unique clinical features of ILC, followed by information on recurrence and metastasis, cancer detection and screening, and influence of breast density (Supplementary Data File 6 , and Supplementary Fig. 1 ). All answers were clustered into one of the topics based on semantic similarity, which can be interactively visualized under ‘Topic’ coloring scheme via https://atlas.nomic.ai/data/chelseax488/ilc-survey---discussion-with-doctors/map .

Current basic/translational research and future priorities identified by survey respondents

For those who self-identified as basic or translational researchers, 48% were very/extremely and 29% were moderately confident in describing differences between ILC and NST. The majority (59.8%) performed none or only a little ILC research with only 20% performing a lot or a great deal of ILC research. Reflecting this, only 23% received funding to work on ILC, and those who focused on ILC were significantly more funded for their ILC work (54%) compared to those who don’t focus on ILC (9%).

There is the need for additional ILC models, as only 11% of respondents found that there were sufficient in vitro and in vivo models for ILC research. 32% of respondents use ILC cell line models in their research, the most common being MDA-MB-134 and SUM44. Majority did not use ILC models due to “lack of facility, resources, or expertise”. 52% of respondents felt that ILC was poorly represented in public genomic datasets, while 69% felt that they were able to obtain lobular breast cancer tissue and/or blood samples from patients with ILC for research.

We asked the three major stakeholders for their opinions on research priorities in ILC (Fig. 3 , and Supplementary Data File 7 ). We posed questions about 6 major areas with each area having subcategories. The main areas were: (1) Epidemiology and Risk Reduction; (2) Diagnosis (Imaging and Pathologic Analysis), (3) Therapy, treatment resistance and disease progression; (4) Local therapy of the primary tumor; (5) Imaging; and, (6) Lobular tumorigenesis (the formation of tumors), and other basic/translational research questions. There was general agreement in prioritization of research priorities by the physicians and laboratory-based researchers. Both chose “Therapy, treatment resistance and disease progression” as their top research area followed by “Diagnosis (Imaging and Pathology)”. For 5 out of the 6 areas there was agreement on the specific subcategories of interest with the two highest being “Determining mechanisms of endocrine resistance in ILC” and “Understanding value of genomic predictors for ILC prognosis and prediction of therapeutic response”. The largest discordance was in the area of “Basic/translational research” with physicians choosing “Focusing on development of a centralized ILC data and tissue registry” whereas laboratory-based researchers chose “Characterizing differences in the tumor microenvironment between ILC and NST”. The top priority areas for patients were “Imaging” and “Diagnosis (Imaging and Pathology)”. Within “Imaging”, all groups identified “Identifying new and specific imaging tools for ILC” as the key research area, whereas in “Diagnosis (Imaging and Pathologic Analysis)”, patients chose “Identifying strategies to improve ILC screening/early detection” and physicians and researchers choose “Role of genomic predictors for ILC prognosis and prediction of therapeutic response”.

Heatmap showing percentage of individuals rating each research question as of highest importance (‘most critical and impactful’, against moderate/low importance) among 6 domains of topics in physicians, lab-based researchers, and patients, respectively. Color and number represents the percentage from 0-100 in each block.

And finally, there was a free text field question asking which other research questions have high priority that might not have been listed. The most frequently mentioned topics (Supplementary Data File 8 ) among a wide range of answers were: (1) Genetic screening, Germline mutations, Familial risks, (2) Awareness education, (3) New Aromatase Inhibitors (AI) and Selective Estrogen Receptor Degraders (SERDs) and duration of treatment, (4) Genomic predictors/markers, and, (5) Chemotherapy-related questions.

Clinical trials focused on ILC

Finally, we asked physicians specifically about their opinions on clinical trials in ILC. Half of the physicians reported that “Most of the time/always” approximately half of the clinical trials and studies they were involved in collected data on tumor histology, with twice as many surgeons (35%) than medical oncologists (16%) “always” collecting histology information. Further, 66% of physicians stated that clinical trials they are involved in do not or only sometimes consider histology in their inclusion/exclusion criteria. Most physicians (86%) have not powered clinical trials they were involved in to specifically allow a subset analysis for ILC, and this was not significantly different between surgeons, medical oncologists and other physicians. However, 50% would “probably” and 36% would “definitely” consider powering clinical trials to do subset analysis of lobular breast cancer in the future, for a wide range of reasons (Supplementary Text File 3 ). Importantly, most physicians (87%) would consider participating in consortia conducting clinical trials in ILC.

ILC is inherently understudied compared to the more common NST subtype of breast cancer. To better understand conceptions about ILC and key research areas, we surveyed patients/advocates, physicians, and laboratory-based researchers. A robust world-wide response ( n  = 1774) was obtained from all three key stakeholder groups. Physicians are confident in describing the differences between ILC and NST and feel that knowledge of histology is important, as it affects their decision making. Importantly, they responded that future refined treatment guidelines would be valuable for patients with ILC. While very few clinical trials have been directed specifically at ILC, most physicians expressed an interest in such trials. Most laboratory researchers felt that ILCs are inadequately presented in large genomic data sets, and there are too few models of the disease. The majority of patients thought that their health care providers did not explain unique features of ILC, and that in general communication was limited. Overall, while there is growing interest in the study and understanding of ILC, there are clear gaps in understanding and presentation of the disease to patients. This challenge is beginning to be addressed by advocacy groups who are developing publicly available educational materials available on websites for examples from the Lobular Beast Cancer Alliance ( https://lobularbreastcancer.org/ ), the European Lobular Breast Cancer Consortium ( https://elbcc.org/ ), and in general there has been an overall increased awareness of unique features of ILC.

Both clinical and laboratory studies are hindered by a lack of studies targeted specifically at ILC and addressing ILC-specific challenges. We asked the three major stakeholders what they felt were the most important areas of ILC research. While there was general concordance between the groups, important areas did show discordance. For example, while physicians and researchers both chose ‘Therapy, treatment resistance and disease progression’ as their top research area, patients/advocates chose ‘Imaging’ and ‘Diagnosis (Imaging and Pathologic Analysis)’. Our survey results are consistent with a recent survey of patients and advocates ( n  = 1476) previously diagnosed with ILC who expressed concerns over current imaging standards 11 . These patients reported that mammography often failed to detect ILC cases until they reach stage 2 or higher, a common issue for ILC. Importantly, tumors were often larger at resection than predicted by imaging. A recent review of the literature also reported that MRI and contrast-enhanced mammogram surpass conventional breast imaging in sensitivity and specificity of ILC detection 12 . There have been recent advances in understanding the reasons for decreased ability to image ILC e.g., reduced uptake of glucose limited FDG-PET 13 and direct comparisons showing better imaging via FES-PET compared to FDG-PET in ILC 14 . This is clearly an area of patient/advocate interest.

Patients and advocates also highlighted the need for improved diagnosis (imaging and pathologic analysis). This is also consistent with a recent survey of pathologists highlighting the lack of standard definitions for diagnosis of ILC 4 . The current World Health Organization (WHO) classification for ILC diagnosis only requires pathologists to note a non-cohesive growth pattern in the tumor and does not require analysis of E-cadherin status. Highlighting challenges in pathologic diagnosis of ILC, thirty-five pathologists diagnosed NST and ILC from a set of breast cancers and showed only a moderate inter-observer agreement, but a substantial agreement was a found when E-cadherin was also used in the diagnosis 5 . Efforts have recently been done by the pathology working group from the European Lobular Breast Cancer Consortium (ELBCC) to harmonize pathological diagnosis of ILC ( https://pubmed.ncbi.nlm.nih.gov/38641322/ ). Finally, the increased development and use of digital pathology and artificial intelligence, such a recently reported algorithm using 51 different types of clinical and morphological features differentiating between NST and ILC with an AUC of 0.97 15 may eventually offer the option to improve diagnosis. Another example is a recent study which used a machine learning system to detect ‘ CDH1 biallelic mutations’ as ground truth rather than histology and then developed an AI-based system that can detect ILCs accurately 16 . These algorithms may help resolve the morpho-molecular diagnosis of ILC 17 , particularly with the complex mixed subtypes.

Different from the patients/advocates, the top two most important research questions identified by clinician and laboratory researchers were 1) determining mechanisms of endocrine resistance, and 2) identifying novel therapeutic targets, repurposing existing drugs and progressing them to clinical trials. These research questions align with the identified priority areas of ELBCC ( https://lobsterpot.eu/organisation/working-groups and https://lobsterpot.eu/organisation/pr2 ), and likely reflect the desire to personalize therapy for patients with ILC through improved understanding of unique biology of ER and other signaling pathways. While preclinical and clinical studies have suggested that ILC may be relatively resistant to antiestrogen therapy 18 , 19 , 20 and sensitive to inhibitors of growth factor receptor/PI3K/ROS1 signals 21 , 22 , 23 , 24 , 25 , clinical trial evidence supporting these concepts remain lacking. The first clinical trial that focused specifically on ILC (GELATO; NCT03147040) which evaluated chemotherapy followed by immunotherapy in patients with metastatic ILC showed a relatively low (27%) clinical benefit rate 26 . It was discontinued in part because the responding tumors were of the rare ER-negative subtype of ILC and because chemotherapy plus immunotherapy is now standard of care for patients with PD-L1+ metastatic TNBC, regardless of histological subtype. Of note, interesting correlative science from this trial as well as another recent study 27 supports the need for further analysis of the immune infiltrate in ILC.

There are limitations to the study, which include uneven representation of the three stakeholder groups. In addition, the physicians are not truly a representative group as only 17% are in private practice suggesting limited participation from community physicians. In addition, physicians involved in the diagnostic practices, including pathologists and radiologists, are underrepresented in the survey respondents, which are skewed towards medical oncologists. As with many surveys, the responses are biased in terms of who takes the time to respond to the survey, ie the respondents are likely highly motivated to improve understanding of ILC. Finally, although we do have representation from 66 countries, almost two thirds of the responses (64%) originate from only three countries.

In summary, we have obtained data on world-wide understanding and interest in the study of ILC. Patients feel that communication of the unique features of ILC by the physician can be improved. While physicians and laboratory researchers feel the need to better understand endocrine resistance, to identify new treatment targets and/or repurpose existing drugs for ILC treatment, patients’ top priority research area is improved imaging. Overall, the survey indicates areas where interventions can be implemented to improve communication and outcomes for patients with ILC.

Survey development and measures

After discussing the concept and development of an early version of the survey, a draft was shared with representatives from the three groups, breast cancer clinicians/researchers, laboratory-based researchers, and the community including patients and patient/advocates (hitherto called “physicians,” “researchers,” and “patients/advocates”). Multiple rounds of edits were circulated among the team, and the survey was then further refined by the UPMC Hillman Cancer Center Population Survey Facility. After beta testing with a subset of physicians, researchers and patients/advocates, final edits were made, and the survey was developed and distributed using the Qualtrics online survey tool, through the Population Survey Facility. The final survey (Supplementary Text File 1 ) was fielded March to May 2022 to email lists compiled from PubMed, ORCID and professional networks, followed by distribution via social media.

For our study, we have complied with all relevant ethical regulations including the Declaration of Helsinki. The survey was anonymized, and responses were not linked to identifiers, however respondents had the opportunity to list names if they chose to be identified as survey participants in the resulting manuscript (Supplementary Data File 1 ). The study received Pitt institutional review board approval (STUDY21010058, initially effective on 03/22/2021, and final version was effective on 02/17/2022).

Analysis of survey results

All responses were collected by the University of Pittsburgh Population Survey Facility. To analyze responses for topic of most critical and impactful research questions, each variable was dichotomized (most impactful or not), a top score was generated which was then analyzed using chi-square analysis across the subgroups.

Free text field questions 34 (“Which ILC cell models are you including in your studies”) and 58 (“Please indicate below other research questions that have high priority that we have not listed”) were manually summarized (SO, AVL) with common themes assigned for each answer with high consistency (overlap rate for Q58 = 98.36%). Natural language processing (Chat GPT, and sentence transformer – see below for details) was used to analyze responses to free text field questions 33 (“Why are you not including ILC cell models in your studies”) and 50 (“What do you now know about ILC that you wish you could have heard from and discussed with your…”), which were all initially filtered to exclude missing or semantically non-meaningful items. For question 33, a prompt was made for ChatGPT4, “Think as a physician scientist, patient, and basic researcher in breast cancer. Summarize the common but non-overlapping reasons shared among answers, ‘Why are you not including ILC cell models in your studies?’, For each reason, list only the respondent number.”, followed by respondent number and free-text answers in two columns, individually. The returned summarization and labeling of each answer were then manually inspected and adjusted (merging of reason 3 and 6). For question 50.1-5 (“What do you now know about ILC that you wish you could have heard from and discussed with your…”), all answers were combined ( N  = 1260), with each answer transformed into a 384-dimentional vector (embedding) via sentence transformers ( https://huggingface.co/sentence-transformers ), and converted to 5-dimension using UMAP with local neighborhood at 15. HDBSCAN was then performed with minimum cluster size of 15, on Euclidean distance and cluster selection method as ‘eom’, generating 23 clusters. Then for each cluster, class-based TF-IDF (c-TF-IDF) vectors were calculated among all words, followed by topic reduction via merging c-TF-IDF vectors with highest cosine similarity with 10 iterations, generating 14 final topics. The resulted topics were merged into 11 via manual assessment of words of top frequency within each cluster, after which all answers of the same topic, except for ‘ambiguous’ group, were passed to gpt-4 api deterministic model (temperature zero) respectively, with a prefix “Think as a patient with breast cancer, and as a physician scientist studying breast cancer, summarize in professional scientific language one single common topic shared among answers, ‘What do you now know about ILC that you wish you could have heard from and discussed with your breast cancer doctor?’ The summarization should be a single, brief sentence”. Then metastasis and recurrence groups were manually merged based on expert suggestion. This eventually led to 10 topic clusters, including one non-specific group (ambiguous).

Crosstabulations were analyzed using Chi-Square test, and for these some groups were combined (such as pathologists, radiation oncologists, gynecologists, and others) due to the limited number in such subgroups analysis.

Data availability

The study does not contain any sequencing or structural data. Majority of responses to survey as well as original survey document have been uploaded into Supplementary Text and Data Files. Additional raw data are available upon reasonable request from the corresponding author.

Code availability

Codes for text analysis are provided in https://github.com/leeoesterreich/ILC-Survey .

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Acknowledgements

We thank all respondents to the survey who made this work possible. This work is dedicated to Leigh Pate, who was not only instrumental in the development of this survey, but who laid the foundation for worldwide lobular breast cancer advocacy. We would also like to thank many other patient advocates representing the different ILC advocacy groups such as LBCA and ELBCC patient advocates (ELBCA) who have contributed to editing the original survey questions. This work was made in part possible by the Survey core of the UPMC Hillman Cancer Center with support from NIH grant award P30CA047904. We would like to thank the Shear Family Foundation for their support of generation of the survey and analysis of results. Fangyuan Chen was a former visiting research scholar at the University of Pittsburgh School of Medicine supported by funds from The China Scholarship Council and Tsinghua University. The study is in part based on work from COST Action LOBSTERPOT (CA19138), supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and innovation networks https://www.cost.eu . Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748; MSK). J.S. Reis-Filho was funded in part by Susan G Komen Leadership, and NIH/NCI P50 CA247749 01 grants. A number of authors are funded by the Breast Cancer Research Foundation (SO, AVL, NMD, CL, CS, CD, JSRF).

