blood cancer research article

Advances in Leukemia Research

Human cells with acute myelocytic leukemia.

NCI-funded researchers are working to advance our understanding of how to treat leukemia. With progress in both targeted therapies and immunotherapies, leukemia treatment has the potential to become more effective and less toxic.

This page highlights some of the latest research in leukemia, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Leukemia Treatment for Adults

The mainstays of leukemia treatment for adults have been chemotherapy , radiation therapy , and stem cell transplantation . Over the last two decades, targeted therapies have also become part of the standard of care for some types of leukemia. These treatments target proteins that control how cancer cells grow, divide, and spread. Different types of leukemia require different combinations of therapies.  For a complete list of all currently approved drugs, see Drugs Approved for Leukemia.

Although much progress has been made against some types of leukemia, others still have relatively poor rates of survival. And, as the population ages, there is a greater need for treatment regimens that are more effective and less toxic  than standard chemotherapy.

Acute Lymphoblastic Leukemia (ALL) Treatment

Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). It usually gets worse quickly and needs rapid treatment. Some recent research includes:

Combining less-toxic therapies

The intensive chemotherapy treatments used for ALL have serious side effects that many older patients cannot tolerate. Targeted therapies may have fewer side effects than chemotherapy. Clinical trials are now testing whether combinations of these types of therapies can be used instead of chemotherapy for older patients with a form of ALL called B-cell ALL.

Immunotherapy

Immunotherapies are treatments that help the body’s immune system fight cancer more effectively. Immunotherapy strategies being used or tested in ALL include:

CAR T-cell therapy

CAR T-cell therapy is a type of treatment in which a patient’s own immune cells are genetically modified to treat their cancer.

• Currently, one type of CAR T cell therapy is  approved for the treatment of some children and young adults with B-cell precursor ALL . This CAR T cell therapy is now being explored for use in older adults with B-cell ALL. 
• A second CAR T-cell therapy has also been approved for adults with B-cell precursor ALL that has not responded to treatment or has returned after previous treatment.

CAR T cell therapies are now being explored for other uses in ALL. For example, scientists hope that it will be possible to use CAR T-cell therapy to delay—or even replace—stem-cell transplantation in older, frailer patients.

Bispecific T-cell engagers

Another immunotherapy being tested in ALL is bispecific T-cell engagers (BiTEs). These drugs attach to immune cells and cancer cells, enabling the immune cells to easily find and destroy the cancer cell by bringing them closer together.

Once such BiTE, called blinatumomab (Blincyto) , was recently shown to improve survival for people with ALL who are in remission after chemotherapy , even when there is no trace of their disease. In 2024, FDA approved blinatumomab for adult and pediatric patients one month and older with a specific type of B-cell precursor ALL. The approval is for use as part of consolidation chemotherapy, which is treatment that is given after cancer has disappeared following initial therapy.

Improving treatment for adolescents and young adults (AYAs)

An intensive treatment regimen developed for children with ALL has been found to also improve outcomes for newly diagnosed AYA patients . The pediatric regimen more than doubled the median length of time people lived without their cancer returning compared with an adult treatment regimen. Further studies are now testing the addition of targeted therapies to the combination .

Acute Myeloid Leukemia (AML) Treatment

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It can cause a buildup of abnormal red blood cells, white blood cells, or platelets.

AML tends to be aggressive and is harder to treat than ALL. However, AML cells sometimes have gene changes that cause the tumors to grow but can be targeted with new drugs. Researchers are starting to look at whether genomic sequencing of tumor cells can help doctors choose the best treatment (such as chemotherapy, targeted therapy, stem-cell transplant, or a combination of therapies) for each patient. Scientists are also testing other ways to treat AML.

New Treatment Option for Some People with AML

Combining ivosidenib with chemo is effective for AML with an IDH1 gene mutation.

Targeted therapies

Targeted therapies recently approved to treat AML with certain gene changes include  Enasidenib (Idhifa) ,  Olutasidenib (Rezlidhia) ,  Ivosidenib (Tibsovo) ,  Venetoclax (Venclexta) ,  Gemtuzumab ozogamicin (Mylotarg) ,  Midostaurin (Rydapt) ,  Gilteritinib (Xospata) ,  Glasdegib (Daurismo) , and  Quizartinib (Vanflyta) . 

An NCI-sponsored precision medicine study called MyeloMATCH is now enrolling people with newly diagnosed AML or a related but less aggressive cancer called myelodysplastic syndrome (MDS) . Participants will undergo genomic testing of blood and bone marrow samples to see if they have specific genetic alterations that can be matched to corresponding targeted therapies.

Other ways to treat AML

• Testing newer targeted therapies.  Researchers continue to develop new drugs to shut down proteins that some leukemias need to grow. For example, new drugs called menin inhibitors stop cancer-promoting genes from being expressed. 
• Studying ways to target AML cells indirectly. These include testing ways to make cancer cells more vulnerable to new and existing treatments.
• Targeting AML and related conditions. MDS can eventually progress to AML. Researchers are testing HDAC inhibitors and other drugs that alter how genes are switched on and off in both MDS and AML.
• Reducing side effects. Some older adults cannot tolerate the intensive treatments most commonly used for AML. Studies have recently found that several drug combinations can help older people with AML live longer while avoiding many serious side effects. New treatments to relieve symptoms of MDS have also been developed.
• Immunotherapy. CAR T-cells and BiTEs are being tested in people with AML.

Chronic Myelogenous Leukemia (CML) Treatment

Chronic myelogenous leukemia (CML) is a type of cancer in which the bone marrow makes too many granulocytes (a type of white blood cell). These granulocytes are abnormal and can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. CML usually gets worse slowly over time.

Blocking an abnormal protein

Most people with CML have a specific chromosome alteration called the Philadelphia chromosome , which produces an abnormal protein that drives the growth of leukemia cells. Targeted therapies that block this abnormal protein— imatinib (Gleevec) , nilotinib (Tasigna) , dasatinib (Sprycel) , and ponatinib (Iclusig) —have radically changed the outlook for people with CML, who now have close to a normal life expectancy.

Testing new combination therapies

Some people with CML continue to have detectable cancer cells in their body even after long-term treatment with drugs that target the protein produced by the Philadelphia chromosome. NCI-sponsored trials are testing whether the addition of immunotherapy or other targeted therapies to these drugs can reduce the number of CML cells in such patients.

Looking at whether patients can stop taking therapy

Researchers have found that some drugs that target the protein produced by the Philadelphia chromosome can be safely stopped in some CML patients rather than taken for life. These patients must undergo regular testing to ensure the disease has not come back.

Chronic Lymphocytic Leukemia (CLL) Treatment

Like ALL, chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). But unlike ALL, CLL is slow growing and worsens over time.

Targeted therapy

Ibrutinib (Imbruvica) . The targeted therapy ibrutinib (Imbruvica) was the first non-chemotherapy drug approved to treat CLL. It shuts down a signaling pathway called the B-cell receptor signaling pathway, which is commonly overactive in CLL cells. Depending on people’s age , ibrutinib may be given in combination with another targeted drug, rituximab (Rituxan) .

Clinical trials have shown that ibrutinib benefits both younger and older patients with CLL.

Venetoclax (Venclexta) and obinutuzumab (Gazyva) . In 2019, the Food and Drug Administration (FDA) approved the second chemotherapy-free initial treatment regimen for CLL , containing the targeted therapies venetoclax (Venclexta) and obinutuzumab (Gazyva) .

Other combinations of these drugs plus ibrutinib are now being used or tested for CLL, including •    ibrutinib and venetoclax in people with newly diagnosed CLL •    ibrutinib, obinutuzumab, and venetoclax in older adults with newly diagnosed CLL •    ibrutinib and obinutuzumab with or without venetoclax in younger adults with newly diagnosed CLL

An ongoing trial at NCI is also testing whether giving the combination of venetoclax and obinutuzumab to some people with CLL before symptoms develop can help them live longer overall.

Zanubrutinib (Brukinsa) . In early 2023, the FDA approved a drug that works in a similar manner to ibrutinib, called zanubrutinib (Brukinsa) , for people with CLL. A large study showed that zanubrutinib alone has fewer side effects and is more effective than ibrutinib for people whose leukemia has returned after initial treatment. More research is now needed to understand how to best combine zanubrutinib with other newer therapies, such as venetoclax.

CAR T-cell therapy is also being tested in adults with CLL. Researchers would like to know if using this type of immunotherapy early in the course of treatment would be more effective than waiting until the cancer recurs.

Hairy Cell Leukemia (HCL) Treatment

Hairy cell leukemia (HCL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). The disease is called hairy cell leukemia because the abnormal lymphocytes look "hairy" when viewed under a microscope. This rare type of leukemia gets worse slowly, or sometimes does not get worse at all.

Combinations of drugs

Researchers are studying combinations of drugs to treat HCL. For example, in a recent small study, a combination of two targeted therapies— vemurafenib (Zelboraf) and rituximab (Rituxan) — led to long-lasting remissions for most participants with HCL that had come back after previous treatments. More drug combinations are currently being tested in clinical trials.

Leukemia Treatment for Children

For the two most common types of leukemia, AML and ALL, standard leukemia treatments for children have been chemotherapy, radiation therapy, and stem-cell transplant. Despite great improvements in survival for children with many types of leukemia, some treatments don't always work. Also, some children later experience a relapse of their disease. Others live with the side effects of chemotherapy and radiation therapy for the rest of their lives, highlighting the need for less toxic treatments.

Now researchers are focusing on targeted drugs and immunotherapies for the treatment of leukemia in children. Newer chemotherapy drugs are also being tested.

Targeted Therapies

Targeted therapies that have been approved or are being studied for children with leukemia include:

• imatinib (Gleevec) and dasatinib (Sprycel), which are  approved for the treatment of children with CML  as well as those with a specific type of ALL. The approvals are for children whose cancer cells have the Philadelphia chromosome. 
• sorafenib (Nexavar) , which has been studied in combination with standard chemotherapy for children with AML whose leukemia has changes in a gene called FLT3. The addition of sorafenib to standard treatment was safe, and its addition may improve survival time free from leukemia. Other ongoing clinical trials are testing drugs that target FLT3 more specifically than sorafenib (such as gilteritinib).
• larotrectinib (Vitrakvi) , which is being tested in children with leukemia that has a specific change in a gene called NTRK . 

More possible targets for the treatment of childhood cancers are discovered every year, and many new drugs that could potentially be used to treat cancers that have these targets are being tested through the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) .

CAR T-cell therapy has recently generated great excitement for the treatment of children with relapsed ALL. One CAR T-cell therapy, tisagenlecleucel (Kymriah) , was approved in 2017 for some children with relapsed ALL.

Researchers continue to address remaining challenges about the use of CAR T-cell therapy in children with leukemia:

• Sometimes, leukemia can become resistant to tisagenlecleucel. Researchers in NCI’s Pediatric Oncology Branch have developed CAR T cells that target leukemia cells in a different way. An  ongoing clinical trial is testing whether the combination of these two types of CAR T cells can provide longer-lasting remissions.
• CAR T cells are currently only approved for use in leukemia that has relapsed or proved resistant to standard treatment. A clinical trial from the Children's Oncology Group ( COG ) is now testing tisagenlecleucel as part of first-line therapy in children with ALL at high risk of relapse.
• More research is needed to understand which children who receive CAR T cells are at high risk of developing resistance to treatment. Researchers also plan to test whether strategies such as combining CAR T-cell therapy with other immunotherapies may help prevent resistance from developing. 
• Other research, both in NCI’s Pediatric Oncology Branch and at other institutions, is focused on creating CAR T-cell therapies that work for children with other types of childhood leukemia, such as AML. Several clinical trials of these treatments, including one led by NCI researchers , are now under way.

Two other drugs that use the body’s immune system to fight cancer have shown promise for children with leukemia:

• In clinical trials, the drug was shown to be more effective than chemotherapy in treating ALL that has relapsed in children and young adults.
• An NCI-sponsored trial is now testing the drug as part of treatment for newly diagnosed ALL in children, adolescents, and young adults.
• A drug called inotuzumab ozogamicin (Besponsa)  is being tested in children with relapsed B-cell ALL. This drug consists of an antibody that can bind to cancer cells linked to a drug that can kill those cells. An NCI-sponsored trial is also testing the drug as part of treatment for newly diagnosed ALL in children and adolescents at higher risk of relapse.

Chemotherapy

In addition to targeted therapies and immunotherapies, researchers are also working to develop new chemotherapy drugs for leukemia and find better ways to use existing drugs. In 2018, a large clinical trial showed that adding the drug nelarabine (Arranon) to standard chemotherapy improves survival for children and young adults newly diagnosed with T-cell ALL.

Other drugs are being tested that may make standard chemotherapy drugs more effective. These drugs include venetoclax , which has been approved for older adults with some types of leukemia and is now being tested in children .

Survivorship

Children’s developing brains and bodies can be particularly sensitive to the harmful effects of cancer treatment. Because many children treated for cancer go on to live long lives, they may be dealing with these late effects for decades to come.

The NCI-funded Childhood Cancer Survivor Study , ongoing since 1994, tracks the long-term harmful effects of treatments for childhood cancer and studies ways to minimize these effects. NCI also funds research into addressing ways to help cancer survivors cope with and manage health issues stemming from cancer treatment, as well into altering existing treatment regimens to make them less toxic in the long term.