Author information

Jorge S. Reis-Filho

Present address: AstraZeneca, GAITHERSBURG, MARYLAND, USA

Deceased: Leigh Pate.

Authors and Affiliations

University of Pittsburgh, Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, Women’s Cancer Research Center, Magee Womens Research Institute, Pittsburgh, PA, USA

Steffi Oesterreich, Adrian V. Lee, Fangyuan Chen & Osama S. Shah

Independent ILC Advocate, Founder LBCA, Pittsburgh, PA, USA

Institute for Precision Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA, USA

Adrian V. Lee

Tsinghua University, Beijing, China

Fangyuan Chen

University of Pennsylvania and Penn Medicine Abramson Cancer Center, Philadelphia, PA, USA

Rachel C. Jankowitz

University of California, San Francisco, Department of Surgery, San Francisco, CA, USA

Rita Mukhtar

Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA

Otto Metzger

Dept. of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Matthew J. Sikora

Fred Hutchinson Cancer Center, Division of Public Health Sciences, Seattle, WA, USA

Christopher I. Li & Nancy M. Davidson

Jules Bordet Institute Belgium, Brussels, Belgium

Christos Sotiriou

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

Thijs Koorman & Patrick Derksen

Molecular Imaging and Therapy, Hoag Family Cancer Institute, Molecular Imaging and Therapy, Irvine, CA. Departments of Radiology and Translational Genomics, University of Southern California, Los Angeles, CA, USA

Gary Ulaner

Memorial Sloan Kettering Cancer Center, New York, NY, USA

Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium

Karen Van Baelen & Christine Desmedt

Lobular Breast Cancer Alliance Inc., White Horse Beach, MA, USA

Laurie Hutcheson

Lobular Ireland, Dublin, Ireland

Siobhan Freeney

Dynami Foundation, Wausau, WI, USA

Flora Migyanka

Lobular Breast Cancer UK, Nottingham, UK

Claire Turner

Department of Family Medicine, University of Pittsburgh, Pittsburgh, patients/advocates, Pittsburgh, PA, USA

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Contributions

L.P., S.O. and A.V.L. conceptualized the study, and developed draft survey. Critical input on survey development including questions from R.C., R.M., O.M., M.J.S., C.L., C.S., T.K., G.U., J.S.R.F., N.M.D., K.V.B., L.H., S.F., F.M., C.T., P.D., T.B., C.D. Further refinement of survey by K.V.B. and C.D., together with S.O., A.V.L. and L.P. Setting up of online survey, and subsequent collection and analysis of survey data by T.B. Analysis of data also by F.C. and O.S.S. S.O., A.V.L., C.D. and L.P interpreted the data, and wrote the manscuript, and other major contributors in writing and figure generation were F.C., O.S.S. and T.D. All authors read and approved the final manuscript except L.P. who passed before finishing final draft of the manuscript.

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Correspondence to Steffi Oesterreich .

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Competing interests.

J.S. Reis-Filho reported receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of AstraZeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the submitted work. The other authors indicated no potential conflicts of interest.

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Oesterreich, S., Pate, L., Lee, A.V. et al. International survey on invasive lobular breast cancer identifies priority research questions. npj Breast Cancer 10 , 61 (2024). https://doi.org/10.1038/s41523-024-00661-3

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• Published: 26 November 2018

The 150 most important questions in cancer research and clinical oncology series: questions 94–101

Edited by Cancer Communications

Cancer Communications

Cancer Communications volume  38 , Article number:  69 ( 2018 ) Cite this article

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Since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has published a series of important questions regarding cancer research and clinical oncology, to provide an enhanced stimulus for cancer research, and to accelerate collaborations between institutions and investigators. In this edition, the following 8 valuable questions are presented. Question 94. The origin of tumors: time for a new paradigm? Question 95. How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma? Question 96. Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor? Question 97. What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction? Question 98. Is high local concentration of metformin essential for its anti-cancer activity? Question 99. How can we monitor the emergence of cancer cells anywhere in the body through plasma testing? Question 100. Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells? Question 101. Is cell migration a selectable trait in the natural evolution of carcinoma?

Until now, the battle against cancer is still ongoing, but there are also ongoing discoveries being made. Milestones in cancer research and treatments are being achieved every year; at a quicker pace, as compared to decades ago. Likewise, some cancers that were considered incurable are now partly curable, lives that could not be saved are now being saved, and for those with yet little options, they are now having best-supporting care. With an objective to promote worldwide cancer research and even accelerate inter-countries collaborations, since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has launched a program of publishing 150 most important questions in cancer research and clinical oncology [ 1 ]. We are providing a platform for researchers to freely voice-out their novel ideas, and propositions to enhance the communications on how and where our focus should be placed [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In this edition, 8 valuable and inspiring questions, Question 94–101, from highly distinguished professionals from different parts of the world are presented. If you have any novel proposition(s) and Question(s), please feel free to contact Ms. Ji Ruan via email: [email protected].

Question 94: The origin of tumors: time for a new paradigm?

Background and implications.

“There is no worse blind man than the one who doesn’t want to see. There is no worse deaf man than the one who doesn’t want to hear. And there is no worse madman than the one who doesn’t want to understand.” —Ancient Proverb

In the past half-century, cancer biologists have focused on a dogma in which cancer was viewed as a proliferative disease due to mechanisms that activate genes (oncogenes) to promote cell proliferation or inactivate genes (tumor suppressor genes) to suppress tumor growth. In retrospect, these concepts were established based on functional selections, by using tissue culture (largely mouse NIH 3T3 cells) for the selection of transformed foci at the time when we knew virtually nothing about the human genome [ 14 ]. However, it is very difficult to use these genes individually or in combinations to transform primary human cells. Further, the simplified view of uncontrolled proliferation cannot explain the tumor as being a malignant organ or a teratoma, as observed by pathologists over centuries. Recently, the cancer genomic atlas project has revealed a wide variety of genetic alterations ranging from no mutation to multiple chromosomal deletions or fragmentations, which make the identification of cancer driver mutations very challenging in a background of such a massive genomic rearrangement. Paradoxically, this increase the evidences demonstrating that the oncogenic mutations are commonly found in many normal tissues, further challenging the dogma that genetic alteration is the primary driver of this disease.

Logically, the birth of a tumor should undergo an embryonic-like development at the beginning, similar to that of a human. However, the nature of such somatic-derived early embryo has been elusive. Recently, we provided evidence to show that polyploid giant cancer cells (PGCCs), which have been previously considered non-dividing, are actually capable of self-renewal, generating viable daughter cells via amitotic budding, splitting and burst, and capable of acquisition of embryonic-like stemness [ 15 , 16 , 17 ]. The mode of PGCC division is remarkably similar to that of blastomere, a first step in human embryogenesis following fertilization. The blastomere nucleus continuously divides 4–5 times without cytoplasmic division to generate 16–32 cells and then to form compaction/morulae before developing into a blastocyst [ 18 ]. Based on these data and similarity to the earliest stage of human embryogenesis, I propose a new theory that tumor initiation can be achieved via a dualistic origin, similar to the first step of human embryogenesis via the formation of blastomere-like cells, i.e. the activation of blastomere or blastomere-like cells which leads to the dedifferentiation of germ cells or somatic cells, respectively, which is then followed by the differentiation to generate their respective stem cells, and the differentiation arrest at a specific developmental hierarchy leading to tumor initiation [ 19 ]. The somatic-derived blastomere-like cancer stem cell follows its own mode of cell growth and division and is named as the giant cell cycle. This cycle includes four distinct but overlapping phases: the initiation, self-renewal, termination, and stability phases. The giant cell cycle can be tracked in vitro and in vivo due to their salient giant cell morphology (Fig.  1 ).

One mononucleated polyploid giant cancer cell (PGCC) in the background of regular size diploid cancer cells. The PGCC can be seen to be at least 100 times larger than that of regular cancer cells

This new theory challenges the traditional paradigm that cancer is a proliferative disease, and proposes that the initiation of cancer requires blastomere-like division that is similar to that of humans before achieving stable proliferation at specific developmental hierarchy in at least half of all human cancers. This question calls for all investigators in the cancer research community to investigate the role of PGCCs in the initiation, progression, resistance, and metastasis of cancer and to look for novel agents to block the different stages of the giant cell cycle.

The histopathology (phenotype) of cancers has been there all the time. It is just the theory of cancer origin proposed by scientists that changes from time to time. After all, trillions of dollars have been invested in fighting this disease by basing on its genetic origin in the past half-century, yet, little insight has been gained [ 14 ]. Here are two quotes from Einstein: “Insanity: doing the same thing over and over again expecting different results”, and “We cannot solve our problems with the same thinking we used when created them”.

In short, it is time to change our mindset and to start pursuing PGCCs, which we can observe under the microscope. But with very little understanding about these cells, it is time for a shift in paradigm.

Jinsong Liu.

Affiliation

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4095, USA.

Email address

[email protected]

Question 95: How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world with a dismal 5-year overall survival rate of less than 5%; which has not been significantly improved since the past decades. Although surgical resection is the only option for curative treatment of PDAC, only 15%–20% of patients with PDAC have the chance to undergo curative resection, leaving the rest with only palliative options in hope for increasing their quality of life; since they were already at unresectable and non-curative stages at their first diagnosis.

The lack of specific symptoms in the early-stage of PDAC is responsible for rendering an early diagnosis difficult. Therefore, more sensitive and specific screening methodologies for its early detection is urgently needed to improve its diagnosis, starting early treatments, and ameliorating prognoses. The diagnosis so far relies on imaging modalities such as abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), and positron emission tomography (PET). One may propose to screen for pancreatic cancer in high-risk populations, which is highly recommended, however screening intervention for all the people is not a wise choice; when considering the relatively low prevalence of PDAC, and the difficulty for diagnosing it in its early stage [ 20 ].

Therefore, alternative diagnostic tools for early detection of PDAC are highly expected. Among the biomarkers currently used in clinical practice, carbohydrate antigen 19–9 (CA19–9) is among the most useful one for supporting the diagnosis of PDAC, but it is neither sufficiently sensitive nor specific for its early detection. Yachida et al. reported in 2010 that the initiating mutation in the pancreas occurs approximately two decades before the PDAC to start growing in distant organs [ 21 ], which indicates a broad time of the window of opportunity for the early detection of PDAC. With the advancement in next-generation sequencing technology, the number of reported studies regarding novel potential molecular biomarkers in bodily fluids including the blood, feces, urine, saliva, and pancreatic juice for early detection of PDAC has been increasing. Such biomarkers may be susceptible to detect mutations at the genetic or epigenetic level, identifying important non-coding RNA (especially microRNA and long non-coding RNA), providing insights regarding the metabolic profiles, estimating the tumor level in liquid biopsies (circulating free DNA, circulating tumor cells and exosomes), and so on.

Another approach to identifying biomarkers for the early detection of pancreatic cancer is using animal models. In spontaneous animal models of pancreatic cancer, such as Kras-mutated mouse models, it is expected that by high throughput analyses of the genetic/epigenetic/proteomic alterations, some novel biomarkers might be able to be identified. For instance, Sharma et al. reported in 2017 that the detection of phosphatidylserine-positive exosomes enabled the diagnosis of early-stage malignancies in LSL-Kras G12D , Cdkn2a lox/lox : p48 Cre and LSL-Kras G12d/+ , LSL-Trp R172H/+ , and P48 Cre mice [ 22 ].

These analyses in clinical samples or animal models hold the clues for the early detection of PDAC, however, further studies are required to validate their diagnostic performance. What’s most important, will be the lining-up of these identified prospective biomarkers, to validate their sensitivities and specificities. This will determine their potential for widespread clinical applicability, and hopefully, accelerate the early diagnosis of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2 .

1 Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan; 2 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.

E-mail address

[email protected]; [email protected]; [email protected]; [email protected]

Question 96: Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers, and nearly half of the patients had metastatic PDAC when they are initially diagnosed. When they are accompanied by metastatic tumors, unlike most solid cancer, PDAC cannot be cured with primary surgical resection alone [ 23 , 24 ]. Also, since PDAC has poor responses to conventional therapies, improvements in adjunctive treatment approach including chemo- and immuno-therapy are earnestly required. From this standpoint, recent results regarding the differences in the molecular evolution of pancreatic cancer subtypes provide a new insight into its therapeutic development [ 25 ], which may lead to the improvement of the prognosis of not only metastatic PDAC but also of locally advanced or recurrent PDAC.

In fact, new chemotherapeutic regimens such as the combination of gemcitabine with nab-paclitaxel and FOLFIRINOX have been reported to show improved prognosis despite a lack of examples of past successes in the treatment of patients with metastatic PDAC who had undergone R0 resection [ 26 ]. While many mutations including KRAS , CDKN2A , TP53, and SMAD4 are associated with pancreatic carcinogenesis, no effective molecular targeted drug has been introduced in the clinical setting so far. A recent report of a phase I/II study on refametinib, a MEK inhibitor, indicated that KRAS mutation status might affect the overall response rate, disease control rate, progression-free survival, and overall survival of PDAC in combination with gemcitabine [ 27 ].

While immunotherapy is expected to bring a great improvement in cancer treatment, until now, immune checkpoint inhibitors have achieved limited clinical benefit for patients with PDAC. This might be because PDAC creates a uniquely immunosuppressive tumor microenvironment, where tumor-associated immunosuppressive cells and accompanying desmoplastic stroma prevent the tumor cells from T cell infiltration. Recently reported studies have indicated that immunotherapy might be effective when combined with focal adhesion kinase (FAK) inhibitor [ 28 ] or IL-6 inhibitor [ 29 ], but more studies are required to validate their use in clinical practice.

As such, we believe that if the dynamic monitoring of drug sensitivity/resistance in the individual patients is coupled with precision treatment based on individualized genetics/epigenetics/proteomics alterations in the patients’ tumor, this could improve the treatment outcomes of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2.

Question 97: What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction?

Recently, cancer immunotherapy has shown great clinical benefit in multiple types of cancers [ 30 , 31 , 32 ]. It has provided new approaches for cancer treatment. However, it has been observed that only a fraction of patients respond to immunotherapy.

Much effort has been made to identify markers for immunotherapeutic response. Tumor mutation burden (TMB), mismatch repair (MMR) deficiency, PD-L1 expression, and tumor infiltration lymphocyte (TIL) have been found to be associated with an increased response rate in checkpoint blockade therapies. Unfortunately, a precise prediction is still challenging in this field. Moreover, when to stop the treatment of immunotherapy is an urgent question that remains to be elucidated.

In other words, there is no available approach to determine if a patient has generated a good immune response against the cancer after immunotherapy treatments. All of these indicate the complexity and challenges that reside for implementing novel man-induced cancer-effective immune response therapeutics. A variety of immune cells play collaborative roles at different stages to recognize antigens and eventually to generate an effective anti-cancer immune response. Given the high complexity of the immune system, a rational evaluation approach is needed to cover the whole process. Moreover, we need to perfect vaccine immunization and/or in vitro activation of T cells to augment the function of the immune system; particularly the formation of immune memory.

Edison Liu 1 , Penghui Zhou 2 , Jiang Li 2 .

1 The Jackson Laboratory, Bar Harbor, ME 04609, USA; 2 Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

[email protected]; [email protected]; [email protected]

Question 98: Is high local concentration of metformin essential for its anti-cancer activity?

Metformin was approved as a first line of anti-diabetic drug since decades. Interestingly, the fact that clinical epidemiological studies have shown that metformin can reduce the risk of a variety of cancers stimulates considerable recognition to explore its anticancer activity.

Although the in vitro and in vivo experimental results have demonstrated that metformin can have some potential anti-tumor effects, more than 100 clinical trials did not achieve such desirable results [ 33 ]. We and others believe that the main problem resides in the prescribing doses used. For cancer treatment, a much higher dose may be needed for observing any anti-tumor activities, as compared to the doses prescribed for diabetics [ 34 , 35 , 36 ].

Further, if the traditional local/oral administration approach is favored, the prescribed metformin may not be at the required dose-concentration once it reaches the blood to have the effective anti-cancer activities. We, therefore, propose that intravesical instillation of metformin into the bladder lumen could be a promising way to treat for bladder cancer, at least. We have already obtained encouraging results both in vitro and in vivo experiments, including in an orthotopical bladder cancer model [ 36 , 37 ]. Now, we are waiting to observe its prospective clinical outcome.

Mei Peng 1 , Xiaoping Yang 2 .

1 Department of Pharmacy, Xiangya Hospital, Central South University. Changsha, Hunan 410083, P. R. China; 2 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.

[email protected]; [email protected]

Question 99: How can we monitor the emergence of cancer cells anywhere in the body through plasma testing?

The early detection of cancer is still a relentless worldwide challenge. The sensitivity and specificity of traditional blood tumor markers and imaging technologies are still to be greatly improved. Hence, novel approaches for the early detection of cancer are urgently needed.

The emergence of liquid biopsy technologies opens a new driveway for solving such issues. According to the definition of the National Cancer Institute of the United States, a liquid biopsy is a test done on a sample of blood to look for tumorigenic cancer cells or pieces of tumor cells’ DNA that are circulating in the blood [ 38 ]. This definition implies two main types of the current liquid biopsy: one that detects circulating tumor cells and the other that detects non-cellular material in the blood, including tumor DNA, RNA, and exosomes.

Circulating tumor cells (CTCs) are referred to as tumor cells that have been shed from the primary tumor location and have found their way to the peripheral blood. CTCs were first described in 1869 by an Australian pathologist, Thomas Ashworth, in a patient with metastatic cancer [ 39 ]. The importance of CTCs in modern cancer research began in the mid-1990s with the demonstration that CTCs exist early in the course of the disease.

It is estimated that there are about 1–10 CTCs per mL in whole blood of patients with metastatic cancer, even fewer in patients with early-stage cancer [ 40 ]. For comparison, 1 mL of blood contains a few million white blood cells and a billion erythrocytes. The identification of CTCs, being in such low frequency, requires some special tumoral markers (e.g., EpCAM and cytokeratins) to capture and isolate them. Unfortunately, the common markers for recognizing the majority of CTCs are not effective enough for clinical application [ 41 ]. Although accumulated evidences have shown that the presence of CTCs is a strong negative prognostic factor in the patients with metastatic breast, lung and colorectal cancers, detecting CTCs might not be an ideal branch to hold on for the hope of early cancer detection [ 42 , 43 , 44 , 45 ].

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the circulatory system, which is mainly derived from the tumor cell death through necrosis and/or apoptosis [ 46 ]. Given its origin, ctDNA inherently carries cancer-specific genetic and epigenetic aberrations, which can be used as a surrogate source of tumor DNA for cancer diagnosis and prognostic prediction. Ideally, as a noninvasive tumor early screening tool, a liquid biopsy test should be able to detect many types of cancers and provide the information of tumor origin for further specific clinical management. In fact, the somatic mutations of ctDNA in different types of tumor are highly variable, even in the different individuals with the same type of tumor [ 47 ]. Additionally, most tumors do not possess driver mutations, with some notable exceptions, which make the somatic mutations of ctDNA not suitable for early detection of the tumor.

Increased methylation of the promoter regions of tumor suppressor genes is an early event in many types of tumor, suggesting that altered ctDNA methylation patterns could be one of the first detectable neoplastic changes associated with tumorigenesis [ 48 ]. ctDNA methylation profiling provides several advantages over somatic mutation analysis for cancer detection including higher clinical sensitivity and dynamic range, multiple detectable methylation target regions, and multiple altered CpG sites within each targeted genomic region. Further, each methylation marker is present in both cancer tissue and ctDNA, whereas only a fraction of mutations present in cancer tissue could be detected in ctDNA.

In 2017, there were two inspiring studies that revealed the values of using ctDNA methylation analysis for cancer early diagnosis [ 49 , 50 ]. After partitioning the human genome into blocks of tightly coupled CpG methylation sites, namely methylation haplotype blocks (MHBs), Guo and colleagues performed tissue-specific methylation analyses at the MHBs level to accurately determine the tissue origin of the cancer using ctDNA from their enrolled patients [ 49 ]. In another study, Xu and colleagues identified a hepatocellular carcinoma (HCC) enriched methylation marker panel by comparing the HCC tissue and blood leukocytes from normal individuals and showed that methylation profiles of HCC tumor DNA and matched plasma ctDNA were highly correlated. In this study, after quantitative measurement of the methylation level of candidate markers in ctDNA from a large cohort of 1098 HCC patients and 835 normal controls, ten methylation markers were selected to construct a diagnostic prediction model. The proposed model demonstrated a high diagnostic specificity and sensitivity, and was highly correlated with tumor burden, treatment response, and tumor stage [ 50 ].

With the rapid development of highly sensitive detection methods, especially the technologies of massively parallel sequencing or next-generation sequencing (NGS)-based assays and digital PCR (dPCR), we strongly believe that the identification of a broader “pan-cancer” methylation panel applied for ctDNA analyses, probably in combination with detections of somatic mutation and tumor-derived exosomes, would allow more effective screening for common cancers in the near future.

Edison Liu 1 , Hui-Yan Luo 2 .

[email protected]; [email protected]

Question 100: Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells?

Though several anticancer agents are approved to treat different types of cancers, their full potentials have been limited due to the occurrence of drug resistance. Resistance to anticancer drugs develops by a variety of mechanisms, one of which is increased drug efflux by transporters. The ATP-binding cassette (ABC) family drug efflux transporter P-glycoprotein (P-gp or multi-drug resistance protein 1 [MDRP1]) has been extensively studied and is known to play a major role in the development of multi-drug resistance (MDR) to chemotherapy [ 51 ]. In brief, overexpressed P-gp efflux out a wide variety of anticancer agents (e.g.: vinca alkaloids, doxorubicin, paclitaxel, etc.), leading to a lower concentration of these drugs inside cancer cells, thereby resulting in MDR. Over the past three decades, researchers have developed several synthetic P-gp inhibitors to block the efflux of anticancer drugs and have tested them in clinical trials, in combination with chemotherapeutic drugs. But none were found to be suitable enough in overcoming MDR and to be released for marketing, mainly due to the side effects associated with cross-reactivity towards other ABC transporters (BCRP and MRP-1) and the inhibition of CYP450 drug metabolizing enzymes [ 52 , 53 ].

On the other hand, a number of phytochemicals have been reported to have P-gp inhibitory activity. Moreover, detailed structure–activity studies on these phytochemicals have delineated the functional groups essential for P-gp inhibition [ 53 , 54 ]. Currently, one of the phytochemicals, tetrandrine (CBT-1 ® ; NSC-77037), is being used in a Phase I clinical trial ( http://www.ClinicalTrials.gov ; NCT03002805) in combination with doxorubicin for the treatment of metastatic sarcoma. Before developing phytochemicals or their derivatives as P-gp inhibitors, they need to be investigated thoroughly for their cross-reactivity towards other ABC transporters and CYP450 inhibition, in order to avoid toxicities similar to the older generation P-gp inhibitors that have failed in clinical trials.

Therefore, the selectivity for P-gp over other drug transporters and drug metabolizing enzymes should be considered as important criterias for the development of phytochemicals and their derivatives for overcoming MDR.

Mohane Selvaraj Coumar and Safiulla Basha Syed.

Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.

[email protected]; [email protected]

Question 101: Is cell migration a selectable trait in the natural evolution of carcinoma?

The propensity of solid tumor malignancy to metastasize remains the main cause of cancer-related death, an extraordinary unmet clinical need, and an unanswered question in basic cancer research. While dissemination has been traditionally viewed as a late process in the progression of malignant tumors, amount of evidence indicates that it can occur early in the natural history of cancer, frequently when the primary lesion is still barely detectable.

A prerequisite for cancer dissemination is the acquisition of migratory/invasive properties. However, whether, and if so, how the migratory phenotype is selected for during the natural evolution of cancer and what advantage, if any, it may provide to the growing malignant cells remains an open issue. The answers to these questions are relevant not only for our understating of cancer biology but also for the strategies we adopt in an attempt of curbing this disease. Frequently, indeed, particularly in pharmaceutical settings, targeting migration has been considered much like trying “to shut the stable door after the horse has bolted” and no serious efforts in pursuing this aim has been done.

We argue, instead, that migration might be an intrinsic cancer trait that much like proliferation or increased survival confers to the growing tumor masses with striking selective advantages. The most compelling evidence in support for this contention stems from studies using mathematical modeling of cancer evolution. Surprisingly, these works highlighted the notion that cell migration is an intrinsic, selectable property of malignant cells, so intimately intertwined with more obvious evolutionarily-driven cancer traits to directly impact not only on the potential of malignant cells to disseminate but also on their growth dynamics, and ultimately provide a selective evolutionary advantage. Whether in real life this holds true remains to be assessed, nevertheless, work of this kind defines a framework where the acquisition of migration can be understood in a term of not just as a way to spread, but also to trigger the emergence of malignant clones with favorable genetic or epigenetic traits.

Alternatively, migratory phenotypes might emerge as a response to unfavorable conditions, including the mechanically challenging environment which tumors, and particularly epithelial-derived carcinoma, invariably experience. Becoming motile, however, may not per se being fixed as phenotypic advantageous traits unless it is accompanied or is causing the emergence of specific traits, including drug resistance, self-renewal, and survival. This might be the case, for example, during the process of epithelial-to-mesenchymal transition (EMT), which is emerging as an overarching mechanism for dissemination. EMT, indeed, may transiently equip individual cancer cells not only with migratory/invasive capacity but also with increased resistance to drug treatment, stemness potential at the expanse of fast proliferation.

Thus, within this framework targeting pro-migratory genes, proteins and processes may become a therapeutically valid alternative or a complementary strategy not only to control carcinoma dissemination but also its progression and development.

Giorgio Scita.

IFOM, The FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), School of Medicine, University of Milan, Via Festa del Perdono 7, 20122, Italy.

[email protected]

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1 in 8 women in the United States will be diagnosed with breast cancer in her lifetime. In 2024, an estimated 310,720 women and 2,800 men will be diagnosed with invasive breast cancer. Chances are, you know at least one person who has been personally affected by breast cancer. 

But there is hope. When caught in its earliest, localized stages, the 5-year relative survival rate is 99%. Advances in early detection and treatment methods have significantly increased breast cancer survival rates in recent years, and there are currently over 4 million breast cancer survivors in the United States. 

Awareness of the facts and statistics surrounding breast cancer in the United States is key in empowering individuals to make informed decisions about their health.

Table of Contents 

Facts & statistics Incidence statistics Statistics by age Statistics by ethnicity Survival & mortality statistics Male breast cancer statistics Facts & statistics images

What Is Breast Cancer?

Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast. There are many different types of breast cancer that can affect both women and men.

To determine the extent of an individual’s breast cancer and if it has spread outside of the breast, the cancer is assigned a stage upon diagnosis . The early detection of breast cancer through annual mammography and other breast exams is the best defense against receiving a late-stage breast cancer diagnosis. Generally speaking, the earlier the cancer is detected, the greater the likelihood of a successful outcome.

Key Statistics & Facts About Breast Cancer In The United States

• In 2024, an estimated 310,720 new cases of invasive breast cancer will be diagnosed in women in the U.S., as well as 56,500 new cases of non-invasive (in situ) breast cancer . 1
• There are currently over 4 million breast cancer survivors in the United States. 1
• An estimated 42,250 U.S. women will die from breast cancer in 2024. 1  
• Risk of breast cancer recurrence depends on the type and staging of the initial breast cancer. Typically, the highest risk of recurrence is during the first few years after treatment and decreases over time. 2

Breast cancer incidence in the United States

• 1 in 8 women, or approximately 13% of the female population in the U.S., will develop breast cancer in their lifetime. 1
• Breast cancer is the most common cancer in American women , except for skin cancers. 1
• It is estimated that in 2024, approximately 30% of all new female cancer diagnoses will be breast cancer. 1
• On average, every 2 minutes a woman is diagnosed with breast cancer in the United States. 1
• Approximately 66% of breast cancer cases are diagnosed at a localized stage , before cancer has spread outside of the breast, when it is easiest to treat. 3
• The 5-year relative survival rate for cancer diagnosed at the localized stage is 99%. 1
• Approximately 15% of women diagnosed have a family history of breast cancer. Those with a first-degree relative (mother, sister, daughter) with breast cancer are nearly twice as likely to develop breast cancer themselves. 4

Breast cancer statistics by age

Though breast cancer in the United States occurs primarily in middle-aged and older women, age is not the only risk factor for a breast cancer diagnosis. Many risk factors beyond age may contribute to a breast cancer diagnosis, and sometimes there are no discernable risk factors at all.

• The average age of U.S. women diagnosed with breast cancer is 62 years old. 1
• Half of U.S. women who develop breast cancer are 62 years of age or younger when they are diagnosed. 1
• About 9% of all new breast cancer cases in the U.S. are diagnosed in women younger than 45 years old. 5
• Younger people, particularly those under age 35 at the time of their original breast cancer diagnosis, face a higher risk of breast cancer recurrence. 6

Breast cancer statistics by ethnicity

In the United States, breast cancer occurs within every racial and ethnic group. However, there are variations in statistics and outcomes across the different groups. Learn more about how NBCF is addressing disparities in breast cancer .