For example, one study found that, in children with ALL, radiation therapy to prevent the cancer from returning in the brain is likely unnecessary . The study found that radiation can even be omitted for children at the highest risk of the cancer coming back, reducing the risk of future problems with thinking and memory, hormone dysfunction, and other side effects of radiation to the brain.

Preventing and Treating Graft Versus Host Disease

Many people with leukemia—both adults and children—have a stem-cell transplant as part of their treatment. If the new stem cells come from a donor, the immune cells they produce may be able to attack any cancer cells that remain in the body.

But sometimes, immune cells produced by donor stem cells attack healthy tissues of the body instead. This condition, called graft versus host disease ( GVHD ), can affect nearly every organ and can cause many painful and debilitating symptoms. 

In recent years, several drugs have been approved by the FDA for the treatment of GVHD, including:

•    ibrutinib, which is also used as a treatment for some types of leukemia •     ruxolitinib (Jakafi) •     belumosudil (Rezurock)

Researchers are also testing ways to prevent GVHD from developing in the first place. For example, a recent study found that removing certain immune cells from donated stem cells before they are transplanted may reduce the risk of chronic GVHD without any apparent increase in the likelihood of relapse.

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus and across the United States and the world are seeking ways to address leukemia more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in leukemia.

NCI’s Leukemia Specialized Programs of Research Excellence (SPORE) promotes collaborative, interdisciplinary research. SPORE grants involve both basic and clinical/applied scientists working together. They support the efficient movement of basic scientific findings into clinical settings, as well as studies to determine the biological basis for observations made in individuals with cancer or in populations at risk for cancer.

The Targeting Fusion Oncoproteins in Childhood Cancers (TFCC) Network is forming a collaborative team of investigators to advance the understanding of how fusion proteins contribute to pediatric cancers, and how they might be targeted with new treatments. Fusion proteins, which can occur when parts of different chromosomal regions are joined, may drive the development of many cancers in children.

NCI has also formed partnerships with the pharmaceutical industry, academic institutions, and individual investigators for the early clinical evaluation of innovative cancer therapies. The Experimental Therapeutics Clinical Trials Network (ETCTN) was created to evaluate these therapies using a coordinated, collaborative approach to early-phase clinical trials.

The Pediatric Early-Phase Clinical Trials Network was established to help identify and develop effective new drugs for children and adolescents with cancer. The network’s focus is on phase I and early phase II trials, as well as pilot studies of novel drugs and treatment regimens to determine their tolerability.

NCI’s Pediatric Preclinical In Vivo Testing Consortium (PIVOT) develops mouse models to allow early, rapid testing of new drugs for pediatric cancers, including leukemia. The models are all derived from tissue samples taken from patients’ tumors. The consortium partners both with commercial drug companies and with drug development efforts at universities and cancer centers.

The NCI-supported Children’s Oncology Group develops and conducts both clinical trials of initial treatments and clinical trials for after cancer relapse for children and adolescents with ALL, AML, and CML.

Researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG)  investigate novel, molecular biomarkers for leukemia, as well as clarify relationships of established risk factors. Studies include those looking at environmental and workplace exposure, families with multiple leukemia cases, and inherited bone marrow failure syndromes to name a few.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Search NCI-Supported Clinical Trials to find leukemia-related trials now accepting patients. 

Leukemia Research Results

The following are some of our latest news articles on leukemia research:

• Quizartinib Approval Adds New Treatment Option for AML, Including in Older Patients
• Blinatumomab Increases Survival for Infants with an Aggressive Type of ALL
• Revumenib Shows Promise in Treating Advanced Acute Myeloid Leukemia
• Help Desk for Oncologists Treating People with a Rare Leukemia Pays Big Dividends
• Zanubrutinib’s Approval Improves Targeted Treatment for CLL
• Trial Suggests Expanded Role for Blinatumomab in Treating ALL

View the full list of Leukemia Research Results and Study Updates .

Blood Cancers and Research Progress

LLS has invested over $1.5 billion in cancer research since our founding in 1949, leading to nearly every advancement in blood cancer treatment and breakthroughs in immunotherapy, genomics and personalized medicine.

Our support of pioneering research at nearly 100 medical institutions worldwide is breaking new ground in the fight against cancer.

Image source: the LLS Annual Report

See our impact across all the disease areas we fund:

Leukemia Research Funded by LLS

Nearly every breakthrough in cancer treatment has emerged from our support of leukemia research, from chemotherapy to groundbreaking CAR T-cell immunotherapy. With more than $65 million committed to leukemia research, we are leading the way to cures.

Lymphoma Research Funded by LLS

Our investment in lymphoma research has led to significant advances, such as rituximab (Rituxan®) and innovative immunotherapy, such as the first first chimeric antigen receptor (CAR) T-cell-therapy approved by the FDA for lymphoma patients: axicabtagene ciloleucel (Yescarta®). Our current lymphoma research commitment exceeds $73 million, so we can continue to bring promising new treatments to patients.

Multiple Myeloma Research Funded by LLS

LLS is a leading funder of visionary myeloma research, and this investment has led to many approved therapies for patients in recent years. While progress has been made, our work continues. We have committed more than $31 million to myeloma research to find cures.

Myelodysplastic Syndrome (MDS) Research Funded by LLS

We are supporting advanced genomics and molecular research to understand the causes of MDS and improve diagnosis and treatment. LLS is funding nearly 30 active grants in MDS research worldwide.

Myeloproliferative Neoplasms (MPN) Research Funded by LLS

LLS is collaborating with the MPN Research Foundation to develop therapies for polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) – the group of blood cancers collectively known as myeloproliferative neoplasms.

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Open Access

Peer-reviewed

Research Article

Incurable but treatable: Understanding, uncertainty and impact in chronic blood cancers—A qualitative study from the UK’s Haematological Malignancy Research Network

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing – original draft

* E-mail: [email protected]

Affiliation Department of Health Sciences, University of York, York, United Kingdom

Roles Data curation, Formal analysis, Investigation, Writing – review & editing

Roles Conceptualization, Funding acquisition, Writing – review & editing

Affiliation Queens Centre for Oncology and Haematology, Castle Hill Hospital, Cottingham, United Kingdom

• Debra A. Howell, 
• Dorothy McCaughan, 
• Alexandra G. Smith, 
• Russell Patmore, 

• Published: February 10, 2022
• https://doi.org/10.1371/journal.pone.0263672
• Reader Comments

Most blood cancers are incurable and typically follow unpredictable remitting-relapsing pathways associated with varying need for treatment, which may be distressing for patients. Our objective was to conduct a qualitative study to explore understanding among patients with such malignancies, including the explanations given by HCPs and the impact of uncertain trajectories, to generate evidence that could guide improvements in clinical practice.

The study is set within a population-based patient cohort (the Haematological Malignancy Research Network), in which care is delivered across 14 hospitals according to national guidelines. In-depth interviews were conducted with 35 patients with chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma or myeloma; and 10 accompanying relatives. Purposive sampling ensured selection of information-rich participants and the data were interrogated using reflective thematic analysis.

Rich data were collected and four themes (11 sub-themes) were identified: 1) Knowledge and understanding of chronic haematological malignancies; 2) Incurable but treatable; 3) Uncertainty about the future; and 4) Treatable (but still incurable): Impact on patients. Patients had rarely heard of blood cancer and many expressed difficulty understanding how an incurable malignancy that could not be removed, was treatable, often for long periods. While some were reassured that their cancer did not pose an immediate survival threat, others were particularly traumatised by the uncertain future it entailed, suffering ongoing emotional distress as a result, which could be more burdensome than any physical symptoms. Nonetheless, most interviewees understood that uncertain pathways were caused by the unpredictability of their disease trajectory, and not information being withheld.

Conclusions

Many participants lacked knowledge about chronic haematological malignancies. HCPs acted to reassure patients about their diagnosis, and while this was appropriate and effective for some, it was less so for others, as the cancer-impact involved struggling to cope with ongoing uncertainty, distress and a shortened life-span.

Citation: Howell DA, McCaughan D, Smith AG, Patmore R, Roman E (2022) Incurable but treatable: Understanding, uncertainty and impact in chronic blood cancers—A qualitative study from the UK’s Haematological Malignancy Research Network. PLoS ONE 17(2): e0263672. https://doi.org/10.1371/journal.pone.0263672

Editor: Andrew Soundy, University of Birmingham, UNITED KINGDOM

Received: July 21, 2021; Accepted: January 24, 2022; Published: February 10, 2022

Copyright: © 2022 Howell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files. Raw data (i.e. transcripts) cannot be shared publicly due to assurances of confidentiality given to participants at the time of consenting. The authors are unable to make the transcripts available upon request to researchers who meet the criteria to access confidential information for the same reason; also, permission to do this was not sought from participants.

Funding: 1. DH, ER, AS and RP: National Institute for Health Research Programme Grant for Applied Research (NIHR PGfAR): RP-PG-0613-2002. https://www.nihr.ac.uk/explore-nihr/funding-programmes/programme-grants-for-applied-research.htm 2. DH, ER, AS: Cancer Research UK (CRUK) 29685. https://www.cancerresearchuk.org/ DH, ER, AS: Blood Cancer UK (BCUK) 15037. https://www.cancerresearchuk.org/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

1. Introduction

Arising in blood and lymph forming tissues, haematological malignancies (leukaemias, lymphomas, and myelomas, also known as blood cancers) are collectively the fifth most common cancer grouping in economically developed countries [ 1 , 2 ]. With diverse aetiologies, treatments, and outcomes, more than 100 subtypes are currently recognized by the World Health Organization (WHO) [ 3 ]. Although some of these cancers are potentially curable with intensive chemotherapy (e.g. diffuse large B-cell lymphoma and acute myeloid leukaemia), around 60% are not; the latter typically comprising more chronic or indolent diseases (e.g. chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and myeloma) [ 4 ]. These malignancies often have a slow manifestation, in which symptoms may be vague, intermittent and commonly seen in benign, self-limiting conditions, particularly in older age groups, meaning cancer is not always immediately suspected [ 5 , 6 ].

Interestingly, despite being incurable, many indolent blood cancers can be successfully managed, sometimes over many years, on what is considered a remitting-relapsing pathway. This trajectory may include periods of observation (known as ‘active monitoring’ or ‘watch and wait’) usually at diagnosis or when the cancer is in remission, interspersed with treatment at progression or as the disease burden increases (manifested by deteriorating blood results, or new/worsening symptoms), to restore remission. While some patients continue on observation without ever requiring treatment, if/when it is needed (which may occur on multiple occasions) it includes combinations of chemotherapy, radiotherapy, stem cell transplant and targeted agents [ 7 ]. Behaviour is known to differ between indolent blood cancers subtypes, with progression almost certain to occur for some (e.g. myeloma), but much less likely for others (e.g. CLL), as is reflected in the five-year relative survival estimates of 48% for myeloma, compared to 86%, 88% and 80% for CLL, FL and MZL, respectively ( https://hmrn.org/statistics/survival ).

With respect to the experiences of patients with chronic haematological malignancies, much existing literature is limited by the inclusion of individuals with both indolent and acute subtypes, with no differentiation between the two with respect to findings. Such studies have focused on issues such as information satisfaction, decision-making, and quality of life, as well as physician communication styles; identifying considerable scope for improvement [ 8 – 14 ]. Several studies have, however, specifically examined patients with chronic blood cancer subtypes in the last decade or so, with a recent survey identifying poorer diagnostic understanding compared to other malignancies [ 15 ]; a worrying issue given the link between information satisfaction and improved quality of life in cancer generally [ 16 ]. Other difficulties linked to chronic haematological malignancies include the issue of living with uncertainty, which may be associated with psychosocial problems [ 17 – 19 ].

There is, however, little qualitative evidence about patient knowledge and understanding of chronic haematological malignancies, the explanations given to patients by clinical staff and the impact the uncertain trajectories of these cancers have on those affected over time. To address this, we conducted an in-depth interview study, to generate evidence that could be used to guide improvements in clinical practice. Set within a broader UK National Institute for Health Research (NIHR) programme, this paper is one of a forthcoming series dedicated to examining patient experiences of chronic blood cancers, including information needs and preferences for involvement in decision-making.

Methods are described in accordance with COREQ [ 20 ].

2.1 Setting

This qualitative study was set within the infrastructure of the UK’s Haematological Malignancy Research Network (HMRN: www.hmrn.org ), a population based patient cohort initiated in 2004 to inform research and clinical practice; locally, nationally and internationally [ 7 ]. HMRN’s configuration, methods and approvals have been published [ 21 ]; and the present study has additional ethical support (REC:16/LO/0740). Briefly, HMRN has a catchment population of ~4 million, with a similar socio-demographic profile to the UK as a whole; and patient care is provided by a unified clinical network (14 hospitals), working to national guidelines. All haematological malignancies in the study area are diagnosed by a single laboratory (the Haematological Malignancy Diagnostic Service: www.hmds.info ), using the latest ICD-O classification [ 3 ]. Patients enter the cohort at diagnosis (~2,400 annually), and have diagnostic, prognostic and clinical data (including all treatment and responses) collected from their medical records.