Black Women:

• The average age of Black women diagnosed with breast cancer is 60 years old , compared to an average age of 62 for white women. 1
• Black women are 40% more likely to die from breast cancer than white women. 1
• Black women have the lowest 5-year relative breast cancer survival rate of any racial or ethnic group. 1  
• 1 in 5 Black women with breast cancer are diagnosed with triple-negative breast cancer , which is harder to treat. This is higher than any other racial or ethnic group. 1

Hispanic Women:

• Overall, Hispanic women have a 20% lower incidence rate of breast cancer than other groups. 7
• Hispanic women are more likely than white women to be diagnosed with breast cancer at later stages when it is more difficult to treat. 1
• Breast cancer is the leading cause of cancer death for Hispanic women. 1

Asian, Pacific Islander, American Indian, and Alaska Native Women:

• Asian and Pacific Islander women are more likely to be diagnosed with localized (earlier stage, more treatable) breast cancer than other groups. 1
• Asian and Pacific Islander women have the lowest death rate from breast cancer . 1
• American Indian and Alaska Native women have the lowest incidence rate of developing breast cancer. 1
• Chinese and Japanese women have the highest breast cancer survival rates. 7

Breast cancer survival & mortality statistics

Breast cancer survival rates are calculated using different forms of data, including the type and staging of breast cancer at diagnosis. These rates give an idea of what percentage of people with the same type and stage of cancer are still alive after a certain time period—usually 5 years—after they were diagnosed. This is called the 5-year relative survival rate.

• The 5-year relative survival rate in the U.S. for all types and stages of breast cancer combined is 91%. 1
• The 5-year relative survival rate in the U.S. of localized ( early stage ) breast cancer is 99%. 1

• Breast cancer is the second leading cause of cancer death in U.S. women, behind lung cancer. The chance that a woman will die from breast cancer is 1 in 39, or about 2.5%. 1
• In 2024, an estimated 42,250 women will die from breast cancer in the U.S. 1
• Breast cancer death rates have slowly decreased since 1989, for an overall decline of 43% through 2020. This is in part due to better screening and early detection efforts, increased awareness, and continually improving treatment options. 1
• Women who receive regular screenings for breast cancer have a 26% lower breast cancer death rate than women who do not receive screenings. 5

Breast cancer in men statistics

All people are born with some breast cells and tissue, including men. Although rare, men get breast cancer too . 

• In 2024, an estimated 2,800 men will be diagnosed with invasive breast cancer in the United States. 1
• An estimated 530 U.S. men will die from breast cancer in 2024. 1
• The lifetime risk of a U.S. man developing breast cancer is about 1 in 726. 1
• Black men with breast cancer tend to have a worse prognosis, or outlook, than white men with breast cancer. 1

Awareness is the first step in making informed choices about breast health. Donate now to help NBCF support more women and men facing breast cancer in communities throughout the United States.

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Breast Cancer Disparities

Sources: 1 American Cancer Society ( cancer.org ) 2 Johns Hopkins ( hopkinsmedicine.org ) 3 National Cancer Institute ( cancer.gov ) 4  BreastCancer.org ( breastcancer.org ) 5  Centers for Disease Control & Prevention ( cdc.gov ) 6  Mayo Clinic ( mayoclinic.org ) 7  National Institutes of Health ( nih.gov )

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Breast Cancer Research Table Topics

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Breast cancer

• Breast cancer caused 670 000 deaths globally in 2022.
• Roughly half of all breast cancers occur in women with no specific risk factors other than sex and age.
• Breast cancer was the most common cancer in women in 157 countries out of 185 in 2022.
• Breast cancer occurs in every country in the world.
• Approximately 0.5–1% of breast cancers occur in men.

Breast cancer is a disease in which abnormal breast cells grow out of control and form tumours. If left unchecked, the tumours can spread throughout the body and become fatal.

Breast cancer cells begin inside the milk ducts and/or the milk-producing lobules of the breast. The earliest form (in situ) is not life-threatening and can be detected in early stages. Cancer cells can spread into nearby breast tissue (invasion). This creates tumours that cause lumps or thickening. 

Invasive cancers can spread to nearby lymph nodes or other organs (metastasize). Metastasis can be life-threatening and fatal.

Treatment is based on the person, the type of cancer and its spread. Treatment combines surgery, radiation therapy and medications.

Scope of the problem

In 2022, there were 2.3 million women diagnosed with breast cancer and 670 000 deaths globally. Breast cancer occurs in every country of the world in women at any age after puberty but with increasing rates in later life.   Global estimates reveal striking inequities in the breast cancer burden according to human development. For instance, in countries with a very high Human Development Index (HDI), 1 in 12 women will be diagnosed with breast cancer in their lifetime and 1 in 71 women die of it.

In contrast, in countries with a low HDI; while only 1 in 27 women is diagnosed with breast cancer in their lifetime, 1 in 48 women will die from it.

Who is at risk?

Female gender is the strongest breast cancer risk factor. Approximately 99% of breast cancers occur in women and 0.5–1% of breast cancers occur in men. The treatment of breast cancer in men follows the same principles of management as for women.

Certain factors increase the risk of breast cancer including increasing age, obesity, harmful use of alcohol, family history of breast cancer, history of radiation exposure, reproductive history (such as age that menstrual periods began and age at first pregnancy), tobacco use and postmenopausal hormone therapy. Approximately half of breast cancers develop in women who have no identifiable breast cancer risk factor other than gender (female) and age (over 40 years). 

Family history of breast cancer increases the risk of breast cancer, but most women diagnosed with breast cancer do not have a known family history of the disease. Lack of a known family history does not necessarily mean that a woman is at reduced risk.

Certain inherited high penetrance gene mutations greatly increase breast cancer risk, the most dominant being mutations in the genes BRCA1, BRCA2 and PALB-2. Women found to have mutations in these major genes may consider risk reduction strategies such as surgical removal of both breasts or chemoprevention strategies. 

Signs and symptoms

Most people will not experience any symptoms when the cancer is still early hence the importance of early detection.

Breast cancer can have combinations of symptoms, especially when it is more advanced. Symptoms of breast cancer can include:

• a breast lump or thickening, often without pain 
• change in size, shape or appearance of the breast
• dimpling, redness, pitting or other changes in the skin
• change in nipple appearance or the skin surrounding the nipple (areola) 
• abnormal or bloody fluid from the nipple.

People with an abnormal breast lump should seek medical care, even if the lump does not hurt. 

Most breast lumps are not cancer. Breast lumps that are cancerous are more likely to be successfully treated when they are small and have not spread to nearby lymph nodes. 

Breast cancers may spread to other areas of the body and trigger other symptoms. Often, the most common first detectable site of spread is to the lymph nodes under the arm although it is possible to have cancer-bearing lymph nodes that cannot be felt. 

Over time, cancerous cells may spread to other organs including the lungs, liver, brain and bones. Once they reach these sites, new cancer-related symptoms such as bone pain or headaches may appear. 

Treatment for breast cancer depends on the subtype of cancer and how much it has spread outside of the breast to lymph nodes (stages II or III) or to other parts of the body (stage IV).

Doctors combine treatments to minimize the chances of the cancer coming back (recurrence). These include:

• surgery to remove the breast tumour
• radiation therapy to reduce recurrence risk in the breast and surrounding tissues
• medications to kill cancer cells and prevent spread, including hormonal therapies, chemotherapy or targeted biological therapies.

Treatments for breast cancer are more effective and are better tolerated when started early and taken to completion. 

Surgery may remove just the cancerous tissue (called a lumpectomy) or the whole breast (mastectomy). Surgery may also remove lymph nodes to assess the cancer’s ability to spread.

Radiation therapy treats residual microscopic cancers left behind in the breast tissue and/or lymph nodes and minimizes the chances of cancer recurring on the chest wall.

Advanced cancers can erode through the skin to cause open sores (ulceration) but are not necessarily painful. Women with breast wounds that do not heal should seek medical care to have a biopsy performed.

Medicines to treat breast cancers are selected based on the biological properties of the cancer as determined by special tests (tumour marker determination).  The great majority of drugs used for breast cancer are already on the WHO Essential Medicines List (EML).

Lymph nodes are removed at the time of cancer surgery for invasive cancers. Complete removal of the lymph node bed under the arm (complete axillary dissection) in the past was thought to be necessary to prevent the spread of cancer. A smaller lymph node procedure called “sentinel node biopsy” is now preferred as it has fewer complications. 

Medical treatments for breast cancers, which may be given before (“neoadjuvant”) or after (“adjuvant”) surgery, is based on the biological subtyping of the cancers. Certain subtypes of breast cancer are more aggressive than others such as triple negative (those that do not express estrogen receptor (ER), progesterone receptor (PR) or HER-2 receptor). Cancer that express the estrogen receptor (ER) and/or progesterone receptor (PR) are likely to respond to endocrine (hormone) therapies such as tamoxifen or aromatase inhibitors.  These medicines are taken orally for 5–10 years and reduce the chance of recurrence of these “hormone-positive” cancers by nearly half. Endocrine therapies can cause symptoms of menopause but are generally well tolerated.

Cancers that do not express ER or PR are “hormone receptor negative” and need to be treated with chemotherapy unless the cancer is very small. The chemotherapy regimens available today are very effective in reducing the chances of cancer spread or recurrence and are generally given as outpatient therapy. Chemotherapy for breast cancer generally does not require hospital admission in the absence of complications.

Breast cancers that independently overexpress a molecule called the HER-2/neu oncogene (HER-2 positive) are amenable to treatment with targeted biological agents such as trastuzumab. When targeted biological therapies are given, they are combined with chemotherapy to make them effective at killing cancer cells.

Radiotherapy plays a very important role in treating breast cancer. With early-stage breast cancers, radiation can prevent a woman having to undergo a mastectomy. With later stage cancers, radiotherapy can reduce cancer recurrence risk even when a mastectomy has been performed. For advanced stages of breast cancer, in some circumstances, radiation therapy may reduce the likelihood of dying of the disease.

The effectiveness of breast cancer therapies depends on the full course of treatment. Partial treatment is less likely to lead to a positive outcome. 

Global impact

Age-standardized breast cancer mortality in high-income countries dropped by 40% between the 1980s and 2020 (1) . Countries that have succeeded in reducing breast cancer mortality have been able to achieve an annual breast cancer mortality reduction of 2–4% per year. 

The strategies for improving breast cancer outcomes depend on fundamental health system strengthening to deliver the treatments that are already known to work. These are also important for the management of other cancers and other non-malignant noncommunicable diseases (NCDs). For example, having reliable referral pathways from primary care facilities to district hospitals to dedicated cancer centres.

The establishment of reliable referral pathways from primary care facilities to secondary hospitals to dedicated cancer centres is the same approach as is required for the management of cervical cancer, lung cancer, colorectal cancer and prostate cancer. To that end, breast cancer is a so-called index disease whereby pathways are created that can be followed for the management of other cancers. 

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Questions to Ask Your Doctor About Breast Cancer

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• Breast Cancer Videos
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• Infographic: 7 Things to Know About Getting a Mammogram
• Frequently Asked Questions About the American Cancer Society’s Breast Cancer Screening Guideline

It’s important to be able to have frank, open discussions with your cancer care team. They want to answer all of your questions so that you can make informed treatment and life decisions. Here are some questions that you can use to help better understand your cancer and your treatment options.

When you’re told you have breast cancer

When deciding on a treatment plan, if you need surgery, during treatment, after treatment, preparing your list of questions.

• Exactly what type of breast cancer do I have?
• How big is the cancer? Where exactly is it?
• Has the cancer spread to my lymph nodes or other organs?
• What is the stage of my cancer? What does it mean?
• Will I need any other tests before we can decide on treatment?
• Do I need to see any other doctors or health professionals?
• What is the hormone receptor status of my cancer? What does this mean?
• What is the HER2 status of my cancer? What does this mean?
• What is the  grade  of my cancer? What does this mean?
• How do these factors affect my treatment options and long-term outlook (prognosis)?
• What are my chances of survival, based on my cancer as you see it?
• Should I think about genetic testing ? What are my testing options? Should I take a home-based genetic test? What would be the reasons for and against testing?
• How do I get a copy of my pathology report?
• If I’m worried about the costs and insurance coverage for my diagnosis and treatment, who can help me?
• How much experience do you have treating this type of cancer?
• Should I get a second opinion ? How do I do that? Will getting a second opinion delay my treatment and can that affect my outcome? 
• What are my treatment choices?
• What treatment do you recommend and why?
• Should I think about taking part in a clinical trial ?
• What would the goal of the treatment be?
• How soon do I need to start treatment?
• How long will treatment last? What will it be like? Where will it be done?
• Should my biopsy tissue be sent for a gene expression test to help decide if chemotherapy might be helpful for me?
• Are there other molecular or protein tests that need to be done on my cancer tissue to help decide my treatment options?
• What should I do to get ready for treatment?
• What risks or side effects are there to the treatments you suggest? Are there things I can do to reduce these side effects?
• How will treatment affect my daily activities? Can I still work fulltime?
• Will I lose my hair? If so, what can I do about it?
• Will I go through menopause as a result of the treatment? Will I be able to have children after treatment? Would I be able to breastfeed?
• Do I have time to freeze my eggs before starting treatment? What are my options?
• What are the chances the cancer will come back (recur) after this treatment?
• What would we do if the treatment doesn’t work or if the cancer comes back?
• What if I have transportation problems getting to and from treatment?
• Is breast-conserving surgery (lumpectomy) an option for me? Why or why not?
• What are the positive and negative sides of breast-conserving surgery versus mastectomy?
• How many surgeries like mine have you done?
• Will you have to take out lymph nodes? If so, would you advise a sentinel lymph node biopsy? Why or why not?
• What side effects might lymph node removal cause?
• How long will I be in the hospital?
• Will I have stitches or staples at the surgery site? Will there be a drain (tube) coming out of the site?
• How do I care for the surgery site? Will I need someone to help me?
• What will my breasts look and feel like after my surgery? Will I have normal feeling in them?
• What will the scar look like?
• Is breast reconstruction surgery an option if I want it? What would it mean in my case?
• Can I have reconstruction at the same time as the surgery to remove the cancer? What are the reasons for and against having it done right away or waiting until later?
• What types of reconstruction might be options for me?
• Could you recommend a plastic surgeon I could speak to about reconstruction options?
• Will I need a breast form (prosthesis), and if so, where can I get one?
• Do I need to stop taking any medications or supplements before surgery?
• When should I call your office if I’m having side effects or concerns?

Once treatment begins, you’ll need to know what to expect and what to look for. Not all of these questions may apply to you, but asking the ones that do may be helpful.

• How will we know if the treatment is working?
• Is there anything I can do to help manage side effects?
• What symptoms or side effects should I tell you about right away?
• How can I reach you on nights, holidays, or weekends?
• Will I need to change what I eat during treatment?
• Are there any limits on what I can do?
• Can I exercise during treatment? If so, what kind of exercise should I do, and how often?
• Can you suggest a mental health professional I can see if I start to feel overwhelmed, depressed, or distressed?
• Will I need special tests, such as imaging scans or blood tests during treatment? If so, how often?
• Will I need a special diet after treatment?
• Am I at risk for lymphedema ?
• What can I do to reduce my risk for lymphedema?
• What should I do if I notice swelling in my arm?
• What other symptoms should I watch for? What kind of exercise should I do now?
• What type of follow-up will I need after treatment?
• How often will I need to have follow-up exams, blood tests, or imaging tests?
• How will we know if the cancer has come back? What should I watch for?
• What will my options be if the cancer comes back?

It’s important to be able to have frank, open discussions with your cancer care team. They want to answer all of your questions, so that you can make informed treatment and life decisions.

Not all of these questions will apply to you, but they should help get you started. Be sure to write down some questions of your own. For instance, you might want more information about recovery times or you may want to ask about nearby or online support groups where you can talk with other women going through similar situations. You may also want to ask if you qualify for any  clinical trials .

Don’t be afraid to take notes and tell the doctors or nurses when you don’t understand what they’re saying. You might want to bring another person with you when you see your doctor and have them take notes to help you remember what was said.

Keep in mind that doctors aren’t the only ones who can give you information. Other health care professionals, such as nurses and social workers, can answer some of your questions.

To find out more about speaking with your health care team, see The Doctor-Patient Relationship .

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Last Revised: November 8, 2021

American Cancer Society medical information is copyrighted material. For reprint requests, please see our Content Usage Policy .

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Breast Cancer May Spread by Recruiting Nearby Sensory Nerves

September 20, 2024 , by Sharon Reynolds

A new study shows how cells in breast tumors (1) recruit nearby nerves to (2) move into the tumors and (3) help the cancer spread to other parts of the body.

The body is packed with sensory nerves that pass sensations like touch, pain, and temperature to the nervous system. Such nerves are tangled through tissues in every organ and many tumors. And according to a new study, breast tumors have an unusual way of exploiting these nerves to help them spread to other parts of the body.

Previous research has found that direct contact between cancer cells and certain kinds of nerve cells can fuel tumor growth. Scientists have even observed some types of cancer cells crawling along nerves to spread ( metastasize ), explained the study’s lead investigator, Veena Padmanaban, Ph.D., a postdoctoral researcher at Rockefeller University. 

Although the research team’s work implicated sensory nerves as a critical contributor to breast cancer metastasis, they found that breast cancer cells use them in an entirely different way. The team identified a complex process that starts with blood vessels within tumors releasing a molecule that draws nerves closer to them. The biological changes initiated by this close proximity eventually leads to the activation of metastasis-fueling genes in the cancer cells .

“This is a contact-independent mechanism. Cancer cells don’t have to be touching the nerves for this [communication] to happen,” Dr. Padmanaban explained.

The findings were published August 7 in Nature .

The discovery of this process provides an opportunity for developing treatments that stop it, the study team believes, and potentially prevent breast cancer from spreading. In fact, in the study, they showed that a drug used to prevent nausea and vomiting caused by chemotherapy can block one of the steps of the nerve – cancer cell interaction and stop tumor growth and metastasis in mouse models of breast cancer.

Harnessing the nervous system to fuel tumor growth

Over the last decade, researchers have begun to uncover the intricate processes by which the nervous system helps tumors grow and spread. The fact that the nervous system appears to contribute to tumor growth isn’t necessarily surprising, said Brunilde Gril, Ph.D., of NCI's Division of Cancer Biology , who was not involved in the study. 

“The nervous system is involved in many physiological functions of the body,” Dr. Gril said. For example, nerves support the development of organs and regulate functions of epithelial cells, which are the most abundant cells in the body and give rise to most breast cancers, she explained.

Previous research from the lab of the study’s senior investigator, Sohail Tavazoie, M.D., Ph.D., found that blood vessels in breast tumors that had spread in the body express a protein called SLIT2, which is known to play a role in directing where nerves grow in the body.

In their new study, funded in part by NCI, Dr. Padmanaban and her colleagues from the Tavazoie lab wanted to see if nerves within the tumor microenvironment interacted with breast cancer cells and whether they helped drive tumor growth and spread.

In a series of experiments, they found that blood vessels within tumors had to express SLIT2 to draw in sensory nerves. For example, when they transplanted human breast cancer cells into mice and deleted SLIT2 from endothelial cells , the resulting tumors lost their ability to attract sensory nerves.

Looking at tumor samples collected from people with breast cancer, the team found that people whose breast tumors had a greater abundance of sensory nerves were more likely to have their cancers metastasize. They observed a similar effect in mice implanted with breast cancer cells. 

Fueling metastasis from a distance

In these experiments, although the sensory nerves appeared to be fueling tumor growth and spread, the two cell types weren’t physically touching, the researchers found. So how were the nerves exerting their effect?

By analyzing and testing substances secreted by both the nerves and the breast cancer cells, the researchers found that a tiny protein called substance P released by sensory nerves substantially boosted growth and spread of breast cancer cells growing in laboratory dishes. Large amounts of substance P were found in samples of human breast tumors that had spread to the lymph nodes.

In mice with breast tumors, blocking substance P greatly reduced tumor growth and metastasis.

But how exactly was substance P promoting metastasis? Dr. Padmanaban and her colleagues found that substance P induces its effects by binding to a receptor on tumor cells called TACR1.

Surprisingly, when this binding occurred, the end result was death for the small subset of breast tumor cells that expressed high levels of the receptor.

When these cells died, they released a type of genetic material called ssRNA, which is normally a signal to the body that a viral infection has occurred. 

This ssRNA switched on another receptor found on cancer cells, called TLR7. While TLR7 is involved in the body’s normal immune response , numerous studies have shown that it can also help tumor cells spread.

In this scenario, metastasis “appears to be dependent on a small but significant number of cancer cells dying,” Dr. Tavazoie explained. “But by dying, they’re helping the rest of the cancer cells in the tumor proliferate and metastasize.”

Can this metastatic process be stopped?

With so many pieces having to fit into place for this process to work, the researchers wondered whether—like pulling out the wrong piece in a Jenga tower—disrupting just one could cause the whole cycle to break down. 

Aprepitant, sold under the brand names of Cinvanti and Emend in the United States, is approved to help treat nausea and vomiting caused by some cancer treatments. It works by blocking TACR1, one of the first molecules involved in this newly discovered metastatic process.

In several mouse models of metastatic breast cancer, tumor growth slowed when the researchers treated the mice with aprepitant. And in other mouse models, those that got the drug were much less likely to develop metastases than those that didn’t.

Although aprepitant is an approved drug, it has never been tested in people for potential effects on tumor progression and metastasis, Dr. Gril explained. But the promising results of the experiments in mice suggest that more research to evaluate its potential long-term use and interactions with other cancer treatments are warranted, she added.

The idea of using aprepitant as part of cancer treatment “adds to a bigger conversation that’s been going on about repurposing drugs for cancer,” Dr. Padmanaban said. For example, other researchers recently found that beta blockers prescribed to treat high blood pressure may have an antimetastatic effect. Clinical trials are now testing this idea .

It's not yet clear how early the communication between sensory nerves and cancer cells starts during breast tumor formation, or if other types of cells in the body, such as immune cells, may also play a role in this process, Dr. Padmanaban said, adding “there’s so much more work to be done.”

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Receiving a mammogram

During a mammogram, you stand in front of an X-ray machine designed for mammography. A technician places your breast on a platform and positions the platform to match your height. The technician helps you position your head, arms and torso to allow an unobstructed view of your breast.

Getting a breast MRI involves lying face down on a padded scanning table. The breasts fit into a hollow space in the table. The hollow has coils that get signals from the MRI . The table slides into the large opening of the MRI machine.

Core needle biopsy

A core needle biopsy uses a long, hollow tube to obtain a sample of tissue. Here, a biopsy of a suspicious breast lump is being done. The sample is sent to a lab for testing and evaluation by doctors, called pathologists. They specialize in analyzing blood and body tissue.

Breast cancer diagnosis often begins with an exam and a discussion of your symptoms. Imaging tests can look at the breast tissue for anything that's not typical. To confirm whether there is cancer or not, a sample of tissue is removed from the breast for testing.

Breast exam

During a clinical breast exam, a healthcare professional looks at the breasts for anything that's not typical. This might include changes in the skin or to the nipple. Then the health professional feels the breasts for lumps. The health professional also feels along the collarbones and around the armpits for lumps.

A mammogram is an X-ray of the breast tissue. Mammograms are commonly used to screen for breast cancer. If a screening mammogram finds something concerning, you might have another mammogram to look at the area more closely. This more-detailed mammogram is called a diagnostic mammogram. It's often used to look closely at both breasts.

Breast ultrasound

Ultrasound uses sound waves to make pictures of structures inside the body. A breast ultrasound may give your healthcare team more information about a breast lump. For example, an ultrasound might show whether the lump is a solid mass or a fluid-filled cyst. The healthcare team uses this information to decide what tests you might need next.

MRI machines use a magnetic field and radio waves to create pictures of the inside of the body. A breast MRI can make more-detailed pictures of the breast. Sometimes this method is used to look closely for any other areas of cancer in the affected breast. It also might be used to look for cancer in the other breast. Before a breast MRI , you usually receive an injection of dye. The dye helps the tissue show up better in the images.

Removing a sample of breast cells for testing

A biopsy is a procedure to remove a sample of tissue for testing in a lab. To get the sample, a healthcare professional puts a needle through the skin and into the breast tissue. The health professional guides the needle using images created with X-rays, ultrasound or another type of imaging. Once the needle reaches the right place, the health professional uses the needle to draw out tissue from the breast. Often, a marker is placed in the spot where the tissue sample was removed. The small metal marker will show up on imaging tests. The marker helps your healthcare team monitor the area of concern.

Testing cells in the lab

The tissue sample from a biopsy goes to a lab for testing. Tests can show whether the cells in the sample are cancerous. Other tests give information about the type of cancer and how quickly it's growing. Special tests give more details about the cancer cells. For example, tests might look for hormone receptors on the surface of the cells. Your healthcare team uses the results from these tests to make a treatment plan.

Staging breast cancer

Once your healthcare team diagnoses your breast cancer, you may have other tests to figure out the extent of the cancer. This is called the cancer's stage. Your healthcare team uses your cancer's stage to understand your prognosis.

Complete information about your cancer's stage may not be available until after you undergo breast cancer surgery.

Tests and procedures used to stage breast cancer may include:

• Blood tests, such as a complete blood count and tests to show how well the kidneys and liver are working.
• Positron emission tomography scan, also called a PET scan.

Not everyone needs all of these tests. Your healthcare team picks the right tests based on your specific situation.

Breast cancer stages range from 0 to 4. A lower number means the cancer is less advanced and more likely to be cured. Stage 0 breast cancer is cancer that is contained within a breast duct. It hasn't broken out to invade the breast tissue yet. As the cancer grows into the breast tissue and gets more advanced, the stages get higher. A stage 4 breast cancer means that the cancer has spread to other parts of the body.

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• Breast cancer staging
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• 3D mammogram
• BRCA gene test
• Breast cancer risk assessment
• Breast self-exam for breast awareness
• Chest X-rays
• Complete blood count (CBC)
• Molecular breast imaging
• Positron emission tomography scan
• Sentinel node biopsy

Breast cancer treatment often starts with surgery to remove the cancer. Most people with breast cancer will have other treatments after surgery, such as radiation, chemotherapy and hormone therapy. Some people may have chemotherapy or hormone therapy before surgery. These medicines can help shrink the cancer and make it easier to remove.

Your treatment plan will depend on your particular breast cancer. Your healthcare team considers the stage of the cancer, how quickly it's growing and whether the cancer cells are sensitive to hormones. Your care team also considers your overall health and what you prefer.

There are many options for breast cancer treatment. It can feel overwhelming to consider all the options and make complex decisions about your care. Consider seeking a second opinion from a breast specialist in a breast center or clinic. Talk to breast cancer survivors who have faced the same decision.

• Breast cancer surgery

A lumpectomy involves removing the cancer and some of the healthy tissue that surrounds it. This illustration shows one possible incision that can be used for this procedure, though your surgeon will determine the approach that's best for your particular situation.

During a total mastectomy, the surgeon removes the breast tissue, nipple, areola and skin. This procedure also is known as a simple mastectomy. Other mastectomy procedures may leave some parts of the breast, such as the skin or the nipple. Surgery to create a new breast is optional. It may be done at the same time as mastectomy surgery or it can be done later.

Sentinel node biopsy identifies the first few lymph nodes into which a tumor drains. The surgeon uses a harmless dye and a weak radioactive solution to locate the sentinel nodes. The nodes are removed and tested for signs of cancer.

Breast cancer surgery typically involves a procedure to remove the breast cancer and a procedure to remove some nearby lymph nodes. Operations used to treat breast cancer include:

Removing the breast cancer. A lumpectomy is surgery to remove the breast cancer and some of the healthy tissue around it. The rest of the breast tissue isn't removed. Other names for this surgery are breast-conserving surgery and wide local excision. Most people who have a lumpectomy also have radiation therapy.

Lumpectomy might be used to remove a small cancer. Sometimes you can have chemotherapy before surgery to shrink the cancer so that lumpectomy is possible.

Removing all of the breast tissue. A mastectomy is surgery to remove all breast tissue from a breast. The most common mastectomy procedure is total mastectomy, also called simple mastectomy. This procedure removes all of the breast, including the lobules, ducts, fatty tissue and some skin, including the nipple and areola.

Mastectomy might be used to remove a large cancer. It also might be needed when there are multiple areas of cancer within one breast. You might have a mastectomy if you can't have or don't want radiation therapy after surgery.

Some newer types of mastectomy procedures might not remove the skin or nipple. For instance, a skin-sparing mastectomy leaves some skin. A nipple-sparing mastectomy leaves the nipple and the skin around it, called the areola. These newer operations can improve the look of the breast after surgery, but they aren't options for everyone.

• Removing a few lymph nodes. A sentinel node biopsy is an operation to take out some lymph nodes for testing. When breast cancer spreads, it often goes to the nearby lymph nodes first. To see if the cancer has spread, a surgeon removes some of the lymph nodes near the cancer. If no cancer is found in those lymph nodes, the chance of finding cancer in any of the other lymph nodes is small. No other lymph nodes need to be removed.
• Removing several lymph nodes. Axillary lymph node dissection is an operation to remove many lymph nodes from the armpit. Your breast cancer surgery might include this operation if imaging tests show the cancer has spread to the lymph nodes. It also might be used if cancer is found in a sentinel node biopsy.
• Removing both breasts. Some people who have cancer in one breast may choose to have their other breast removed, even if it doesn't have cancer. This procedure is called a contralateral prophylactic mastectomy. It might be an option if you have a high risk of getting cancer in the other breast. The risk might be high if you have a strong family history of cancer or have DNA changes that increase the risk of cancer. Most people with breast cancer in one breast will never get cancer in the other breast.

Complications of breast cancer surgery depend on the procedures you choose. All operations have a risk of pain, bleeding and infection. Removing lymph nodes in the armpit carries a risk of arm swelling, called lymphedema.

You may choose to have breast reconstruction after mastectomy surgery. Breast reconstruction is surgery to restore shape to the breast. Options might include reconstruction with a breast implant or reconstruction using your own tissue. Consider asking your healthcare team for a referral to a plastic surgeon before your breast cancer surgery.

• Radiation therapy

External beam radiation uses high-powered beams of energy to kill cancer cells. Beams of radiation are precisely aimed at the cancer using a machine that moves around your body.

Radiation therapy treats cancer with powerful energy beams. The energy can come from X-rays, protons or other sources.

For breast cancer treatment, the radiation is often external beam radiation. During this type of radiation therapy, you lie on a table while a machine moves around you. The machine directs radiation to precise points on your body. Less often, the radiation can be placed inside the body. This type of radiation is called brachytherapy.