2.2 Sampling strategy

In-depth interviews were conducted with patients from HMRN’s established Partnership ( https://yhhn.org/partnership ), who had agreed they could be contacted for research purposes. Purposeful sampling was utilised, in which patients were intentionally selected based on their demographic and diagnostic characteristics, in the likelihood of them being ‘information-rich’ sources, able to provide data that were relevant to the research aims [ 22 ]. In this context, initial inclusion criteria included: diagnosis of CLL, FL, MZL or myeloma (reflecting the spectrum of chronic cancers) in men and women close to the median diagnostic age for each subtype. Variation was then introduced by socio-economic area, age strata and time since diagnosis, to capture more diverse experiences [ 22 , 23 ]. The number of interviews conducted was guided by the concept of information power [ 24 , 25 ], which aligns with our analytical method, outlined in 2.4.

2.3 Recruitment and data collection

After checking with NHS staff that patients were alive, and well enough to participate, potential interviewees were sent an information sheet and asked to contact the research team if they wanted to take part, and to ask a relative/friend to join the interview, if they wished. Interviews were conducted February to October 2019, at a time and place chosen by the patient, usually their home. Informed written consent was obtained (permitting use of direct quotes) following assurances about confidentiality and anonymity, and the opportunity to ask questions. Interviews were conducted by an experienced researcher, lasted ~90 minutes and were digitally audio-recorded. Patients were asked to tell their own story from diagnosis, with a topic guide used to direct questioning ( S1 File ). Recordings were transcribed externally, then checked, corrected and anonymised by the interviewer.

2.4 Data analysis

Data analysis was conducted by the interviewer and a second researcher utilising reflexive thematic analysis, a method commonly used in studies seeking to identify patterns of meaning (‘themes’), which does not adhere to any particular theoretical stance [ 26 , 27 ]. The initial step in this approach involved familiarization and engagement with the data by active (i.e. analytical, critical) reading and re-reading of the transcripts, while constantly attempting to interpret the information provided. This was followed by the generation of useful, meaningful codes, by means of a fluid, organic, active process in which codes evolved, were renamed, divided, collapsed and/or deleted [ 25 ]. The next step was to search for and develop themes from the codes, which were then reviewed within a thematic map, before finally being defined and named.

Thirty-five patients were interviewed, 10 with a relative present (contributing to varying degrees). Pathway overviews and participant characteristics, based on routine HMRN data collection from medical records are shown in Table 1 . The majority were aged in their sixth or seventh decade at interview, nineteen were male, and most resided with a relative, with three living alone. Twelve had myeloma, ten CLL, eight FL, and five MZL. Rich data were accumulated and reflexive thematic analysis resulted in the identification of four themes and 11 sub-themes. Key themes included: 1) Knowledge and understanding of chronic blood cancers; 2) Incurable but treatable; 3) Uncertainty about the future; and 4) Treatable (but still incurable): Impact for patients. Each theme is described below with sub-themes. Quotations are shown in italic and linked to participant numbers (e.g. P1 for the patient, P1R for P1’s relative) and diagnosis. Fig 1 depicts the hierarchy of themes and sub-themes.

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• TIFF original image

https://doi.org/10.1371/journal.pone.0263672.g001

https://doi.org/10.1371/journal.pone.0263672.t001

Theme 1, knowledge and understanding of chronic blood cancers

This theme contains five sub-themes that focus on patient knowledge, understanding and expectation regarding blood cancers.

Sub-theme 1, prior knowledge.

Many people said they had no prior knowledge of their malignancy type, with one saying he knew about ‘ standard cancers ’ but not myeloma (P16). In the context of CLL, P13 said she had known ‘ nothing ’ about her disease; and P29 said she had known leukaemia was a ‘blood cancer’, but no more. P30 said he ‘didn’t even know the word myeloma until I went to the doctors’ . Patients did not always immediately understand the nature of their chronic blood cancer, but initially reported focusing on specific phrases such as ‘not curable’ and ‘leukaemia’, which could be distressing, incurring shock and fear, particularly as there was little awareness about indolent and acute subtypes, or the different pathways and outcomes associated with each of these.

Sub-theme 2, unexpected diagnosis.

Some patients had been diagnosed incidentally and otherwise considered themselves well, so were confused to discover they had cancer. In patients with myeloma, for example, P21 was diagnosed at a routine check-up ‘by accident’; and P16 said his diagnosis came ‘ out of the blue ’ as he considered himself fit and active. Others had only minor symptoms and didn’t always feel ill, with P22 (CLL) explaining his surprise at being told he was ‘ a very poorly man’ at his first appointment, as his only prior symptom was tiredness; P15 (FL) declaring ‘ I wasn’t ill…it was just the lumps I found’ ; and P27 (CLL) saying apart from difficulty walking, he felt fine.

This was augmented in a number of patients, as they had actually attended medical appointments for what they presumed to be unrelated symptoms, but which were later attributed to their blood cancer. Examples include diagnosis following screening to assess breast lumps (P15: FL, P20: CLL); a GP visit for leg pains (P29: CLL); an ENT appointment for a neck lump (P17: FL); and a scan for osteoporosis (P35, myeloma). Conversely, however, some individuals had heard of their cancer and knew of its clinical signs, with one saying that the ‘jigsaw fell into place’ (P12: MZL), as he had thought his symptoms were due to lymphoma.

Sub-theme 3, expectations about chronic blood cancers.

A number of patients struggled to understand the characteristics of their cancer and why it could not simply be removed. In this context, P5 (MZL) described her main barrier being that what seemed like a stomach problem couldn’t be treated with a simple ‘zap’ ; she did, however, accept that her cancer was different to the type you could just ‘get rid of’ . Similarly, P13 (CLL) said she had found it hard to understand she had leukaemia because the first symptom was a lump in the armpit, which led her to presume that: ‘if it’s a lump they can just take it out’ and resulted in ‘ a bit of a shock ’ when she found this was not possible as the cancer was in her blood, so in her ‘whole body’ .

Based on their knowledge of other cancers, most people expected to start treatment immediately after diagnosis, whereas many were initially observed. While this satisfied some, particularly if a HCP had clearly explained the underpinning rationale, many found it difficult to comprehend. P26 (myeloma), for example, said: ‘it’s hard to understand you have something that is so…really frightening…yet nothing happens’ . P15 (FL), said she found it challenging to understand and accept and was ‘not prepared’ for the situation; she was also unclear about the circumstances that would lead to her starting treatment, saying: ‘ that was always a question I had; how doctors would know when to start treatment : it was almost like you had to become ill… .’. Similarly, P6 (CLL) and her husband described difficulty comprehending that ‘nothing was being done’ , whilst they just waited for things to get worse before: ‘they’ll sock it (treatment) to you’ .

Sub-theme 4, ongoing lack of knowledge.

While some later came to have a good grasp of their illness, others didn’t seem to reach this point and were still unclear about their malignancy a number of years post-diagnosis. P32 (MZL), for example, said she could not discuss her diagnosis with family, partly because she didn’t really understand it: ‘we’ve never ever… we’ve got a son and a daughter , we’ve never told them because really , we don’t know what we’re talking about…’ . Knowledge and understanding was found to impact on diagnostic disclosure, with P20 (CLL) saying he told his immediate family, but not his friends as he believed they wouldn’t comprehend why treatment had not started: ‘I don’t publicise it’ . This was echoed by P25 (FL), who said others didn’t understand the characteristics and impact of her cancer.

Sub-theme 5, signs of progression/relapse.

Several patients demonstrated clear knowledge of the signs of progression/relapse and how to respond: ‘(I) keep a look out and get in contact with them (HCPs) when…I get any…B symptoms of night sweats…itchy skin , tiredness , you know , problem with breathing and all that’ (P34: FL); with P25 (FL) saying she would ‘ know straightaway if something was wrong ’. Others were, however, worried about their lack of awareness. P19 (FL) for example, said that initially she hadn’t been told what to look for, and was ‘ not convinced that I would know if it was back ’. Having responsibility for recognising potential signs of progression and deciding when to report these was difficult for some, with P35 (myeloma) explaining: ‘That’s why it’s so complicated . So , it’s kind of down to me to tell them if I don’t feel right and I just find , that’s just a massive pressure’ .

Theme 2, incurable but treatable

This theme focuses on the information provided by HCP to promote understanding among patients and families about the characteristics of the chronic haematological malignancies; it also contains a sub-theme about response to this. Patients often mentioned that HCPs had referred to their cancer as being incurable but treatable. Phrases HCPs were said to use include: ‘ it’s very treatable’ (21R, myeloma); and ‘ there’s no cure but it is not life-threatening ’ (P20R, CLL). Similarly, P34 (FL) described being told he had cancer, but that it was: ‘ …low grade…slow growing but harder to get rid of … an incurable cancer; (that) the chemo was probably going to be effective in some way , but… I’d never be in full remission’ .

A number of people said their HCP likened their diagnosis to living with a chronic illness, with comparisons made to ‘ diabetes ’ (P15: FL), and ‘ similar to me COPD’ [sic] (P25: FL). In terms of prognosis, several others said that reassurance emerged via HCPs implying they would die from other causes, not the blood cancer itself, recounting phrases such as: ‘(you) could actually die with it , not because of it’ (P7, CLL). P32 (MZL), described being told she could expect a lifespan that was ‘same as anybody else’ . P32R went on to say ‘…it’s the stigma , with the word cancer and that . Everybody thinks it’s a death sentence , don’t they ? So (doctor) sort of said it , there’s something wrong with you , but you can live with it . It wasn’t life threatening or anything like that…’ .

Sub-theme 1, relief or distress? Many interviewees described feeling relief at hearing their cancer was incurable but treatable, with P7 (CLL) considering this: ‘ a big ray of hope in the distance’ ; and P3 (CLL) feeling ‘positive’ after his haematologist told him he would certainly be attending clinic ten years hence. P12 (MZL) said that after being told ‘it’s more likely you’ll die with it than of it… . that phrase settled me…’ . Another was similarly reassured when their consultant said: ‘ …this could take weeks to develop , months , decades…go and live your life’ (P26: myeloma). P17 (FL) described being ‘ in a bit of state of shock at diagnosis ’, but relieved when the haematologist said: ‘we can treat this’ . The relative of P22 (CLL), said she and her husband coped by focusing on such positive phrases.

While some patients were reassured, however, others were deeply troubled. P35 (myeloma) for example, said progression was always on her mind: ‘ it’s just horrible being in this position where you know (the paraprotein) it’s creeping up’ . Similarly, P34 (FL), said: ‘it’s hard not to think that everything is related to lymphoma . Any time something happens to me I’ve got it in the back of my mind , what’s this ache I’ve got ? ’ . P17 (FL) described the sudden appearance of a neck lump (later diagnosed as a cyst), saying: ‘you obviously think it’s something to do with the lymphoma’ . The need for counselling, or psychological/emotional support was noted by some patients, and also family members. P4 (MZL), P13 (CLL) and P19 (FL), for example, reported accessing such services to help them manage diagnostic distress; although P12 (SMZ), said his diagnosis didn’t affect him ‘ psychologically ’ as he had a ‘ low-grade type ’. This issue of distress is picked up in greater detail in Theme 4, Sub-theme 2.

Theme 3, uncertainty about the future

Uncertainty generally pertained to the occurrence and timing of cancer progression, the need for treatment, and prognosis, as described within the two sub-themes below.

Sub-theme 1, progression.

Although patients were told progression might never occur, they were aware it could still happen at any time and on numerous occasions, with the need for multiple lines of increasingly intensive chemotherapy. In the context of myeloma, P28 said ‘ they’ve wanted to put me on a 4 th line of treatment… . my light chains are very high…’ . Changes were said to happen slowly or rapidly, and could lead to altered treatment plans. P18 (myeloma), for example, described gradually ‘getting more and more breathless’ in the post-transplant period as he relapsed, with further chemotherapy given prior to a planned second transplant, which was then abruptly ‘ruled out’ as his ‘free light chains had rocketed back up again’ .

Uncertainty about the timing of progression/relapse was said to be clearly communicated at various time-points on the pathway. At diagnosis, for example, P20 said his CNS ‘went through it very thoroughly’ explaining that his CLL may progress, but that ‘nothing might happen during (his) life-time…you might live with it as long as you live’ ; and P30 (myeloma) noted how one doctor ‘went straight to the point’ , telling him ‘sometime or other chemo will have to come in , but he didn’t say when’ . Uncertainty about future progression/relapse was also conveyed post-treatment, as noted by P34 (FL) whose HCP ‘basically explained…how you cannot predict what’s going to happen . It may never , ever come back . It may come back tomorrow . It’s just completely uncertain and that’s what you have to have in your head…’ . Similarly, P10 (FL), described how after second-line chemotherapy, his consultant had said the cancer: ‘had gone completely , but could come back 5 or 10 years down the line (as there wasn’t) 100% guarantee that it won’t , but in all honesty , we think it probably will at some stage come back…it’s a raffle really…you could be lucky or it could come back’ . P16 (myeloma) said ‘(HCPs) advise you…be prepared it could return…I know mine will…’ .

Sub-theme 2, prognosis.

With respect to prognosis, patients described being told that their survival duration was also unclear. Importantly, however, there was often recognition and understanding that this reflected genuine clinical uncertainty, due to the unpredictability of their cancer, rather than the withholding of information by HPCs ( Box 1 ) . P11 (myeloma), for example said he had reached ‘ a plateau ’ and that his clinicians had said: ‘ some people stay on that plateau for quite a long time , others don’t ’. This patient seemed to understand that doctors couldn’t be certain about individual patients, and that nobody can ‘ really know what’s in store down the line ’. P25 (FL) described how she wanted to know more about her prognosis including: ‘what is the likelihood of (the cancer) coming back…what’s the odds ? ’ and ‘ how many people live to a ripe old age and die of something else ? ’ but compared this to asking ‘how long is a piece of string ? ’ ; and P3 (CLL) explained that having an uncertain pathway meant it was difficult to know when was the right time to ask about prognosis.