Radiation therapy is often used after surgery. It can kill any cancer cells that might be left after surgery. The radiation lowers the risk of the cancer coming back.

Side effects of radiation therapy include feeling very tired and having a sunburn-like rash where the radiation is aimed. Breast tissue also may look swollen or feel more firm. Rarely, more-serious problems can happen. These include damage to the heart or lungs. Very rarely, a new cancer can grow in the treated area.

• Chemotherapy

Chemotherapy treats cancer with strong medicines. Many chemotherapy medicines exist. Treatment often involves a combination of chemotherapy medicines. Most are given through a vein. Some are available in pill form.

Chemotherapy for breast cancer is often used after surgery. It can kill any cancer cells that might remain and lower the risk of the cancer coming back.

Sometimes chemotherapy is given before surgery. The chemotherapy might shrink the breast cancer so that it's easier to remove. Chemotherapy before surgery also might control cancer that spreads to the lymph nodes. If the lymph nodes no longer show signs of cancer after chemotherapy, surgery to remove many lymph nodes might not be needed. How the cancer responds to chemotherapy before surgery helps the healthcare team make decisions about what treatments might be needed after surgery.

When the cancer spreads to other parts of the body, chemotherapy can help control it. Chemotherapy may relieve symptoms of an advanced cancer, such as pain.

Chemotherapy side effects depend on which medicines you receive. Common side effects include hair loss, nausea, vomiting, feeling very tired and having an increased risk of getting an infection. Rare side effects can include premature menopause and nerve damage. Very rarely, certain chemotherapy medicines can cause blood cell cancer.

Hormone therapy

Hormone therapy uses medicines to block certain hormones in the body. It's a treatment for breast cancers that are sensitive to the hormones estrogen and progesterone. Healthcare professionals call these cancers estrogen receptor positive and progesterone receptor positive. Cancers that are sensitive to hormones use the hormones as fuel for their growth. Blocking the hormones can cause the cancer cells to shrink or die.

Hormone therapy is often used after surgery and other treatments. It can lower the risk that the cancer will come back.

If the cancer spreads to other parts of the body, hormone therapy can help control it.

Treatments that can be used in hormone therapy include:

• Medicines that block hormones from attaching to cancer cells. These medicines are called selective estrogen receptor modulators.
• Medicines that stop the body from making estrogen after menopause. These medicines are called aromatase inhibitors.
• Surgery or medicines to stop the ovaries from making hormones.

Hormone therapy side effects depend on the treatment you receive. The side effects can include hot flashes, night sweats and vaginal dryness. More-serious side effects include a risk of bone thinning and blood clots.

Targeted therapy

Targeted therapy uses medicines that attack specific chemicals in the cancer cells. By blocking these chemicals, targeted treatments can cause cancer cells to die.

The most common targeted therapy medicines for breast cancer target the protein HER2 . Some breast cancer cells make extra HER2 . This protein helps the cancer cells grow and survive. Targeted therapy medicine attacks the cells that are making extra HER2 and doesn't hurt healthy cells.

Many other targeted therapy medicines exist for treating breast cancer. Your cancer cells may be tested to see whether these medicines might help you.

Targeted therapy medicines can be used before surgery to shrink a breast cancer and make it easier to remove. Some are used after surgery to lower the risk that the cancer will come back. Others are used only when the cancer has spread to other parts of the body.

Immunotherapy

Immunotherapy is a treatment with medicine that helps the body's immune system to kill cancer cells. The immune system fights off diseases by attacking germs and other cells that shouldn't be in the body. Cancer cells survive by hiding from the immune system. Immunotherapy helps the immune system cells find and kill the cancer cells.

Immunotherapy might be an option for treating triple-negative breast cancer. Triple-negative breast cancer means that the cancer cells don't have receptors for estrogen, progesterone or HER2 .

Palliative care

Palliative care is a special type of healthcare that helps you feel better when you have a serious illness. If you have cancer, palliative care can help relieve pain and other symptoms. A team of healthcare professionals provides palliative care. The team can include doctors, nurses and other specially trained professionals. Their goal is to improve quality of life for you and your family.

Palliative care specialists work with you, your family and your care team to help you feel better. They provide an extra layer of support while you have cancer treatment. You can have palliative care at the same time as strong cancer treatments, such as surgery, chemotherapy or radiation therapy.

When palliative care is used along with all of the other appropriate treatments, people with cancer may feel better and live longer.

• Brachytherapy
• Breast cancer supportive therapy and survivorship
• Chemotherapy for breast cancer
• Hormone therapy for breast cancer
• Precision medicine for breast cancer
• Radiation therapy for breast cancer
• Common questions about breast cancer treatment
• Paulas story A team approach to battling breast cancer

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Alternative medicine

No alternative medicine treatments have been found to cure breast cancer. But complementary and alternative medicine therapies may help you cope with side effects of treatment.

Alternative medicine for fatigue

Many people with breast cancer have fatigue during and after treatment. This feeling of being very tired and worn down can continue for years. When combined with care from your healthcare team, complementary and alternative medicine therapies may help relieve fatigue.

Talk with your healthcare team about:

• Expressing your feelings. Find an activity that allows you to write about or discuss your emotions. Examples include writing in a journal, participating in a support group or talking to a counselor.
• Gentle exercise. If you get the OK from your healthcare team, start with gentle exercise a few times a week. Add more exercise, as you feel up to it. Consider walking, swimming, yoga and tai chi.
• Managing stress. Take control of the stress in your daily life. Try stress-reduction techniques such as muscle relaxation, visualization, and spending time with friends and family.

Coping and support

Some breast cancer survivors say their diagnosis felt overwhelming at first. It can be stressful to feel overwhelmed at the same time you need to make important decisions about your treatment. In time, you'll find ways to cope with your feelings. Until you find what works for you, it might help to:

Learn enough about your breast cancer to make decisions about your care

If you'd like to know more about your breast cancer, ask your healthcare team for the details of your cancer. Write down the type, stage and hormone receptor status. Ask for good sources of information where you can learn more about your treatment options.

Knowing more about your cancer and your options may help you feel more confident when making treatment decisions. Still, some people don't want to know the details of their cancer. If this is how you feel, let your care team know that too.

Talk with other breast cancer survivors

You may find it helpful and encouraging to talk to others who have been diagnosed with breast cancer. Contact a cancer support organization in your area to find out about support groups near you or online. In the United States, you might start with the American Cancer Society.

Find someone to talk with about your feelings

Find a friend or family member who is a good listener. Or talk with a clergy member or counselor. Ask your healthcare team for a referral to a counselor or other professional who works with people who have cancer.

Keep your friends and family close

Your friends and family can provide a crucial support network for you during your cancer treatment.

As you begin telling people about your breast cancer diagnosis, you'll likely get many offers for help. Think ahead about things you may want help with. Examples include listening when you want to talk or helping you with preparing meals.

Preparing for your appointment

Make an appointment with a doctor or other healthcare professional if you have any symptoms that worry you. If an exam or imaging test shows you might have breast cancer, your healthcare team will likely refer you to a specialist.

Specialists who care for people with breast cancer include:

• Breast health specialists.
• Breast surgeons.
• Doctors who specialize in diagnostic tests, such as mammograms, called radiologists.
• Doctors who specialize in treating cancer, called oncologists.
• Doctors who treat cancer with radiation, called radiation oncologists.
• Genetic counselors.
• Plastic surgeons.

What you can do to prepare

• Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
• Write down key personal information, including any major stresses or recent life changes.
• Write down your family history of cancer. Note any family members who have had cancer. Note how each member is related to you, the type of cancer, the age at diagnosis and whether each person survived.
• Make a list of all medicines, vitamins or supplements that you're taking.
• Keep all of your records that relate to your cancer diagnosis and treatment. Organize your records in a binder or folder that you can take to your appointments.
• Consider taking a family member or friend along. Sometimes it can be difficult to absorb all the information provided during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your healthcare professional.

Questions to ask your doctor

Your time with your healthcare professional is limited. Prepare a list of questions so that you can make the most of your time together. List your questions from most important to least important in case time runs out. For breast cancer, some basic questions to ask include:

• What type of breast cancer do I have?
• What is the stage of my cancer?
• Can you explain my pathology report to me? Can I have a copy for my records?
• Do I need any more tests?
• What treatment options are available for me?
• What are the benefits from each treatment you recommend?
• What are the side effects of each treatment option?
• Will treatment cause menopause?
• How will each treatment affect my daily life? Can I continue working?
• Is there one treatment you recommend over the others?
• How do you know that these treatments will benefit me?
• What would you recommend to a friend or family member in my situation?
• How quickly do I need to make a decision about cancer treatment?
• What happens if I don't want cancer treatment?
• What will cancer treatment cost?
• Does my insurance plan cover the tests and treatment you're recommending?
• Should I seek a second opinion? Will my insurance cover it?
• Are there any brochures or other printed material that I can take with me? What websites or books do you recommend?
• Are there any clinical trials or newer treatments that I should consider?

In addition to the questions that you've prepared, don't hesitate to ask other questions you think of during your appointment.

What to expect from your doctor

Be prepared to answer some questions about your symptoms and your health, such as:

• When did you first begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Cancer facts and figures 2023. American Cancer Society. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html. Accessed Aug. 9, 2023.
• Abraham J, et al., eds. Breast cancer. In: The Bethesda Handbook of Clinical Oncology. 6th ed. Kindle edition. Wolters Kluwer; 2023. Accessed March 30, 2023.
• Breast cancer. Cancer.Net. https://www.cancer.net/cancer-types/breast-cancer/view-all. Accessed Aug. 2, 2023.
• Mukwende M, et al. Erythema. In: Mind the Gap: A Handbook of Clinical Signs in Black and Brown Skin. St. George's University of London; 2020. https://www.blackandbrownskin.co.uk/mindthegap. Accessed Aug. 10, 2023.
• Townsend CM Jr, et al. Diseases of the breast. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 21st ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed Aug. 2, 2023.
• Breast cancer risk reduction. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1420. Accessed Aug. 2, 2023.
• Breast cancer prevention (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/breast/patient/breast-prevention-pdq. Accessed Aug. 2, 2023.
• Breast cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419. Accessed Aug. 2, 2023.
• Klimberg VS, et al., eds. Breast cancer diagnosis and techniques for biopsy. In: Bland and Copeland's The Breast: Comprehensive Management of Benign and Malignant Diseases. 6th ed. Elsevier; 2024. https://www.clinicalkey.com. Accessed Aug. 2, 2023.
• Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Aug. 2, 2023.
• Cancer-related fatigue. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1424. Accessed Aug. 2, 2023.
• Breast SPOREs. National Cancer Institute. https://trp.cancer.gov/spores/breast.htm. Accessed Aug. 9, 2023.
• Ami TR. Allscripts EPSi. Mayo Clinic. Jan. 31, 2023.
• Ami TR. Allscripts EPSi. Mayo Clinic. April 5, 2023.
• Member institutions. Alliance for Clinical Trials in Oncology. https://www.allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=%2FPublic%2FInstitutions. Accessed Aug. 9, 2023.
• Giridhar KV (expert opinion). Mayo Clinic. Oct. 18, 2023.
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• Beyond BRCA1/2: Pinpointing the risk of inherited breast cancer genes Oct. 28, 2023, 11:00 a.m. CDT
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• Patients with multiple tumors in one breast may not need mastectomy, research finds March 28, 2023, 09:00 p.m. CDT
• Mayo Clinic researchers identify women with twice the risk of cancer in both breasts Jan. 19, 2023, 02:58 p.m. CDT
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Immune to Cancer: The CRI Blog

Breast Cancer Awareness Month: How Immunotherapy Personalizes Treatment for This Common Cancer

Breast cancer is the second most common cancer among U.S. Women. When Breast Cancer Awareness Month was established in 1985, breast cancer was initially resistant to immunotherapy, considered “cold” and unresponsive. Nearly 40 years later, recent advances and clinical trials in immunotherapy are offering new hope, showing potential for better outcomes in breast cancer patients once considered untreatable with these methods.

Immunotherapy changed my life. It saved my life when I had no other options.” Karen Peterson, CRI ImmunoAdvocate and breast cancer survivor

Advocating with Energy and Grace

Thanks to scientific breakthroughs, the five-year survival rate for breast cancer patients has reached 89 percent, and it rises to an incredible 99 percent when the cancer is caught early. This progress has transformed the lives of countless survivors, including Karen Peterson , a CRI ImmunoAdvocate . Karen now dedicates her time to supporting others, sharing her own treatment journey to inspire hope and strength in current patients facing similar challenges. It’s stories like hers that remind CRI just how powerful donor support is in driving life-saving advances.

“I’ve got a second chance to really take care of this body that I’ve worked so hard to keep and stay alive,” Peterson said in conversation with CRI. “I take the responsibility of being an ImmunoAdvocate very seriously.”

Immunotherapy was not her first-line treatment. When Peterson’s cancer returned and spread two years after she was treated with chemotherapy and surgery, she enrolled in a clinical trial. Peterson was eager for treatment and became the first triple-negative breast cancer (TNBC) patient in her immunotherapy trial.  Eight weeks later, a CT scan showed that her cancer had shrunk by nearly three-quarters of its original size. TNBC is the most aggressive form of breast cancer, with a higher risk of relapse and metastasis. Unlike other types of breast cancer, TNBC doesn’t rely on hormone signals for its rapid growth, making patients ineligible for hormone therapy. As a result, TNBC patients often face more intensive treatments, combining chemotherapy, radiotherapy, and surgery.

“Standard care didn’t work for me, but everybody’s cancer journey is different,” the Harlem, NY resident explained. She stressed that dealing with cancer involves nuance, and there is no standard rule book. “I feel the renewed energy of patients and caregivers who I speak to about my journey and what it was like to be in a clinical trial. Any emotions, any reactions that you are having are all normal. Give yourself grace and space.”

The Challenges and Opportunities of the Current Breast Cancer IO Landscape

For over 40 years, the Cancer Research Institute (CRI) has been at the forefront of breast cancer immunotherapy, driving innovation and hope. In the 2023-24 fiscal year alone, CRI invested over $4 million in the fight against this devastating disease. CRI-funded scientists are leading groundbreaking research, from tackling TNBC to developing a lactate-responsive drug delivery system that targets cancer metabolism. Their relentless dedication is transforming patient care and bringing us closer to life-saving therapies, offering renewed hope for a future without cancer.

Giulia Furesi , PhD, a CRI Postdoctoral Fellow at Washington University School of Medicine, is researching how a protein in the tumor environment called Osterix impacts the immune system’s ability to fight breast cancer. She explains that breast cancer is difficult to treat because it’s not a one-size-fits-all disease—it’s made up of many different types.

“One significant development has been the growing use of immune checkpoint inhibitors , particularly for TNBC,” she said. Checkpoint inhibitors are an immunotherapy that takes the ‘brakes’ off the immune system, allowing the treatment to target and attack cancer cells. “These inhibitors, which have succeeded in other cancers, are now offering hope for patients with TNBC.”

What’s Next on the Horizon

Sarah Sammons, MD, associate director of the Metastatic Breast Cancer Program at the Dana-Farber Cancer Institute, spoke in detail at CRI’s 2023 Annual Patient Summit about challenges and progress regarding breast cancer immunotherapy. Dr. Sammons noted that immunotherapy has made remarkable progress in the past decade and is now a first-line treatment for some breast cancer subtypes, including TNBC.

“ Pembrolizumab (commonly known by its brand name, Keytruda® ) with five months of chemotherapy before surgery for stage 2 and 3 TNBC has improved cure rates and has improved the pathological complete response,” she said during the patient summit. A pathological complete response means there are no traces of cancer in tissue examined after treatment. “These patients have a 93 to 94 percent chance of being cured of their cancer.”

Dr. Sammons stressed that clinical trials are crucial for discovering new treatments, as they are the pathway for approving drugs for all types of cancer. Currently, there are promising late-stage clinical trials for breast cancer patients, regardless of whether their tumors are PD-L1 positive or negative. PD-L1 is a protein on the surface of tumors that helps them avoid being targeted by the immune system.

Alongside TNBC, immunotherapy can also be effective in treating other breast cancers, as Dr. Sammons explains. “I’m very hopeful that patients with fast-growing hormone receptor-positive breast cancer may have an opportunity to get immunotherapy in the future. This is on the horizon.” Hormone receptors are proteins located on breast cancer cells, and they can latch on to estrogen or progesterone signals, promoting cancer cell growth. Eligible patients with tumors expressing these hormone receptors can be treated by using hormone antagonist drugs. With advancements in immunotherapy these patients will have more options of treatment available for them.

Thanks to the tireless research of scientists like Drs. Furesi and Sammons, and the dedicated advocacy of passionate breast cancer survivors like Karen Peterson, we are closer to creating a world immune to cancer.

Let's spread the word about Immunotherapy! Click to share this page with your community.

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Top 10 questions doctors are asked about breast cancer

We asked Dr. Graham King, a high-risk breast consultant, to share the top 10 questions about breast cancer that he hears from patients.

Breast cancer receives much attention during October’s awareness month. Although sightings of pink ribbons and breast cancer-related information increase during the month, it’s crucial to keep screenings and clinical breast exams at the forefront of preventive care year-round.

We asked Dr. Graham King, a high-risk breast consultant and breast cancer awareness advocate with the Mayo Clinic Health System, to share the top 10 questions about breast cancer that he hears from patients.

Why do I need to worry about breast cancer and having routine mammograms?

This is the most common question shared during breast clinic consultations. Many people mention that they don’t have any family history of breast cancer. However, approximately just 20 percent of breast cancer is related to family history and genetic links. People are considered at the highest risk after a breast cancer diagnosis in a first-degree relative, such as a mom or sister.

What can I do to prevent breast cancer from developing?

For most people, the answer is to live a healthy lifestyle, including not smoking, minimizing alcohol consumption and maintaining an ideal body weight through diet and exercise. The majority of the risk for breast cancer comes from being female, having breasts and aging.

What steps can I take to be informed of my risk of breast cancer?

This answer has two parts. The first part is to learn about your family’s medical history. The second part is to follow your health care team’s recommended preventive screening plan, including a mammogram if necessary.

Should I continue doing self-checks of my breasts and have an annual clinical breast exam?

The American College of Obstetricians and Gynecologists and the U.S. Preventive Services Taskforce update breast screening recommendations annually, but more research studies need to be done. Your health history and conversations with your health care team will help inform the best approach for you. Although not all health care professionals perform a yearly clinical breast exam as part of an annual physical, you may choose to perform monthly or quarterly self-checks to increase your breast awareness. Both a yearly breast exam by a medical professional and regular self-checks are recommended if you have a higher risk of breast cancer.

What does it mean to have dense breasts, and how does that affect mammograms?

Approximately 30 percent of people have moderately dense breasts, and up to 10 percent have extremely dense breasts. While dense breast tissue does affect the detection of breast cancer through mammography, a mammogram is still a recommended annual screening starting at age 40 for people with average breast cancer risk.

Does taking a birth control pill increase my risk of developing breast cancer?

No strong connection has been identified to suggest any such connection in average-risk patients during childbearing years. However, studies suggest that continuing hormone therapy after age 60 can increase the risk of breast and endometrial cancer.

Does pregnancy and breastfeeding increase my risk of breast cancer?

No, it’s quite the opposite. The risk of developing breast cancer decreases based on the duration of time spent pregnant and breastfeeding.

How do environmental toxin exposure and radiation affect breast cancer?

Certain factors, such as radiation exposure from previous cancer treatment, working in an environment with toxins, or other radiation exposure can increase your risk of many cancer types, including breast cancer.

Should I have genetic testing to determine if I have a family-related risk of breast cancer?

The short answer is, for some people, yes. However, genetic testing is recommended only after a discussion with your health care team or breast specialist about your cancer risks. You may be asked to meet with a genetics counselor to ensure that there is a strong indication for testing.

Does my race affect my risk of breast cancer?

The answer to this question is complex. According to the Centers for Disease Control and Prevention, African Americans, American Indians, Pacific Islanders and Alaskan Native Americans have a much higher rate of breast cancer and breast cancer-related mortality. However, there are many nuances to this concerning medical equity, racial disparity and other considerations that need to be explored and addressed.

If you have been identified as having a higher risk of breast cancer and referred to a high-risk breast clinic, you can expect a comprehensive meeting with a health care professional who is skilled and passionate about breast cancer prevention and survivorship.

Michele Klimke has been a dedicated medical dosimetrist for forty years and joined the Comprehensive Cancer Centers of Nevada (Comprehensive) team in 2007. With extensive experience in developing and managing radiation plans for patients undergoing cancer treatment, she never anticipated finding herself on the other side of the machine. After undergoing a routine mammogram, Michele […]

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Lifetime Launches 30th Annual Stop Breast Cancer for Life Campaign Supporting BCRF

PSA stresses importance of learning your risk, especially for younger women

For its influential Stop Breast Cancer for Life public service campaign supporting BCRF, longtime partner Lifetime has teamed up with stars Lyndsy Fonesca, Karrueche Tran, and Jackie Cruz to highlight rising rates of breast cancer in younger women and the importance of early detection and learning your personal risk .

“We are grateful for Lifetime’s continued support in raising awareness about breast cancer and advancing our mission,” BCRF’s Chief Scientific Officer Dorraya El-Ashry said. “While the incidence of breast cancer in younger women remains low, diagnoses in women under 50 are rising. We’re making strides in understanding the disease better and improving care for younger patients, with the goal of reversing this trend. Lifetime’s ongoing commitment to highlighting breast cancer year after year plays a vital role in propelling this lifesaving research forward.”

This marks the 30 th year of Lifetime’s Stop Breast Cancer for Life initiative. The PSA campaign will air on Lifetime and across digital platforms and will be amplified by Lifetime’s distribution partners. Stop Breast Cancer for Life will also feature four Lifetime films with breast cancer at the center including the breast cancer short film anthology FIVE from directors Jennifer Aniston, Demi Moore, Alicia Keyes, Penelope Spheeris, and Patty Jenkins and starring Fonseca, Jeanne Tripplehorn, and Patricia Clarkson. "Breast cancer continues to affect far too many lives, including women of all ages and backgrounds,” A+E Networks Group President and Chairman Paul Buccieri said. “A+E Networks is proud to join BCRF to raise awareness about early detection, galvanize funding for critical research, and continue to pave the way to find a cure and breast cancer once and for all.”

Watch the PSA above and learn more about Stop Breast Cancer for Life here .

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65 Breast Cancer Questions to Ask a Doctor

From your first visit to after diagnosis and treatment

• After Diagnosis
• When Treatment Is Complete

Frequently Asked Questions

If you’ve been told you have breast cancer , it’s important to ask your doctor and other healthcare providers questions so you thoroughly understand your diagnosis , treatment plan options, and what you can expect throughout treatment and recovery.

Because this can be an overwhelming time, it’s a good idea to write down any questions you have in advance and bring them with you to your medical appointments. Bring a notepad so you can write down the answers to your questions. If possible, bring a family member or friend with you to appointments as well.

Srdjanns74 / Getty Images

This article will go over questions to ask after you initially receive a breast cancer diagnosis, before, during, and after treatment, before and after surgery, and when all treatments are completed.

A cancer care team is made up of different types of healthcare providers. In addition to an oncologist , providers you might see if you have breast cancer include:

• A breast surgeon or surgical oncologist
• A radiation oncologist
• A medical oncologist
• A plastic surgeon

Other members of your care team can include physician assistants, nurse practitioners, nurses, mental health professionals, nutritionists, social workers, and patient/nurse navigators.

Questions to Ask: After Diagnosis

If you’ve been diagnosed with breast cancer, you’ll want to learn more about your type of breast cancer , treatment options, and support. If your primary healthcare provider suspects you might have cancer, they will likely refer you to an oncologist (a doctor specializing in diagnosing and treating cancer).

The following are initial questions to ask your oncologist:

• What type of breast cancer do I have?
• Where exactly is it in my breast?
• What is the stage of my breast cancer? Has it spread to my lymph nodes or elsewhere in my body?
• What is the hormone receptor status of my cancer?
• How can I have a copy of my pathology report?
• Do I need further testing before treatment?
• Should I have a tumor profiling test? Why or why not?
• Should I talk to a genetic counselor or undergo genetic testing ?
• What other doctors or healthcare providers will I see?
• Are there options for more than one treatment for my type of cancer?
• What treatment plan do you recommend?
• What are the benefits, risks, and side effects of recommended treatments?
• How much experience do you have in treating my type of cancer?
• Should I get a second opinion, and how? Will that delay my treatment and is it safe to do so?
• What is the prognosis for my type and stage of cancer?
• Are there any clinical trials I might want to consider?
• Who can help me go over my insurance coverage for my care?
• Who can help me if I’m concerned about costs?
• What mental health support resources are available to me?
• Are there any support groups you can recommend? 

What About Genetic Testing?

Genetic testing can help determine if your breast cancer or family history of breast cancer is due to an inherited gene mutation, which can help guide treatment. Only 5–10% of breast cancers are related to an inherited gene mutation. Questions to ask your doctor about genetic testing include:

• Should I consider genetic testing or see a genetic counselor?
• What are my testing options?
• How might my family history affect my current and future cancer risk?

Questions to Ask: Treatment

Treatments for breast cancer include surgery , radiation , chemotherapy , hormone therapy , targeted therapy, and immunotherapy . Treatments can be given separately or combined. Your treatment options will depend on your type of cancer, its stage, your health, and other factors. It's important to ask questions to your radiation oncologist, medical oncologist, and surgical oncologist or breast surgeon before, during, and after treatment.

Questions to ask before treatment include:

• How soon do I need to start treatment?
• Where will I receive treatments?
• How long will each treatment last? How long will I need treatment?
• What are the treatment’s benefits, risks, and side effects?
• How will this treatment affect my daily life? Work life?
• Will this treatment put me in menopause?
• Will having this treatment affect my chances of having children?
• How successful is this treatment for my type of cancer?

Questions to ask during treatment include;

• How do I know if the treatment is working?
• What tests might I need during treatment?
• For which side effects should I contact you? Are there any that require emergency medical attention?
• Is there anything I can do to help myself feel better during treatment ? To manage side effects?
• Are there any complementary therapies that might help me during treatment?
• Are there mental health resources to help me during treatment?

Questions to ask after treatment include:

• Do I have any post-treatment limitations? How long will they last?
• What can I do to reduce my risk for lymphedema ?
• Are there any post-treatment side effects or symptoms? When should I seek medical attention for them?
• Do I need follow-up appointments or tests?
• What happens if the treatment didn't work as expected?

Communication Methods

Make sure to ask your healthcare providers how you can communicate or ask questions outside of scheduled appointment times. Find out if there are options such as email, patient portals, or after-hours phone services available and how you can access them.  

Questions to Ask: Surgery

Surgery is a part of breast cancer treatment for most people. Types of surgeries include breast-conserving surgery (lumpectomy) to remove the tumor and surrounding tissue, mastectomy to remove the entire breast, breast reconstruction surgery , and procedures to remove lymph nodes .

If you’re having surgery, there are specific questions you should ask your breast surgeon or surgical oncologist before and after your surgery.

Questions to ask before surgery include:

• How many surgeries that are similar to mine have you performed? Are you board certified?
• Am I a candidate for more than one type of breast surgery?
• What are the risks and benefits of any surgeries for which I'm a candidate?
• Will you have to remove any lymph nodes?
• Do you recommend a sentinel lymph node biopsy ? What are the benefits and risks?
• Will my tumor be subject to any testing? If so, which tests, and what do we expect to learn from them?
• Is it possible I will need further treatments after surgery?
• When and how will I receive my pathology report?
• What will my recovery be like in the hospital and at home?
• What will my breasts look like after surgery? What about scars?
• Am I a candidate for breast reconstruction? Can I have it at the same time as my other surgery?

What Is a Patient Advocate?

A patient advocate is an important resource for assisting you with healthcare decisions, problems, coordination of care, and more. Different types of patient advocates include those affiliated with nonprofit organizations, for-profit organizations, or hospitals. In addition, private patient advocates can be hired on an individual basis.

Questions to ask after surgery include:

• Were you able to remove all of the cancer?
• Were any lymph nodes removed?
• Who can go over my pathology report with me?
• Do you anticipate that I'll need further surgery? Further treatment?
• What post-surgery symptoms might I experience? How long should they last?
• What complications or side effects might I have? When should I seek medical care if I experience them?
• Do I have any restrictions? When can I resume normal activities?

Questions to Ask: When All Treatments Are Done

When you complete your treatment, you will still need to make follow-up appointments. You can ask any doctors or other healthcare providers who are involved in your follow-up care the following questions:

• What types of follow-up tests and appointments do I need? When and for how long?
• Are there any long-term side effects? When do I need to contact you if I experience any?
• What are the chances the cancer will come back after treatment?
• What will we do if the cancer comes back?
• What are the chances I will develop another type of cancer after treatment?
• Can I do anything to lower my risk of cancer returning?
• Are there any survivor support groups you can recommend?
• Are there mental health resources that can support me after treatment?

Though a breast cancer diagnosis can be overwhelming, it's important to ask questions throughout every stage of your care. It's a good idea to write down questions in advance of your medical appointments. Make sure you have a list of questions to ask after your initial diagnosis, throughout treatment, before and after surgery, and when your treatments are complete.

Remember, you are the most important member of your healthcare team. Don’t ever be afraid to ask your doctors and other healthcare providers questions about your diagnosis, treatment, recovery, or anything else that concerns you. Doing so will help you make informed decisions about your cancer care.

For your first visit, you can narrow questions down to those about the type of cancer you have, treatment options, and prognosis. You can also ask your doctor how to contact them if you have further questions after your first appointment.

Cancer stage will be determined by how large your tumor is, whether it has hormone receptors, and whether it has spread. It is given a number between 0 and 4. A biopsy (microscopic examination of a sample of the tumor) first confirms you have breast cancer. A clinical stage may be assigned before surgery, and this may be updated (pathological or surgical stage) after surgery and further imaging or tests.