Box 1. Reflections on genuine clinical uncertainty

○ ‘(HCPs) couldn’t say for sure what my prognosis was because they really didn’t know… everyone is different , that’s what I learned’ (P3: CLL)

○ ‘(HCPs) just don’t know how it will evolve in your body’ (P4: MZL)

○ ‘there aren’t any answers…you’ve just got to wait and see’ (P7R: CLL)

○ ‘everyone is different and so it’s difficult to say , well this is going to happen…it’s not that certain’ (P15: FL)

○ ‘(HCPs) can’t give you a timescale…you accept the worst and hope for the best’ (P16: myeloma)

○ ‘there are a lot questions that people just don’t know the answers to’ (P18: myeloma)

○ ‘(HCP) just said “we don’t know…” , they’ve never actually said “the average is 6 years or the average is… [before relapse]” I don’t think they can’ (P19: FL)

○ ‘(HCP said) we can’t give you an answer (about prognosis) , we don’t know…everybody is different , which I can accept that’ (P25: FL)

○ ‘myeloma is a very individual disease…you get the same treatment , same this , same that , but you have different outcomes’ (P28: myeloma)

Theme 4, treatable (but still incurable): Impact on patients

Having a treatable but incurable chronic haematological malignancy, affected patients differently, with the diagnosis gaining or losing impact over time, and some individuals experiencing particular emotional difficulties coping with uncertain future pathways, as depicted in the sub-themes below.

Sub-theme 1, diminishing impact.

For some, the impact of their indolent blood cancer diminished as they became more accustomed to it, especially if they had not required any treatment, and were being monitored less often. This was particularly apparent in CLL, but also to a lesser extent other diagnoses, with one patient (P26, myeloma) starting with 3 monthly monitoring, which reduced to checks every 6 months, before being replaced by telephone appointments. In another example, P29 said she had spoken to her consultant about the future and been told ‘ right at the beginning , maybe 5 years , maybe more ’; 3 years post-diagnosis at interview, she said: ‘ so I’ll just keep going’ , saying she didn’t want to dwell on her disease, as keeping positive helped her cope.

Sub-theme 2, increasing impact and emotional difficulties.

For many, having a chronic haematological malignancy had a significant impact on their life. One such group included patients for whom severe emotional distress appeared to be ongoing, causing greater difficulty than any physical effects from the cancer. Such anxiety was clearly portrayed by P35 (myeloma), who said: ‘ …you’re at different stages all the time , and I’m in a bit of a difficult [stage] I think it’s like fear of not knowing what’s going on is harder than like , if someone says , you’ve got to have this and [you can] psych up for it . I’m just in an awful time for me , but then again , I’m constantly wrangling with myself , because then I just think , I’m just so grateful to be here and I do have treatment options , you know , it could be worse…and my quality of life is good at this point and I don’t want to waste it by [being] up and down . Oh , I’m so anxious , you know , I really don’t want to do that . I just want to get on . It’s bloody hard though’ . Similarly, P25 (FL) described distress caused by wondered how long her cancer would be ‘manageable’ , comparing her situation to ‘Russian roulette (where) someone has got a gun against my head…’ . The same patient, who had attended the haematology clinic regularly since diagnosis, reported being anxious when she didn’t receive her usual appointment and ‘kept ringing up’ , only to be told she was on a waiting list. She said she just needed reassuring that she was ‘alright’ , but felt her HCPs were simply ‘ waiting for me to die’ .

Sub-theme 3, survival.

Despite being treatable, chronic blood cancers are generally considered incurable, and can potentially effect survival, which was of great concern to some, including younger patients, such as P28 (age 59 at diagnosis; myeloma): ‘it’s a non-curable cancer… certainly , it’s treatable , but nonetheless , that was kind of a big shock in itself , a huge shock (finding) 50% of people survive 5 years’ . In an ‘ unforgettable’ exchange with an HCP, P4 (age 57, MZL) recounted being reassured that her cancer was treatable, but then learning it could significantly limit her life expectancy: ‘the first thing (HCP) said to me was “you might only live 5 years with it…” . I just couldn’t take it in…you’ve just been told you’ve got cancer and she’s saying “you might only live for 5 years ! ”‘ . S ome older patients viewed their prognosis in the context of their life-span, however; P15 (FL, age 72), for example, saying: ‘ 10 years , which at my age is more than you could hope for’ .

Interestingly, P35 (myeloma) noted undue optimism from clinical staff about her treatment and prognosis: ‘They kind of just acted in a positive way . They don’t say : “it might not work” . They’re just being really positive , but…I was in the unfortunate situation of knowing someone really well who had (myeloma) , and he’d had a really bad time and none of the treatment worked’ . P35 went on to describe having asked: ‘… can I live to be an old person ? And (nurse) said…I’ll never forget it , it’s in my mind a lot , she said , “you might have to re-evaluate what you mean by old” , and it really sticks in my mind but I couldn’t bring myself to ask any more questions [became upset]’ . She then demonstrated a mix of fear and hope, saying: ‘ I’ve never dared ask how long I might live and things like that , because they don’t know , because like , what works for one person doesn’t work for another , and you get these people who get long remissions . I always have a few questions , but I don’t ask the things that are sort of on my mind . It’s just too big’ .

Maintaining optimism was considered important by P35 (above) and other interviewees. P24 (FL) said it was important for doctors to give patients hope, and for patients to maintain a positive mental outlook. Patients themselves often placed their hope in new therapies, with P34 (FL) saying he hoped his prognosis had improved since diagnosis: ‘treatments have changed… and obviously it’s going to be a lot better outcome (now) . I know that the outcome would have been different if I hadn’t have had (drug) … you know , I don’t think I would have been told 5 years . But now , who knows . They told me if I went now , they’d give me a different… prognosis . They’d be looking at what I am now…going forward…’ . P11 (myeloma) said: ‘they are constantly improving medication’ ; and the relative of P27 (CLL) reported their consultant saying ‘things are moving on all the time… we can re-treat’ , which gave them ‘a lot of confidence’ .

4. Discussion

This study contributes novel evidence about the experiences of patients with chronic haematological malignancies. Specifically, we identified a distinct lack of knowledge about such cancers among patients, HCP communication strategies that often aimed to reassure individuals about their indolent diagnosis, and an immense amount of uncertainty about the future. The resulting impact on patients varied, with some feeling relieved that although their chronic cancer may not be curable, it could be treated (if treatment was ever required), while others struggled to grasp and deal with this. Living with uncertainty often caused marked ongoing emotional distress, even among patients with the most indolent diseases, who were asymptomatic and did not require treatment; and in many cases this appeared more burdensome than any physical consequences of the cancer.

The unusual pathways of chronic haematological malignancies clearly impacted on the well-being of some patients. Compared to other cancers, for example, where relapse may only need to be considered once or twice, individuals with chronic blood cancers may have to face this repeatedly, on a third, fourth or subsequent occasion, across their remaining life. This is also a crucial difference between the chronic subtypes targeted in the current study and the more aggressive entities that may be potentially curable with intensive treatment; after which (similar to many other cancers) a distinct ‘survivorship’ phase begins. This marks another divergence, as traditional concepts of survivorship denote a phase ‘beyond’ treatment [ 28 – 30 ], a time-point never reached on the remitting-relapsing pathway of chronic blood cancers, meaning resources and national initiatives set-up to meet long-term needs are not always applicable to these patients.

Although communicating information about uncertain pathways is a major component of existing good clinical practice, which was clearly appreciated by participants, some continued to struggle with this constantly being a part of their lives. Described as an ‘ever-shifting perspective between illness and wellness’ in the context of myeloma [ 18 ], this situation has been linked to anxiety, distress, depression, isolation and quality of life levels that match those of patients receiving treatment [ 12 , 17 – 19 , 31 , 32 ]. Indeed, psychological adjustment has been described as more difficult in these cancers than physical effects [ 12 ]. Unfortunately, the very nature of chronic haematological malignancies means patients attend clinic infrequently, or less often those with acute subtypes, so may have little face-to-face time with clinicians [ 19 ], reflecting fewer opportunities for HCPs to identify difficulties, provide reassurance and facilitate interventions.

Interestingly, patients with cancer have been described as experiencing ‘a journey of never-ending making sense’ as they attempt to regain control over their lives, despite changes in their disease and treatment [ 33 ]; a compelling perspective in the context of chronic blood cancers. A further interesting notion pertinent to the inherent uncertainty associated with blood cancers is that discussions about the future and prognosis should adopt an individualized, sensitive and honest approach that achieves a balance between hope and a realism [ 34 – 37 ]. Not a new idea, this concept gained importance in the last decade and may protect patients from over-optimism regarding prognosis, as was noted in our study and is recognised to exist more generally among HCPs providing cancer care [ 38 , 39 ]. It may also improve preparedness for disease progression or relapse, and the need for (more) treatment, or indeed end of life care, where this situation arises.

As noted, patients with chronic blood cancers do not always commence treatment immediately at diagnosis, but may instead be observed, only receiving treatment at disease progression or when they become (more) physically symptomatic; a concept many patients found difficult to process and a factor that contributed to their anxiety. Such anxiety is perhaps unsurprising, however, as preventing delayed cancer diagnosis is at the forefront of NHS policy and, combined with early treatment, is recognised as a means of maximising survival [ 40 , 41 ]. In this context, and as similar initial management strategies may also occur in other cancers (e.g. active surveillance in prostate cancer [ 42 ]), raising awareness among the public that such pathways are evidence-based and set within national guidance may be helpful.

In line with our findings, other studies note a pre-diagnostic lack of knowledge about haematological malignancies, and an ongoing lack of understanding about these diseases, although there was recognition that they differed from other cancers [ 5 , 12 , 43 ]. The patients we interviewed who had been diagnosed with myeloma described what appeared to be particularly difficulty pathways compared to those with the other subtypes of interest, perhaps because disease progression was almost inevitable in myeloma [ 18 ]; complications (e.g. fractures and renal failure) often occurred before and after diagnosis [ 44 ]; and quality of life and physical functioning was considered more problematic than for other blood cancers [ 45 ]. This group of patients is also reported to have limited understanding of their diagnosis, compared to levels of comprehension among people with other cancers [ 15 ].

Worryingly, patients in a UK study of CLL noted how their doctors do not always seem to fully appreciate how they feel, or are affected by their cancer [ 17 ]. The research we present here, however, in conjunction with that of others, has clearly shown that problems (e.g. psycho-social and information needs) may be significant and enduring [ 12 , 17 – 19 , 31 , 32 ]. This is important in the context of clinical practice and health policy (including survivorship), in order to ensure the unmet needs and challenges experienced by patients with chronic blood cancers are not overlooked by HCPs, simply because their disease is less acute than other haematological malignancies, and more long-term. It is also important that further research takes place examining the extent to which HCPs are aware of anxieties and distress; and the availability and effectiveness of interventions to address this.

To our knowledge this is the first study focusing solely on the experiences of patients with chronic haematological malignancies. Purposive sampling ensured information rich participants were included [ 22 ], thereby aligning with the concept of information power [ 24 , 25 ]. The analytical process involved two experienced researchers and quality was ensured via ongoing engagement with the data and reflexive interpretation [ 25 ]. Findings are comprehensively described and provide new insights into an important, under-researched area, which highlights significant challenges for patients. Our results are likely to be transferable [ 46 ] within the UK and countries with similar health-care services, and to other chronic cancers/conditions. Despite significant efforts, we were unsuccessful in recruiting interviewees ethnic minority backgrounds, and future dedicated research is required in this area. Finally, we interviewed patients who consented to further contact via the HMRN Partnership, thus did not capture the experiences of those too ill to be approached.

5. Conclusion

Many participants lacked knowledge about chronic haematological malignancies. HCPs acted to reassure patients about their diagnosis, and while this was appropriate and effective for some, it was less so for others, as the cancer-impact involved struggling to cope with ongoing, uncertainty, anxiety, distress and a shortened life-span, which could be more burdensome than any physical symptoms.

Supporting information

https://doi.org/10.1371/journal.pone.0263672.s001

Acknowledgments

We wish to thank the study participants who openly shared sensitive information about emotive issues.

Patient and public involvement (PPI)

All HMRN studies benefit from significant PPI via a Patient Partnership. The present study arose due to PPI into HMRN’s research agenda. Patients were involved as co-applicants for funding and on the steering committee; they commented on paperwork and provided a ‘Sounding Board’ for findings.

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Blood cancers affect the production and function of your blood cells. Most of these cancers start in your bone marrow where blood is produced. Stem cells in your bone marrow mature and develop into three types of blood cells: red blood cells, white blood cells, or platelets. In most blood cancers, the normal blood cell development process is interrupted by uncontrolled growth of an abnormal type of blood cell. These abnormal blood cells, or cancerous cells, prevent your blood from performing many of its functions, like fighting off infections or preventing serious bleeding.