Additional questions to ask if you have been diagnosed with invasive breast cancer include:

• Where in my body has the cancer spread?
• Are you experienced in treating people with metastatic breast cancer?
• What is my prognosis and is there anything I can do to improve it?

American Cancer Society. Treating breast cancer .

Lindenberg Cancer & Hematology Center. When are patients referred to an oncologist?

Susan G. Komen. Genetic testing after a breast cancer diagnosis .

Susan G. Komen. Genetic testing to learn about breast cancer risk .

American Cancer Society. Surgery for breast cancer .

Breastcancer.org. Breast cancer stages .

American Society of Clinical Oncology. Breast cancer-metastatic: questions to ask the health care team .

By Cathy Nelson Nelson is a freelance writer specializing in health, wellness, and fitness for more than two decades.

Dense breasts can make it harder to spot cancer on a mammogram

A new U.S. rule requires mammography centers to inform women about their breast density

When a woman has a mammogram, the most important finding is whether there’s any sign of breast cancer.

The second most important finding is whether her breasts are dense.

Since early September, a new U.S. rule requires mammography centers to inform women about their breast density — information that isn’t entirely new for some women because many states already had similar requirements.

Here’s what to know about why breast density is important.

No, dense breasts are not bad. In fact, they’re quite normal. About 40% of women ages 40 and older have dense breasts.

Women of all shapes and sizes can have dense breasts. It has nothing to do with breast firmness. And it only matters in the world of breast cancer screening, said Dr. Ethan Cohen of MD Anderson Cancer Center in Houston.

With the new rule, “there are going to be a lot of questions to a lot of doctors and there’s going to be a lot of Googling, which is OK. But we want to make sure that people don’t panic,” Cohen said.

Doctors who review mammograms have a system for classifying breast density.

There are four categories. The least dense category means the breasts are almost all fatty tissue. The most dense category means the breasts are mostly glandular and fibrous tissue.

Breasts are considered dense in two of the four categories: “heterogeneously dense” or “extremely dense.” The other two categories are considered not dense.

Dr. Brian Dontchos of the Seattle-based Fred Hutchinson Cancer Center said the classification can vary depending on the doctor reading the mammogram "because it’s somewhat subjective.”

Two reasons: For one, dense breasts make it more difficult to see cancer on an X-ray image, which is what a mammogram is.

“The dense tissue looks white on a mammogram and cancer also looks white on a mammogram,” said Dr. Wendie Berg of the University of Pittsburgh School of Medicine and chief scientific adviser to DenseBreast-info.org. “It’s like trying to see a snowball in a blizzard.”

Second, women with dense breast tissue are at a slightly higher risk of developing breast cancer because cancers are more likely to arise in glandular and fibrous tissue.

Reassuringly, women with dense breasts are no more likely to die from breast cancer compared to other women.

If you find out you have dense breasts, talk to your doctor about your family history of breast cancer and whether you should have additional screening with ultrasound or MRI, said Dr. Georgia Spear of Endeavor Health/NorthShore University Health System in the Chicago area.

Researchers are studying better ways to detect cancer in women with dense breasts. So far, there’s not enough evidence for a broad recommendation for additional screening. The U.S. Preventive Services Task Force called for more research in this area when it updated its breast cancer screening recommendations earlier this year.

Yes, women with dense breasts should get regular mammograms, which is still the gold standard for finding cancer early. Age 40 is when mammograms should start for women, transgender men and nonbinary people at average risk.

“We don’t want to replace the mammogram,” Spear said. “We want to add to it by adding a specific other test.”

For now, that depends on your insurance, although a bill has been introduced in Congress to require insurers to cover additional screening for women with dense breasts.

Additional screening can be expensive — from $250 to $1,000 out of pocket, so that’s a barrier for many women.

“Every woman should have equal opportunity to have their cancer found early when it’s easily treated,” Berg said. “That’s the bottom line.”

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

Related Topics

• Breast Cancer

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“It must be more than just bad luck – it must be genetic”: Three women with BRCA gene mutations share their experiences

9 October 2024

This month, we’ve been marking the 30 th anniversary of the discovery of the BRCA1 gene . That discovery, along with that of BRCA2 just a year later, revolutionised how we prevent, diagnose and treat certain cancers.   

Faulty BRCA genes can be inherited from either parent, and people with these mutations can have an increased risk of developing certain cancers, including breast, ovarian, prostate and pancreatic cancer.   

Here, three women with faulty BRCA genes share their experiences of cancer.   

Maria’s story  

Maria’s experience of cancer started at an early age, when her mum lost two of her sisters, both in their 30s, to breast cancer. Her mum’s grandmother also died from the disease.  

“Fast forward 30 years to my own grandmother and her two sisters passing away from the same thing. It was obviously a worry in the family.  

“Surely that can’t be coincidence; something about that screams it must be more than just bad luck – it must be genetic.”  

Then, in 2018, Maria’s mum was also diagnosed with breast cancer and tests showed that she had the BRCA2 gene mutation.   

This resulted in the rest of Maria’s family also coming forward to have genetic testing. They were also eligible for earlier breast cancer screening from the age of 30, so Maria booked a mammogram while she was waiting for her genetic test results to come through. 

Unfortunately, the mammogram showed that she, like her mum, had breast cancer.  

“It was such a blow, as my husband and I were planning to get married and try for a baby and were only able to have one round of IVF before I started chemotherapy.”  

Maria’s first treatment was a lumpectomy in October 2018 and shortly after, her genetic test results came back showing that she also had the BRCA2 gene mutation.     

Maria had six cycles of chemotherapy followed by a double mastectomy with simultaneous reconstruction with implants.   

Maria is now on a five-year course of tamoxifen, a hormone therapy that can help to reduce the risk of breast cancer coming back.   

She’s also waiting for a preventative oophorectomy (surgical removal of the ovaries) as the BRCA2 gene also increases the risk of ovarian cancer.  

Our involvement in tamoxifen    

Around 8 in every 10 breast cancers diagnosed in the UK are classified as oestrogen receptor-positive, or ER-positive for short. This means that they are encouraged to grow by the hormone oestrogen, which circulates in the bloodstream. Tamoxifen stops oestrogen from affecting cancer cells, stopping them growing.      

We supported clinical trials showing that taking tamoxifen could help prevent breast cancer in certain women who are at higher risk of the disease.  

Our researchers also helped prove the benefits of taking tamoxifen after surgery, for women with the most common type of breast cancer.   

Learn more about our work into tamoxifen .  

“I have been in early menopause since the end of my treatment, which has left me feeling drained, tired and in pain. Everyone thinks you just get back to normal after treatment for cancer, but I have found everything a struggle, including just going to work every day.  

“It has been particularly hard coming to terms with the fact I will never be able to have children, but I am grateful every day to be here.”

Maria’s big family meant many of her relatives were eligible for genetic testing.   

“My mother is 1 of 10 children and I have countless first and second cousins. I am one of six children of whom four tested positive, as did several of my uncles and aunties; nine of us in all have had preventative surgery, along with those who have had surgery due to having cancer.  

“Had my mum not had the genetic test I might not be here now. Instead, I have survived for more than five years after diagnosis and been treated, as has my mum. We are all so thankful to her; the best way I can show this is by telling our story and helping to spread awareness of the fact that there can sometimes be a genetic link to cancer.”  

Gillian’s story  

At the age of 38, almost a year after losing her mum to breast cancer in June 1999, Gillian found a small lump in her breast. She visited her GP who sent her to the local hospital to get it checked.   

After a needle biopsy, where a sample of cells is taken using a small needle, and an ultrasound, Gillian was diagnosed with a rare type of cancer called medullary breast cancer .   

Medullary breast cancer occurs more often in younger women and in women who have inherited a faulty BRCA1 gene.   

Fortunately, as the cancer had been caught early, it hadn’t spread. So, Gillian had surgery to remove the lump and surrounding tissue. Her doctors also recommended five weeks of radiotherapy once she had recovered from her operation.  

As part of her treatment, Gillian took part in the Cancer Research UK-funded START trial.   

“The treatment wasn’t too bad, although I did get very tired. I followed the nurses’ advice and although it was a bit uncomfortable the area being treated wasn’t painful.”  

The START Trial  

We funded the START trial, which was split into two branches, START A and START B . The trials looked at different ways of giving radiotherapy after surgery for early-stage breast cancer.   

In 2013 the researchers published their 10-year follow up of the trials. This showed that fewer, but higher, doses of radiotherapy is as effective as the then-standard dose of 50 Gy in 25 fractions.  

As a result, most UK centres have now adopted a dose schedule of 40 Gy in 15 fractions as the standard care for women with breast cancer.  

“Then in March 2007 I started to feel really bloated which was unusual for me as I’d always been rather slim. I wondered if it was something to do with my menstrual cycle or maybe menopause. But my GP said it wasn’t normal for me and sent me straight off for a blood test and ultrasound.”  

The ultrasound showed a solid mass on one side of her stomach and a fluid filled mass on the other side. Gillian was referred for a CT scan and further blood tests, which showed that she had ovarian cancer.  

“By this time, I looked like I was six months pregnant and on 7 June 2007 I had a full hysterectomy, and the surgeons removed a tumour the size of a football.  

“A few weeks after the operation I started chemotherapy – a combination of carboplatin and paclitaxel. Chemo wasn’t as bad as I’d thought it would be. The worst side effect was that I ached all over, it was hard to sleep I ached so much. Losing my hair was no big deal really; it was a case of saving my life or saving my hair, so it was an easy decision to make!”  

Gillian had five cycles of chemotherapy, finishing in November 2007.    

Then, a month later in December, Gillian tested positive for the BRCA1 gene mutation, which she was found to have inherited from her father.   

Because this meant that she had an increased risk of her breast cancer returning, Gillian had a double mastectomy with implant reconstruction in March 2023.   

She has since made a good recovery from the surgery and is doing well.   

Sue’s story

Sue first started noticing signs that something wasn’t quite right for her body in November 2016 when she started gaining weight, despite trying to lose it.   

“Over Christmas I felt bloated but put it down to overindulgence until my sister came to stay. We talked about our recent discovery that our cousin, who had had breast cancer, had been found to carry a BRCA gene mutation.  

“Our mother had died of breast cancer, but although we had not been tested my sister drew my attention to the fact the gene could also be associated with ovarian cancer.”  

On the advice of her sister, Sue made a GP appointment, where she was referred for an ultrasound and blood tests. The next day, her GP called her in urgently to tell her that her levels of CA125 – a protein that is often higher in people with ovarian cancer – were very high. The ultrasound found a 15cm mass, further pointing towards a suspected ovarian cancer diagnosis. 

“At the end of January, the consultant confirmed the diagnosis of ovarian cancer. I was with my sister, who is a nurse and was able to take in all the information I was given. 

“Trying to remain strong whilst all I wanted to do was scream was a real challenge. If it wasn’t for my husband, I would have fallen apart; he was and is still my rock and an absolute hero.”  

Sue had a hysterectomy in February 2017 and started chemotherapy in March as part of a clinical trial called JAVELIN Ovarian.   

During her chemotherapy, Sue was tested for BRCA gene mutations and found out she had a faulty BRCA1 gene.   

As she had been part of a trial, Sue had regular CT scans and blood tests. Unfortunately, in June 2018 there was a rise in her CA125 levels. By the autumn her CA125 had increased even more, and she was put back on chemotherapy.   

In March 2019, Sue joined the Cancer Research UK funded ICON9 trial . This trial was looking at the effectiveness of long-term treatment with two drugs called olaparib and cediranib for women whose ovarian cancer has started to grow again.  

Sue was in the group taking just olaparib tablets twice daily.   

“I feel so lucky my oncologists are the chief investigators of the trial. I am currently on two-monthly investigations, and my CA125 count has remained stable.

Our involvement in PARP inhibitors  

Olaparib, which is one of the drugs that was used in the ICON9 trial, belongs to a group of drugs known as PARP inhibitors.   

PARP inhibitors block a protein called PARP that helps damaged cancer cells to repair themselves. By blocking PARP, this helps stop cancer cells repairing themselves.   

Our researchers led the underpinning work to understand PARP’s role in DNA repair, and we supported the early development and first-in-human testing of two early PARP inhibitor drugs.   

Learn more about how we were involved in the development of PARP inhibitors .   

Sue, who has three children, is now doing well.  

“My health in general is great and all my children treat me as if life is back to normal, which is lovely,” said Sue.   

“As someone who is receiving first-hand the benefits of the wonderful research of Cancer Research UK, I am endlessly thankful and fully appreciate the relentless funding that is needed to achieve so many new therapies and wonderful outcomes. Without funding and the tireless work of Cancer Research UK, we would have no success stories to share.”  

Continuing to make progress  

Since the discovery of the BRCA genes 30 years ago, we’ve made huge leaps forward in understanding faulty BRCA-driven cancers – leaps that are saving and improving lives right now.  

But our work isn’t done yet. We want to bring about a world where everybody lives longer, better lives free from the fear of cancer. No matter who they are or where they’re from.   

Absolutely brilliant, this is why I donate, for people who are sick with this terrible disease, to help towards getting better treatments for people who are trying to fight this disease.

Thank you for the BRCA information. I have recently been diagnosed with BRCA 1 and had a double mastectomy and awaiting removal of ovaries and fallopian tubes.

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Highlighted content

30 years of brca: how the discovery of two breast cancer genes continues to drive progress, cancer metabolism: finding how fast-growing cancers get their energy, groundbreaking trial launches for everyone with ewing sarcoma, introducing diy steps to genetic testing could catch more brca-linked cancer cases, we’re accelerating brain tumour research with £8m more for our brain tumour centres of excellence, cancer vaccines - where are we, more like this, olaparib approved for 800 prostate and breast cancer patients in england, how serendipity sent this oncologist in search of a cure for cancer, related topics.

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Secondary breast cancer

I had a primary breast cancer, had a lumpectomy and lymph nodes removed. No cancer found in the nodes. My question. If it came back in the same breast or the other. Is that described as terminal..?

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Hello and thanks for posting

If breast cancer comes back in the same breast it is called a local recurrence. If it appears in the other breast then this would be classified as a new primary breast cancer. This can often be treated effectively with further surgery, radiotherapy or other treatments as recommended by the breast care team.

It sounds from what you have described that you had an early cancer which has not spread to nearby lymph nodes and as a result is less likely to spread in the future.

Your breast care team or nurse specialist can advise you further on this as they are familiar with all your medical details.

I hope this is of some help. Give us a ring if you would like to talk anything over. The number to call is Freephone 0808 800 4040 and the lines are open from 9am till 5pm Monday to Friday.

Kind regards,

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Hi Vivienbegonia,

A very warm welcome to our forum.

I was diagnosed with a primary cancer in one breast and had a lumpectomy. There was no lymph node involvement. Less than a year later I discovered another lump, in the same breast. This was also cancerous. This was a second primary cancer. I had a double mastectomy and I still lead a busy and fulfilling life, even though that was all 14 years ago now.

Jolamine xx

Thank you  Jolamine, so happy for you.

No problem, Vivienbegonia. Have you had a recurrence?

Hi Jolamine

No I have not had a recurrence. Xx

Good, I'm glad to hear that you haven't had a recurrence.

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