There are three main types of blood cancers:

• Leukemia , a type of cancer found in your blood and bone marrow, is caused by the rapid production of abnormal white blood cells. The high number of abnormal white blood cells are not able to fight infection, and they impair the ability of the bone marrow to produce red blood cells and platelets.
• Lymphoma  is a type of blood cancer that affects the lymphatic system, which removes excess fluids from your body and produces immune cells. Lymphocytes are a type of white blood cell that fight infection. Abnormal lymphocytes become lymphoma cells, which multiply and collect in your lymph nodes and other tissues. Over time, these cancerous cells impair your immune system.
• Myeloma  is a cancer of the plasma cells. Plasma cells are white blood cells that produce disease- and infection-fighting antibodies in your body. Myeloma cells prevent the normal production of antibodies, leaving your body's immune system weakened and susceptible to infection. 

Cancer Cells vs. Healthy Cells

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• v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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• Published: 27 August 2024

Epidemiology

Intention to have blood-based multi-cancer early detection (MCED) screening: a cross-sectional population-based survey in England

• Ninian Schmeising-Barnes 1 , 2 ,
• Jo Waller 1 , 2 &
• Laura A. V. Marlow   ORCID: orcid.org/0000-0003-1709-2397 1 , 2  

British Journal of Cancer ( 2024 ) Cite this article

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Metrics details

• Human behaviour

Trials assessing the clinical utility of blood-based multi-cancer early detection (MCED) tests are underway. Understanding public attitudes towards MCED screening is essential if these tests are to be used. We aimed to quantify MCED screening intention and potential barriers and facilitators to uptake.

Adults aged 50–77 ( n  = 958) completed an online survey. The primary outcome was intention to have MCED screening if offered. Psychological variables including barriers and facilitators were assessed. We used logistic regressions to explore associations between socio-demographics and psychological factors and intention.

93.8% of participants said they would ‘definitely’ or ‘probably’ have MCED screening if offered. Intention was significantly associated with previous screening participation and general cancer attitudes but not with socio-demographic factors. Participants were more likely to be intenders if they had higher health motivation, and perceived greater benefits of blood tests. Participants were less likely to be intenders if they perceived greater disadvantages of blood tests, more practical barriers, were more worried about the outcome and more concerned about a positive result.

Conclusions and implications

MCED screening intention was high. The lack of socio-demographic variation suggests equitable interest in this type of screening; however, future research should consider how intention translates to uptake.

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Earlier stage of cancer diagnosis is generally associated with improved survival [ 1 ], as it often increases the chance of successful treatment and outcomes [ 2 ]. The NHS Long Term plan set the ambition that 75% of cancers should be diagnosed at stage 1 or 2 by 2028 [ 3 ]. Cancer screening aims to identify cancer and pre-cancerous conditions in asymptomatic individuals, but at present only around 6% of cancers are diagnosed through screening in England [ 4 ]. Although England currently has three single cancer screening programmes and targeted lung health checks [ 5 , 6 ], many other cancers have no effective screening test, including aggressive cancers such as pancreatic and stomach cancer. Multi-cancer early detection (MCED) blood tests show potential for detecting cancers before symptoms appear. Blood-based MCED tests look for the presence of circulating tumour DNA or other biomarkers in a standard blood sample and can predict the location of the cancer, in order to direct diagnostic follow-up [ 7 ]. A number of MCED tests are in development [ 8 ] and trials are currently underway to establish the clinical utility of these tests in asymptomatic individuals, with the hope that MCED tests could be used for population screening in the future [ 9 , 10 , 11 ].

The UK National Screening Committee recognises that any new screening programme should be acceptable to the target population and the public [ 12 ], since acceptability has implications for engagement, uptake and the overall success of a screening programme [ 13 ]. One qualitative study has suggested that the introduction of a population-based MCED screening programme will be appealing due to the simplicity and familiarity of the blood test procedure. However, the potential for positive results and follow-up testing to cause anxiety was an area of concern for participants, and personal beliefs about the benefits of diagnosing cancer early influenced desire for the test [ 14 ]. The proportion of people who would want MCED screening, and the barriers and facilitators to this kind of test, have not yet been quantified. It is essential that public attitudes to MCED screening are better understood prior to any future implementation [ 15 ].

Many studies investigating the acceptability of screening programmes use intention to participate as a proxy for acceptability [ 16 , 17 , 18 , 19 ]. Intention has been shown to be a good predictor of future screening uptake, and to be indicative of programme acceptability [ 20 , 21 ], though there is a gap between intention and behaviour [ 22 ]. Quantifying intention can support estimates of cost-effectiveness of a screening programme and plans for resource allocation. There are well-established inequalities in uptake of cancer screening programmes [ 23 ], so, research identifying health inequalities should be embedded in the evaluation and introduction of a new screening programme [ 12 ]. Understanding the barriers and facilitators to screening participation and whether these might be more/less prevalent among people from lower socio-economic or ethnic minority backgrounds is also important. This can help identify content for information materials to ensure they address questions or concerns that people might face in response to screening invitations and inform proactive interventions to promote equitable uptake.

To our knowledge, no other studies to date have explored intention to participate in population-based MCED blood test screening. Our objectives were: (1) to estimate the proportion of people in a population-representative sample with positive intentions to have an MCED blood test for screening, (2) to quantify the prevalence of barriers and facilitators to having an MCED blood test, (3) to explore socio-demographic predictors of barrier and facilitator endorsement and (4) to explore socio-demographic and psychological predictors of intention to have an MCED blood test.

This study is reported following the CROSS reporting guidelines [ 24 ] and a copy of the checklist is available in Supplementary material  A .

We ran a cross-sectional online population-based survey of men and women aged 50–77 years in England. The sample was representative of the English population within this age-group in terms of age, sex, ethnicity, social grade and region. Ethical approval for this study was granted by King’s College London Research Ethics committee (LRM-22/23-36139, 06/06/2023). Informed consent was obtained. The study protocol is available at: https://osf.io/zm4v6/ .

Data collection was carried out in June 2023 by YouGov. Participants were identified through YouGov’s online research panel. The UK panel includes 2.7 million people recruited via the YouGov website and through social media advertising. Participants receive points for taking part in surveys which can then be exchanged for shopping vouchers.

Participants

Eligible participants were aged 50–77 years, and currently living in England. This age range matches participants in the ongoing trial of an MCED test (the NHS-Galleri trial; NCT05611632 [ 11 ]) and is likely to reflect the population who would be offered MCED blood test screening if it were rolled out at population level. Participants who had taken part in the NHS-Galleri trial and/or had received a cancer diagnosis in the previous three years were not eligible to participate. Potential participants were identified by YouGov from their panel.

Our target sample size was n  = 1000. This was designed to allow us to estimate intention to have an MCED blood test with good precision (±3%, with 95% confidence, assuming a prevalence of 60–70% for positive intentions).

Materials and measures

A survey was created by the authors (behavioural scientists) in collaboration with patient and public involvement (PPI) representatives. A detailed description of all survey items is available at: https://osf.io/ka3t7 . The survey was only available in English. Participants were shown introductory information about MCED screening followed by additional information about diagnostic work-up following a positive result, including an estimated false positive rate of 0.5% (1 in 200) and a positive predictive value of 50% (1 in 2 with a positive result having cancer); see Box  1 . After the introductory information participants answered three knowledge-based attention check questions before completing questions assessing intention, barriers and facilitators. After the additional information about follow-up diagnostic testing, they answered more questions. All questions were mandatory to avoid missing data, except for questions relating to personal details such as health and gender identity, which participants could skip. Participants were excluded from any analyses for which their data were missing.

The full survey is available here: https://osf.io/68wvb . The primary outcome was intention to have MCED screening if offered, measured on a five-point scale with a single item: ‘If you were offered a blood test that looks for a range of cancers would you have it?’ (response options ordered as follows: definitely not; probably not; yes probably; yes definitely and don’t know). Participants who responded probably or definitely not were offered a free-text box to say why. We asked this question twice, at the beginning of the survey after the introductory information (initial intention) and then again after additional information had been provided (considered intention).

The survey included items assessing perceived barriers and facilitators to MCED screening. These items were developed to cover a range of constructs from several theories e.g. the Health Belief Model [ 25 ], previous research in the cancer screening context (e.g. [ 26 , 27 ]) and a qualitative study exploring attitudes to MCED blood tests [ 14 ]. It also contained items assessing cancer-related attitudes: attitudes to screening [ 28 ], cancer fatalism [ 29 ], cancer risk perceptions [ 30 , 31 ] and attitudes to overdiagnosis [ 28 ]. Detail about the source of each item is in the protocol ( https://osf.io/ka3t7 ).

We adopted YouGov’s standard socio-demographic questions for age, ethnicity, social grade (based on occupation of the highest household earner), and region, with additional items from the UK census included to assess sex, marital status, education and self-reported disability. We also assessed previous screening behaviour (items adapted from the Cancer Awareness Measure [ 26 ]), and global self-rated health [ 32 ]. The survey items were a combination of validated and unvalidated measures and were assessed for face validity via PPI feedback.

Box 1 Information presented to participants about MCED tests within the survey

Initial information:

This survey is about your thoughts on a new blood test that looks for a range of cancers. This type of test looks for cancer markers in a blood sample. This is called a Multi Cancer Early Detection (MCED) blood test.

This test would be a normal blood test. A health professional would take a small tube of blood and send this to a lab for testing.

This would be a screening test for healthy people without symptoms. The test would be used alongside existing cancer screening.

If cancer markers are found, you would need to have follow-up tests at a local hospital to see if you have cancer. About half of the people who are sent for further tests are expected to have a cancer found.

Further information:

If a cancer marker is found in your blood, you would need to have follow-up tests (e.g. scans) at a local hospital to see if you have cancer.

Imagine that 200 people have this test: 2 out of 200 people will have a cancer marker found in their blood. 1 of these would have cancer diagnosed after further tests and 1 would not.

(This is an estimate, we do not know exactly how these tests will perform yet).

Participants were sent an email including a unique re-direct link taking them to the survey. This allowed YouGov to link responses to socio-demographic data and avoided multiple submissions. Participants who clicked the link were shown a participant information page and asked to indicate consent to take part.

When participants completed the survey, they were thanked for their participation and offered sources of support. Participants received 150 YouGov points (approximately £1.50) upon completion of the survey.

All datasets were anonymous. The data were analysed using the Complex Samples functionality in IBM SPSS Statistics 29 and followed a pre-written analysis plan (available here: https://osf.io/zm4v6/ ) . Deviations from this plan were recorded in a separate document ( https://osf.io/zm4v6/ ). Weights were provided by YouGov to account for outstanding variation between the recruited sample and the wider population with respect to age, sex, social grade, region and ethnicity so that the sample was representative of English adults aged 50–77 years [ 33 ]. All analyses were weighted so that the sample was population representative. Participants were excluded prior to analyses if they completed the survey too quickly (in less than 5 min), too slowly (in more than 3 standard deviations above the mean time taken) or if they answered all three attention check questions incorrectly.

Frequencies and proportions (with 95% confidence intervals) of individuals giving each response option for the two intention items (initial and considered) were reported. For further analysis exploring intention, a single binary variable was created using considered intention and classifying participants as ‘intenders’ or ‘non-intenders/don’t knows’. We used logistic regression to assess whether intention (using the binary outcome) was associated with socio-demographic characteristics.

The frequency and proportion of individuals responding ‘agree’/‘strongly agree’ or ‘quite a bit’/‘a great deal’ to each barrier/facilitator item is reported (full breakdown of responses available in Supplementary Tables  1 and 2 ). Following Exploratory Factor Analysis (EFA, see supplementary material), the 21 items assessing barriers and facilitators were reduced to five scales assessing: Health Motivation (4 items; Cronbach’s alpha = 0.85); Benefits of blood tests (4 items; Cronbach’s alpha = 0.87); Disadvantages of blood tests (4 items, Cronbach’s Alpha = 0.80); Practical barriers (3 items, Cronbach’s alpha = 0.71) and Fear of outcome (3 items, Cronbach’s alpha = 0.82). The six items assessing concern about a positive result formed an additional scale (Cronbach’s alpha = 0.90). Scales were created by summing the items and adjusting for a minimum score of zero. Three items did not fit in the scales and were analysed individually. We used fully adjusted ANCOVAs to assess whether age, sex, social grade, ethnicity or employment status were independently associated with barriers/facilitators scores. For the three single item barriers, we ran logistic regressions to examine demographic associations. We used a Bonferroni correction to adjust for multiple comparisons (45 in total), resulting in a p-value of <0.001 being considered statistically significant.

We used logistic regression to assess whether intention (using the binary outcome) was associated with any of the psychological variables including: perceived risk of cancer, cancer worry, fatalism, attitudes to screening/overdiagnosis and the six scales or three individual items assessing barriers/facilitators. We used content analysis to analyse the free text responses recorded by participants who responded ‘probably not’ or ‘definitely not’ to the intention item. Two authors worked together to develop a coding frame and independently coded each response. Discrepancies were discussed and resolved.

Public and patient involvement (PPI)

A PPI panel consisting of five participants was involved in the development of the participant information page, consent form, and survey. The panel included two women and three men aged 50–70 years and included people with and without personal cancer experience. Development of the research questions was carried out before recruitment of the PPI panel. Our PPI panel had substantial influence on the information that was presented and the need to split this into different sections. Discussion also included in-depth debate about the best wording for items and their response options. The discussions provided an indication of the face validity of newly created items, and ensured they were presented in a logical and user-friendly way.

Of the 1250 people who clicked the survey link, 1052 were eligible and consented (representing an 84.2% completion rate based on survey completes/survey started). The survey was fully completed by 1002 participants but 44 were excluded prior to analysis ( n  = 10 for answering all three attention check items incorrectly; n  = 34 for completing the survey too quickly/slowly). Data from 958 participants was included in the analysis. Sample characteristics are presented in Table  1 .

Intention to have MCED screening

Initially, most participants said they would ‘probably’ ( N  = 299; 31.3%) or ‘definitely’ ( n  = 595; 62.2%) have MCED screening (initial intention) with a slight increase in intention strength after reading additional information, ( n  = 257; 26.9% and n  = 641; 66.9% respectively). All 36 people who said they would probably or definitely not have the test after the initial intention question recorded a free-text response. Participants gave a range of different reasons for their response. The most frequent were: ‘test causing anxiety’ ( n  = 12), ‘not wanting to know about cancer’ ( n  = 7), ‘low perceived need for the test’ ( n  = 7) and ‘wanting to focus on living life’ ( n  = 5) (see Supplementary Table  3 for all responses).

Using the binary outcome (intenders versus non-intenders/don’t know), we did not find significant associations between intention to have MCED screening and any of the socio-demographic characteristics we assessed (age, sex, social grade, ethnicity, education, employment and marital status) or with self-rated health (see Table  2 ). Of the 860 participants who were eligible for any of the three screening programmes, those who reported never attending any screening or only attending some screening were less likely to be intenders than those who had attended all the screening they were eligible for ( n  = 5/7; 71.2% who had never attended and n  = 172/203; 84.7% who had attended some compared with n  = 629/650; 96.6% who had attended all). Those who reported ‘a bad experience’ of screening in the past were less likely to be intenders (83.0%) than those who had not (94.4%)

Barriers and facilitators to MCED screening

The percentage of participants who endorsed each barrier and facilitator to MCED screening is presented in Table  3 . The most frequently endorsed barriers were: being frightened about what the test might find (45.0%), needing to know more about how the test works (39.6%) and the potential for MCED screening to cause worry about cancer (32.0%). The least frequently endorsed barrier to MCED screening was being ‘too busy’ (1.2%). The most frequently endorsed facilitators to MCED screening related to blood tests being safe (92.7%), quick (92.9%) and familiar (86.7%).

We looked at whether socio-demographic characteristics (age, sex, social grade, ethnicity and employment status) were associated with any of the six composite scales (Supplementary Tables  6 and 7 ). Scores for the ‘practical barriers’ were significantly higher in individuals from lower social grades (C1, C2 and D/E) compared to those from the highest social grade (A/B; p  < 0.001). Older age groups had lower ‘fear of outcome’ scores compared with the youngest group ( p  < 0.001). Participants from ethnic minority backgrounds were also more likely to say that they would need more information than participants from white ethnic backgrounds ( p  < 0.001).

Psychological predictors of intention

General beliefs about cancer risk, fatalism and general attitudes to cancer screening were significantly associated with intention to have MCED screening (see Tables  2 and 4 ). Participants were less likely to be intenders if they felt their risk of cancer was ‘above average’ or ‘below average’ (82.2%) versus ‘same as average’ (95.4%), and if they worried about cancer ‘often’ or ‘very often’ (88.4%) versus ‘never’/‘rarely’/‘sometimes’ (94.4%). Participants who believed cancer is predetermined were also less likely to be intenders (86.4%) than those who did not hold this fatalistic belief (95.7%).

Participants were more likely to be intenders if they believed: cancer screening is always a good idea, that finding cancer early means that treatment saves lives, or that finding cancer means a person has less treatment ( p  < 0.001). Views on overdiagnosis were also associated with intention, with participants more likely to be intenders if: they said they would want to be tested for cancer, even if nothing could be done; they said they would still have screening, even if it was for a slow-growing cancer that would not cause them harm in their lifetime; they said they would have the recommended treatment for early-stage cancer ( p  < 0.001).

Using the six barrier and facilitator scales we looked at the association between barriers and facilitators and intention. In unadjusted analyses, all scales were significantly associated with intention to have MCED screening ( p  < 0.001) (Table  5 ). Higher ‘Health motivation’ and ‘Benefits of blood tests’ scores were associated with increased odds of being an intender. Conversely, higher scores on ‘Disadvantages of blood tests’, ‘Fear of outcome’, ‘Practical barriers’ and ‘Concerns about a ‘positive’ result’ were associated with decreased odds of being an intender. Participants who said that they would need more information ( F (1957) = 16.15 p  < 0.001), that they wouldn’t trust the results (F(1957) = 30.79 p  < 0.001), or that they had more important things to worry about (F(1957) = 24.83 p  < 0.001) were less likely to be intenders. After adjusting for all the barriers and facilitators (scales and items), three scales remained significant predictors of intention to have MCED screening: health motivation (F(1957) = 64.37 p  < 0.001), practical barriers (F(1957) = 6.19 p  = 0.013) and concerns after results (F(1957) = 16.66 p  < 0.001) (Supplementary Tables  4 and 5 ).

In this population-based survey in England, most people said they would have MCED screening and intention remained high after receiving additional information about diagnostic work-up following a positive result and the potential for false-positive results. Intention to have MCED screening was not associated with socio-demographic characteristics but did vary according to previous screening behaviours and attitudes to cancer and screening in general. General health motivation, anticipated practical barriers and concerns about what would happen following a positive result, were the strongest predictors of intention to have MCED screening. The need for additional information, fear of the outcome and concern about what would happen after results were endorsed by a sizeable minority (i.e. over a third of participants).

This is the first study to quantify intention to have MCED screening in a sample representative of the English population following provision of brief information. The findings add to evidence from a 2021 report investigating public priorities in cancer research which reported that 70% of participants would want a single blood test for multiple cancers, but they were not given any further information about blood tests for cancer screening [ 34 ]. Since intention is a strong predictor of uptake [ 20 ], the high intention demonstrated in our study, following brief information, suggests MCED screening uptake could be high if rolled out across England. Nevertheless, it is important to consider that intention does not always translate into action in cancer screening contexts [ 22 ]. For example, in colorectal cancer screening 80% of people who said they would probably or definitely have screening subsequently attended flexi-sigmoidoscopy [ 21 ]. Future research is needed to assess how intention translates to action in the context of MCED screening and factors influencing this. The finding that intention did not vary by socio-economic and demographic characteristics suggests motivation to have MCED screening may be equally high across socio-demographic groups. Nevertheless, as outlined in widely used behaviour change frameworks (e.g. COM-B [ 35 ]), capability (whether someone has the knowledge, skills and abilities to engage in particular behaviour) and opportunity (external factors influencing whether a behaviour can be executed) are also important determinants of health behaviour.

Previous screening behaviour significantly predicted intention to have MCED screening, consistent with previous research in other screening contexts [ 19 , 36 ]. MCED screening does hold potential to engage people whose previous non-attendance/participation is driven by aversion to more invasive procedures, and intention to have an MCED test was still high in those who had never or inconsistently attended (71% and 85% respectively). This suggests uptake may be high even in those who do not participate in other screening programmes. However, individuals who had never or inconsistently attended screening were still less likely to intend to have MCED screening. Non-intenders were also less likely to support screening in general and scored significantly lower on the ‘health motivation’ scale. This suggests that for some, cancer screening is not in line with their values, and if this is the case it makes sense that previous behaviour would continue to predict intention to some degree. This finding has also been observed in qualitative work [ 14 ]. An individual’s informed choice not to have MCED screening should be respected. Nevertheless, efforts should be made to ensure that never or infrequent screening participation is a choice, and not the result of specific, modifiable barriers to screening such as lower knowledge or fatalistic attitudes that could warrant intervention.

The benefits of blood tests as a procedure were highly endorsed with few perceiving disadvantages. This supports qualitative findings suggesting that the primary test procedure will be appealing to most people [ 14 ]. Individuals who were non-intenders were more likely to be concerned about a positive result, the need for follow-up testing and the potential for this to cause anxiety. If MCED screening is rolled out in the future, it will be important to manage these concerns and detailed information materials should be developed to give reassurance regarding follow-up tests, since it seems these could put individuals off MCED screening at the point of invitation. Interestingly, providing participants with estimated detail about the positive predictive value of an MCED test (i.e. ‘2 out of 200 people will have a cancer marker found in their blood. 1 of these would have cancer diagnosed after further tests and 1 would not’) did not decrease intention, in fact it was stronger after this information was provided. Research exploring attitudes to mammography suggests that people are extremely tolerant of false-positive results [ 37 ]; however, further work is needed to explore public tolerance of false-positive results in MCED testing, for finding cancer overall and for different types of cancer. We did not present information about false negative results (of which there is much lower public tolerance), since it is not possible to make an estimate about this at the moment.

Another frequently cited barrier was the need for additional information. This finding is not surprising since MCED screening is still relatively unheard of, and participants received limited information within the survey. If implemented, participants will likely be given comprehensive informational resources at the time of invitation to support informed choice, as seen in other national screening programmes [ 38 , 39 , 40 ]. Materials outlining the benefits and harms of screening, and explaining procedural elements, are highly valued by potential participants, as has been reported elsewhere [ 41 , 42 , 43 ]. At present there is limited information available about MCED tests [ 44 ]. Care and thorough testing should be undertaken to ensure that sufficiently detailed and accessible materials answering relevant questions are available.

Whilst motivation did not vary by demographic characteristics, some of the barriers and enablers were more prominent in particular sub-groups. Average scores on the ‘fear of the outcome’ scale were higher for younger than older participants. This is in line with some evidence suggesting that cancer worry decreases with age [ 45 ], although this relationship has been refuted in other studies [ 46 ]. This suggests that interventions designed to reassure people about the treatability of cancer and emphasise good survival outcomes could be particularly important for younger participants. Practical barrier scores were higher in those from lower occupational social grades. Other studies have found that practical barriers to screening such as appointment times, lacking spare time [ 47 ] and transport issues [ 48 ] are more prevalent in individuals from more deprived backgrounds. If MCED screening is implemented, flexible appointments should be offered in accessible locations and booking processes should be simplified to reduce inequity.

Strengths and limitations

The use of a sample that was population-representative with respect to age, sex, ethnicity, social grade and region should allow the results to be generalised beyond the research setting and could help inform understanding of potential uptake if MCED screening is implemented in England. There are nevertheless some limitations. The survey was set up so that the proportion of people from ethnic minority backgrounds represented the proportion in the English population. However, this meant there were relatively small numbers of participants from each ethnic minority background. Consequently, we were not able to consider variation within broader ethnic minority groups. For example, there is evidence that within South Asian minority groups, uptake of existing screening is lowest among participants from Bangladeshi backgrounds [ 49 ]. In addition, since the survey was text-based and in English, those who were unable to read English would not have been able to take part. A deeper understanding of attitudes to MCED screening in different ethnic minority communities and non-English speakers will be important.

Data collection was completed online. There is some evidence that this type of data collection is equivalent to home-based interviewer led data collection [ 50 ], but as with all research methods there are likely to be some participation biases, for example those with low digital literacy are unlikely to participate. It is possible that there are broader inequalities in the opportunity to participate. For example, our research likely under-represents the least literate in the population. The small drop-out between engaging with the invitation (which did not describe what the survey was about) and survey completion suggests that interest in the topic area itself did not bias participation (i.e. self-selection bias). However, those on the YouGov panel may be people who are more interested in research participation broadly. It is likely that alternative methodologies (e.g. community-based face-to-face surveys, using multilingual interviewers) will be required to reach some groups and provide a more complete picture of attitudes to blood-based MCED tests across all sections of the society.

Whilst it was essential to provide participants with information about MCEDs within the study, it is still uncertain how MCED screening would be offered and what the performance characteristics of any test might be. If MCED screening is offered in a context that is very different from what was described to participants, intentions and attitudes may differ. As the potential for MCED screening develops, future work will be needed to ensure our understanding of acceptability accurately reflects the provision on offer. For most of our analyses we combined those who would not have a blood-based MCED tests and those who were unsure. These groups are likely quite different and further work to understand why people (i) actively do not want the test or (ii) are not sure is needed.

Since this was the first study in this context, we developed many of the items for the questionnaire rather than using validated scales. The items drew largely on our qualitative work as well as the existing literature in the screening field. The six scales we developed could be further validated and used in future work. This would allow for comparison of the literature as more evidence becomes available. However, since the questionnaire was developed in a UK context, the items likely exclude domains that will warrant exploration in different populations e.g. the relevance of insurance pay-outs in the US healthcare system. Engagement with PPI prior to development of the research questions would have strengthened the study.

This is the first study to quantify intention to have MCED blood test screening in a population-based sample. The findings suggest that intentions to take up MCED screening in England are high. While motivation to have MCED screening appears to be equitable across socio-demographic groups, inequity in uptake will likely be driven by access and opportunity which will require further consideration if a programme is implemented. Further work is needed to explore attitudes to blood-based MCED tests in different countries with different healthcare contexts. Supporting individuals with clear and accessible information will be imperative prior to an offer of an MCED test and measures should be put in place to reduce concern surrounding MCED screening results.

Data availability

The dataset and syntax will be made available upon reasonable request.

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Acknowledgements

We would like to thank our patient and public involvement representatives including: Sue Duncombe, Tim Ward, Rashmi Kumar and Julian Ashford for their insight throughout the design of this study.

This work was supported by GRAIL Bio UK Ltd. King’s College London sponsored this study. The funder played no role in the design, conduct, analysis or interpretation of the findings but did have the opportunity to review a draft of the manuscript prior to submission.

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Ninian Schmeising-Barnes, Jo Waller & Laura A. V. Marlow

Cancer Prevention Group, School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK

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Ninian Schmeising-Barnes: data curation, formal analysis, investigation, methodology, project administration, visualisation, writing—original draft, writing—review and editing. Jo Waller: conceptualisation, funding acquisition, investigation, methodology, supervision, writing—review and editing, visualisation. Laura A.V. Marlow: conceptualisation, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, visualisation, writing—review and editing.

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Correspondence to Laura A. V. Marlow .

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Competing interests.

JW reports research income from GRAIL Bio UK Ltd, which funds 20% of her salary and the full salaries of LAVM and NSB through a contract with King’s College London/Queen Mary University of London.

Ethics approval and consent to participate

Ethics approval was granted by King’s College London, June 2023 (LRM-22/23-36139). Consent was assessed with a single question presented to participants after they had read the information page. This study was performed in accordance with the Declaration of Helsinki.

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Supplementary tables, supplementary material - exploratory factor analysis, checklist for reporting of survey studies (cross), rights and permissions.

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Schmeising-Barnes, N., Waller, J. & Marlow, L.A.V. Intention to have blood-based multi-cancer early detection (MCED) screening: a cross-sectional population-based survey in England. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02822-4

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A metabolite-based liquid biopsy for detection of ovarian cancer

• Johannes F. Fahrmann 1 ,
• Seyyed Mahmood Ghasemi 2 ,
• Chae Y. Han 3 ,
• Ranran Wu 1 ,
• Jennifer B. Dennison 1 ,
• Jody Vykoukal 1 ,
• Joseph Celestino 4 ,
• Karen Lu 3 ,
• Zhen Lu 3 ,
• Charles Drescher 5 , 6 ,
• Kim-Anh Do 2 ,
• Samir Hanash 1 ,
• Robert C. Bast 3 &
• Ehsan Irajizad 2  

Biomarker Research volume  12 , Article number:  91 ( 2024 ) Cite this article

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Serial CA125 and second line transvaginal ultrasound (TVS) screening in the UKCTOCS indicated a shift towards detection of earlier stage ovarian cancer (OvCa), but did not yield a significant mortality reduction. There remains a need to establish additional biomarkers that can complement CA125 for even earlier and at a larger proportion of new cases. Using a cohort of plasma samples from 219 OvCa cases (59 stage I/II and 160 stage III/IV) and 409 female controls and a novel Sensitivity Maximization At A Given Specificity (SMAGS) method, we developed a blood-based metabolite-based test consisting of 7 metabolites together with CA125 for detection of OvCa. At a 98.5% specificity cutpoint, the metabolite test achieved sensitivity of 86.2% for detection of early-stage OvCa and was able to capture 64% of the cases with low CA125 levels (< 35 units/mL). In an independent test consisting of 65 early-stage OvCa cases and 141 female controls, the metabolite panel achieved sensitivity of 73.8% at a 91.4% specificity and captured 13 (44.8%) out of 29 early-stage cases with CA125 levels < 35 units/mL. The metabolite test has utility for ovarian cancer screening, capable of improving upon CA125 for detection of early-stage disease.

To the editor

Currently, over 70% of patients with ovarian cancer present with advanced stage (III-IV) disease, which contributes to dismal long-term survival rates of less than 30%. Five-year survival rates up to 70–90% can be achieved with conventional surgery and chemotherapy, when disease is localized to the ovary (stage I) or pelvis (stage II) [ 1 , 2 ]. A two-stage strategy using the Risk of Ovarian Cancer Algorithm (ROCA) whereby rising CA125 prompts transvaginal ultrasound (TVS) has been applied for screening and shown to achieve adequate specificity [ 3 ]. However, a recent United Kingdom-based randomized controlled trial reported that no significant reduction in ovarian or tubal cancer deaths was observed in the multimodal screening (longitudinal CA125 and second line TVS) or ultrasound screening (TVS first and second-line test) groups compared with the no screening group, which may be attributed to a modest stage-shift of 10–14% [ 4 ]. There remains a need for additional circulating marker(s) to improve lead-time detection of disease that would complement the performance shortcomings of CA125.

Using mass spectrometry technology ( see Supplemental Methods), we assessed the predictive performance of polyamines diacetylspermine (DAS), acetylspermidine (AcSpmd), diacetylspermidine (DiAcSpmd), and N-(3-acetamidopropyl)pyrrolidin-2-one (N3AP) as well as a previously validated 3-marker panel (3MetP: DAS + N3AP + CA125) [ 5 ] for detection of OvCa using plasma samples from an NCI-sponsored EDRN reference set consisting of 219 newly diagnosed OvCa cases (59 stage I + II and 160 stage III + IV) as well as 409 healthy controls (Table S1). The 3MetP had an AUC of 0.97 (95% CI: 0.95–0.99) for detection of OvCa, and an AUC of 0.95 (95% CI: 0.91–0.98) when considering early-stage disease (Table S2-4). Among individuals below the clinical cut-off for CA125 (< 35 units/mL), the 3MetP had an AUC of 0.81 (95% CI: 0.70–0.93) (Figure S1).

In our prior study, we demonstrated that, in addition to acetylated polyamines, carbohydrate antigens NANA, NAcMan, and NAcLac as well as the oncometabolite HBA were elevated in plasma of OvCa cases compared to patients with benign pelvic masses [ 6 ]. These four metabolites were also found to be significantly (Wilcoxon rank sum test 2-sided p  < 0.050) elevated in OvCa cases compared to healthy controls with AUC estimates ranging from 0.57–0.91 (Table S2-3).

Using a novel Sensitivity Maximization At A Given Specificity (SMAGS) method ( see Supplemental Methods ), we developed a model consisting of 7 metabolites plus CA125 that yielded an AUC of 0.98 (95% CI: 0.97–0.99) for early-stage disease (Fig.  1 A; Table S5). At a 98.5% specificity cutoff, the SMAGS-derived model had sensitivity of 86.2%, correctly identifying 50 of 58 early-stage OvCa cases, which was improved compared to a sensitivity of 75.9% for CA125 alone identifying 44 of 58 early-stage OvCa cases (Table S6). Moreover, the SMAGS-derived model captured 64% of the 14 early stage OvCa cases with CA125 < 35 units/mL, with an AUC estimate of 0.96 (95% CI: 0.92–0.99) (Fig.  1 B; Table S7).

Performance estimates of the SMAGS model for detection of early-stage ovarian cancer in the EDRN Reference Set. A  AUC curves for the SMAGS model and CA125 for detection of early-stage ovarian cancer. B  AUC curves for the SMAGS model for detection of early-stage ovarian cancer among individuals with CA125 levels < 35 units/mL

The SMAGS-derived model was validated in an independent set of plasma samples from 65 early stage (I + II) OvCa cases and 141 healthy female controls (Testing Set). The SMAGS-derived model had an AUC of 0.91 (95% CI: 0.87–0.95) for early-stage OvCa, which was improved compared to CA125 alone (AUC: 0.85 (95% CI: 0.78–0.91); 2-sided p -value: 0.04) (Fig.  2 A; Figure S2). Using the same cut point developed in the EDRN reference set, the SMAGS-derived model achieved a sensitivity of 73.8% and specificity of 91.4%. In comparison, CA125 at the clinical cutoff of 35 units/mL had 55.4% sensitivity and specificity of 97.2% (Tables S6).

Performance estimates of the SMAGs model for detection of early-stage ovarian cancer in the independent Test Set. A  AUC curves for the SMAGs model and CA125 for detection of early-stage ovarian cancer. B  AUC curves for the SMAGs model for detection of early-stage ovarian cancer among individuals with CA125 levels < 35 units/mL

Among the 29 early-stage OvCa cases with CA125 levels < 35 units/mL, the SMAGS-derived model had an AUC of 0.82 (95% CI: 0.74–0.89) (Fig.  2 ). At the cut point, the SMAGS-derived captured 13 of the 28 early-stage OvCa cases (44.8% sensitivity) that would otherwise have been missed by CA125 (Tables S7).

The blood-based metabolite test provides a potential clinical tool for identifying women at high-risk of harboring OvCa and that would benefit from surveillance and screening with TSV or MRI for earlier detection of disease, which is anticipated to result in mortality reduction due to OvCa [ 7 , 8 ]. Given the low incidence of ovarian cancer (11.4 in every 100,000 women) in the general population, the blood-based metabolite test may best be suited for detection of OvCa among higher-risk women presenting with non-specific symptoms such as pelvic/abdominal pain [ 9 , 10 ] or those with BRCA pathological variants [ 11 ].

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No datasets were generated or analysed during the current study.

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Acknowledgements

This project was supported by MD Anderson SPORE in Ovarian Cancer Caeer Enhancement Program Award (JFF), the National Cancer Institute Early Detection Research Network U01 CA200462 (RCB), the MD Anderson Ovarian SPOREs P50 CA83639 and P50CA217685 (RCB), National Cancer Institute, Department of Health and Human Services; the Cancer Prevention Research Institute of Texas (RP160145) (RCB); Golfer’s Against Cancer, the Mossy Foundation, the Anne and Henry Zarrow Foundation, the Roberson Endowment, National Foundation for Cancer Research, UT MD Anderson Women’s Moon Shot, and generous donations from Stuart and Gaye Lynn Zarrow, Karen and Barry Elson, and Arthur and Sandra Williams.

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Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Johannes F. Fahrmann, Ranran Wu, Jennifer B. Dennison, Jody Vykoukal & Samir Hanash

Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, 6767 Bertner Street, Houston, TX, 77030, USA

Seyyed Mahmood Ghasemi, Kim-Anh Do & Ehsan Irajizad

Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

Chae Y. Han, Karen Lu, Zhen Lu & Robert C. Bast

Department of Gynecological Oncology and Reproductive Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

Joseph Celestino

Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Charles Drescher

Division of Gynecologic Oncology, Swedish Cancer Institute, Seattle, WA, USA

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Contributions

Conceptulization: Johannes F. Fahrmann, Ehsan Irajizad. Methodology: Johannes F. Fahrmann, Seyyed Mahmood Ghasemi, Ranran Wu, Ehsan Irajizad. Validation: Johannes F. Fahrmann, Ehsan Irajizad. Formal Analysis: Johannes F. Fahrmann, Seyyed Mahmood Ghasemi, Ehsan Irajizad. Investigation: Johannes F. Fahrmann, Ehsan Irajizad. Resources: Joseph Celestino, Karen Lu, Zhen Lu, Charles Drescher, Samir Hanash, Robert C. Bast. Data Curation: Johannes F. Fahrmann, Ranran Wu. Writing—original draft preparation: Johannes F. Fahrmann, Seyyed Mahmood Ghasemi, Ehsan Irajizad. Writing—review and editing: Chae Y Han, Ranran Wu, Jennifer B. Dennison, Jody Vykoukal, Joseph Celestino, Karen Lu, Zhen Lu, Charles Drescher, Kim-Anh Do, Samir Hanash, Robert C. Bast.

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Correspondence to Ehsan Irajizad .

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Ethics approval and consent to participate.

The study is a retrospective analysis of blood specimens that were obtained preoperatively with informed consent under IRB/ethical committees approved protocols at the University of Texas M.D. Anderson Cancer Center (MDACC, LAB04-0687) and at the Fred Hutchinson Cancer Research Center (FHCRC, IRB 4563) [ 12 ]. Control plasma were obtained from women who did not develop cancer while participating in the Normal Risk Ovarian Screening Study (NROSS) trial coordinated by MDACC [ 13 ] or were healthy donors at the FHCC under improved IRB protocols.

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Competing interests

Dr. Bast receives royalties from Fujirebio Diagnostics, Inc, for the discovery of CA125.

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Fahrmann, J.F., Ghasemi, S.M., Han, C.Y. et al. A metabolite-based liquid biopsy for detection of ovarian cancer. Biomark Res 12 , 91 (2024). https://doi.org/10.1186/s40364-024-00629-2

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Exploring the immunometabolic potential of Danggui Buxue Decoction for the treatment of IBD-related colorectal cancer

• Yang Zhang 1 ,
• Qianming Kang 1 ,
• Luying He 1 ,
• Ka Iong Chan 2 ,
• Wenjing Xue 1 ,
• Zhangfeng Zhong 2 &
• Wen Tan   ORCID: orcid.org/0000-0003-0895-1604 1  

Chinese Medicine volume  19 , Article number:  117 ( 2024 ) Cite this article

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Danggui Buxue (DGBX) decoction is a classical prescription composed of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), used to enrich blood, and nourish Qi in Chinese medicine, with the potential to recover energy and stimulate metabolism. Chronic inflammation is a risk factor in the development of inflammatory bowel disease (IBD)-related colorectal cancer (CRC). More importantly, AR and ASR have anti-inflammatory and anti-cancer activities, as well as prefiguring a potential effect on inflammation-cancer transformation. We, therefore, aimed to review the immunometabolism potential of DGBX decoction and its components in this malignant transformation, to provide a helpful complement to manage the risk of IBD-CRC. The present study investigates the multifaceted roles of DGBX decoction and its entire components AR and ASR, including anti-inflammation effects, anti-cancer properties, immune regulation, and metabolic regulation. This assessment is informed by a synthesis of scholarly literature, with more than two hundred articles retrieved from PubMed, Web of Science, and Scopus databases within the past two decades. The search strategy employed utilized keywords such as “Danggui Buxue”, “Astragali Radix”, “Angelicae Sinensis Radix”, “Inflammation”, and “Metabolism”, alongside the related synonyms, with a particular emphasis on high-quality research and studies yielding significant findings. The potential of DGBX decoction in modulating immunometabolism holds promise for the treatment of IBD-related CRC. It is particularly relevant given the heterogeneity of CRC and the growing trend towards personalized medicine, but the precise and detailed mechanism necessitate further in vivo validation and extensive clinical studies to substantiate the immunometabolic modulation and delineate the pathways involved.

Graphical Abstract

Danggui Buxue decoction is a classical prescription consisting of Astragali Radix and Angelicae Sinensis Radix with the efficacy of tonifying blood and invigorating qi in traditional Chinese medicine.

Astragali Radix and Angelicae Sinensis Radix, both have a variety of pharmacological activities, including anti-inflammation and anti-cancer effects.

In view of inflammation and malignant transformation in inflammatory bowel disease-related colorectal cancer and the curative effects of Astragali Radix and Angelicae Sinensis Radix, immunometabolism modulation potential of DGBX were reviewed and discussed in the present study.

Danggui Buxue (DGBX) decoction is a classical prescription consisting of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR) in traditional Chinese medicine. Given the documented anti-inflammatory and anti-neoplastic properties, this review aims to discuss the potential of mitigating the inflammation-cancer transformation and to offer an immunometabolic adjunct in IBD-CRC risk management.

Overview of IBD and CRC

Pathogenesis and epidemiological characteristics of ibd.

IBD includes ulcerative colitis (UC) and Crohn’s disease (CD) and is a chronic inflammatory disease occurring in the gastrointestinal tract [ 1 ]. UC characteristically initiates in the rectum, and subsequently spreads to the entire colon in a continuous manner, while CD predominately involves the terminal ileum and perianal region with a discontinuous pattern of involvement extending throughout the gastrointestinal tract [ 2 ]. UC inflammation in the mucous membrane leads to ulcers and bloody diarrhea [ 3 ]. CD typically involves abdominal pain, chronic diarrhea, weight of loss, and fatigue [ 4 ]. In the past, IBD was regarded as a Western disease; however, in the twenty-first century, the incidence and prevalence of IBD are increasing worldwide. Although still lower than in Western countries, the incidence and prevalence of IBD in Asia is increasing over time [ 5 ]. Therefore, comprehending the evolving epidemiological patterns and pathogenesis thereof is crucial in addressing the escalating global burden. The pathogenesis of IBD is related to heredity, the intestinal microbe, the environment, and immunity [ 6 ]. Genome-wide associated studies of genes and genetic loci involved in IBD identified 99 non-overlapping genetic risk loci and revealed the exact role of disease-related genes. Nucleotide-binding oligomerization domain containing protein 2 (NOD2), for example, is appropriately regulated to maintain intestinal homeostasis [ 2 ]. Tens of thousands of microbes living in the human gut are involved in the regulation of health and disease [ 7 ], and the human gut contains more than 2000 species of microbes, including Firmicutes, Bacteroides, Actinomycetes, and Proteus [ 8 ]. Patients with IBD have significantly less microbial diversity than that of healthy individuals [ 9 ]. Environmental determinants, such as tobacco smoking, appendectomy, oral contraceptive use, and dietary habits, exert distinct influences on the risk profiles for celiac disease and CD. Appendectomy has different effects on UC and CD, with a general protective effect and reduced risk of UC, and with an increased risk of stenosis and reduced risk of anal fistula in CD [ 10 , 11 ]. Contraceptive use in women with a history of smoking is also associated with the occurrence and development of IBD [ 12 , 13 ]. Even though there is no conclusive evidence that dietary factors are directly related to the pathogenesis of IBD, low-fiber and high-fat foods have been proposed as risk factors [ 14 ]. In healthy people, the initial immune response is rigorously regulated, this regulation determines immune tolerance or defensive inflammatory responses, and some disturbances in the balance of these responses may lead to IBD [ 15 ]. IBD in patients who are failing to achieve effective disease control may ultimately lead to the development of cancer.

Pathogenesis and epidemiological characteristics of colorectal cancer

CRC is the fourth leading cause of cancer-related deaths and the most common malignancy worldwide [ 16 ]. In 2020, there were nearly 4.56 million newly diagnosed cancer cases and 30 million cancer deaths in China [ 17 ]. Of the 147,000 people diagnosed with colorectal cancer, approximately 53,000 will eventually die. Despite variations in CRC incidence and mortality by age, ethnicity, and geographic location, a concerning trend of escalating incidence and mortality rates has been observed for CRC [ 18 ]. The susceptibility to CRC is influenced by a spectrum of individual-specific factors, encompassing age, lifestyle, and a history of chronic disease. IBD patient are notably at an elevated risk for the development of CRC. Chronic inflammation is postulated to foster aberrant cell proliferation, and prolonged exposure to inflammation can lead to cellular atypia, potentially culminating in the formation of neoplastic lesion [ 19 , 20 , 21 ]. The occurrence and development of CRC goes through several stages, including normal mucosal epithelium, abnormal crypt foci, microadenoma, and finally the malignant tumor. The progression from normal mucosal epithelium to abnormal crypts is ordinarily considered to be the onset of dysplasia, and a single dysplasia crypt is considered the first histological manifestation of a tumor [ 22 ]. Adenomatous polyps progressing to sporadic CRC typically undergo a protracted period of development, and CRC associated with colitis is believed to evolve through multiple stages of precursor lesions, ranging from inflammation to low-grade dysplasia, high-grade dysplasia, and finally, CRC [ 23 ]. CRC is not an abrupt occurrence; hence, timely detection and treatment during its formation can effectively prevent it.

Risk and epidemiological characteristics of CRC in IBD

Patients with IBD have an elevated risk of developing CRC, and chronic inflammation leads to dysplastic precursor lesions that may appear in multiple regions of the colon through a local carcinization process. Patients with IBD are at 2–6 times higher risk of developing CRC compared to the general population. IBD-related colorectal cancer accounts for approximately 2% of total annual CRC mortality and 10–15% of annual mortality in patients with IBD [ 24 ]. The pathogenesis of IBD-related CRC diverges from that of sporadic CRC, typically manifesting through a distinct sequence characterized by chronic inflammation, dysplastic transformation, and eventual carcinomatous progression. Research has demonstrated that intestinal inflammation can lead to the dysregulation of the host's immune response and a disruption in the homeostasis of the intestinal microbiota. The gut microbiota plays a crucial role in maintaining intestinal homeostasis by impeding pathogen colonization and modulating immune cell networks. Bacteroides fragilis , Fusobacterium nucleatum , and Porphyromonas gingivalis are known to be closely related to IBD-CRC [ 25 ]. Intestinal microbiota and their metabolites modulate the metabolic pathways of immune cells, thereby ameliorating IBD within the gastrointestinal tract and augmenting the efficacy of CRC immunotherapy [ 26 , 27 , 28 , 29 ]. Colonoscopy and staging biopsies should be performed in patients with long-term IBD since early detection of dysplasia is critical for the prevention of CRC [ 30 ]. A slow transition from IBD to cancer is associated with chronic inflammation, so reducing inflammation caused by colitis is a preventive approach and strategy to decrease risk of IBD-CRC [ 31 , 32 , 33 ]. Chemoprophylaxis is also one of the main means of continuous and complete control of inflammation [ 34 , 35 ]. The risk of IBD patients developing CRC has decreased recently, which may be due to early monitoring and appropriate treatments.

Immunometabolism regulation in IBD-related CRC

Immune regulation in the tumor microenvironment (tme).

The TME is a cellular environment in which the tumor exists, and the continuous interaction between tumor cells and the surrounding microenvironment plays a crucial role in the genesis, progression, and metastasis of tumors. This complex microenvironment consists of tumor cells, stromal cells, and extracellular matrix. Stromal cells include immune cells and the cytokines or chemokines secreted by these cells [ 36 , 37 ]. Immune cells play an important role in tumorigenesis, including innate immune cells, such as natural killer (NK) cells, macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and adaptive immune cells, such as T cells and B cells [ 38 , 39 ]. The cytotoxic activity of NK cells is primarily mediated through two well-characterized mechanisms, one is the release of cytotoxic granules containing perforin and granzymes, and the other is the secretion of pro-inflammatory cytokines. NK cells from IBD patients exhibit a diminished production of interferon-gamma (IFN-γ), yet an increased secretion of tumor necrosis factor-alpha (TNF-α) [ 40 ]. Elevated levels of TNF-α have been correlated with the presence of aberrant crypt foci within colorectal polyps [ 41 ]. The dynamic equilibrium between M1 and M2 macrophage polarization is a critical determinant of the inflammatory microenvironment and has profound implications for tumor and inflammation [ 42 , 43 , 44 , 45 ]. Clinical observations have highlighted a significant association between the overexpression of M2 macrophages and the progression of CRC [ 46 , 47 ]. DCs function as specialized antigen presenting cells, whereas MDSCs consist of monocytes and polymorphonuclear immature bone marrow cells. In the CRC microenvironment, MDSCs represent the predominant immunosuppressive cell population within the TME and play a critical role in promoting immune resistance [ 48 , 49 , 50 , 51 , 52 , 53 ]. T cells play a pivotal role in orchestrating the immune response against CRC, rendering them one of the most critical components of immune system. Activated CD8 + T cells have cytotoxic effects on CRC cells, while activated CD4 + T cells can differentiate into subtypes that promote or inhibit tumor growth. Tumor-infiltrating B lymphocytes are considered the main effector cells of the humoral adaptive immune response, and B cells are recognized in the immune system for their ability to produce antibodies and secrete pro-inflammatory and anti-inflammatory cytokines regulating CRC progression [ 54 ]. Immune cells play a multifaceted role in the pathogenesis of CRC, influencing the survival, proliferation, and metastatic potential of CRC cells, and actively participating in the regulation of cancer progression. The activation and differentiation of these immune cells are accompanied by significant metabolic reprogramming, which is essential for their functional capabilities. The unique metabolic characteristics of immune cells also have a profound impact on their ability to perform their immune functions [ 38 , 55 ].

Immunometabolism aspects in the TME

Metabolic dysregulation is a defining characteristic of cancer cells and significantly influences the development and progression of CRC. Immunometabolism, the interplay between immune cell function and metabolism, is a critical determinant in cancer progression, particularly in the context of CRC [ 56 ]. Abnormal metabolic pathways of cancer include fatty acid, glucose, and amino acid metabolism. Other metabolic pathways include the one-carbon metabolism, pentose phosphate pathway, and nicotinamide adenine dinucleotide phosphate metabolism [ 57 , 58 , 59 , 60 ]. Metabolism and immunity are both important components in maintaining the normal operation of human body. They reinforce each other, and the components complement one another, as shown in Fig.  1 . Glycolytic metabolism is the process of converting glucose uptake from the extracellular environment to pyruvate and releasing adenosine triphosphate (ATP) [ 61 ]. T-cell activation significantly increases glycolytic flux and transports glycolytic pyruvate into the tricarboxylic acid (TCA) cycle [ 62 ]. The metabolic profile of CD4 + T cells significantly influence their immune functions, which in turn, can modulate the pathogenesis of IBD [ 63 , 64 ]. The macrophages undergo differentiation into either M1 or M2 cells [ 65 ].In M1 macrophages, the TCA cycle results in metabolite accumulation and enhances cell immune function. Fatty acid oxidation regulates the balance between inflammatory effector and suppressor T cells. Increased fatty acid oxidation and oxidative phosphorylation support Treg differentiation and function. Treg accumulates in inflamed tissues of colitis and is involved in the progression of CRC [ 66 ]. The differentiation of M2 macrophages also depends on the fatty acid oxidation program. The fatty acid synthesis pathway produces lipids, which are essential for cell growth and proliferation. Fatty acid synthesis also links innate and adaptive immunity by regulating DCs function. Amino acid metabolism is closely related to the mTOR pathway and nucleotide synthesis, and the metabolism of glutamine, arginine, and tryptophan regulates the activity of immune cells. The intricate metabolic demands shared by cancer and immune cells imply that effective targeting on cancer metabolism necessitates consideration of gene type, tumor type, and the composition of the tumor microenvironment. A comprehensive understanding of their respective roles and mechanisms is essential to realize the cancer metabolic therapy. The main regulation of immunometabolism in the TME involves the various critical signaling pathways in immunity. The phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/mammalian target of rapamycin (mTOR) and liver kinase B1-5’ (LKB1)-AMP-activated protein kinase (AMPK) signaling pathways are important in regulating immune metabolism [ 67 ]. The PI3K/AKT/mTOR signaling cascade is a critical cellular signaling pathway that governs a myriad of cellular processes, including cell growth, proliferation, metabolism, and survival. mTORC1 is highly activated in the intestinal mucosa of IBD patients, and inhibition of mTORC1 is effective in the treatment of UC [ 68 ]. mTORC1 subsequently activates the transcription factor hypoxia-inducible factor 1 (HIF1). In macrophages of IBD patients, glycolysis is significantly enhanced by mTORC1 and HIF-1 [ 69 ]. HIF-1 promotes glycolysis and cancer-related inflammation by stimulating hexokinase and pyruvate dehydrogenase kinase, co-inducing glycolytic gene expression with other oncogenes or transcription factors. On the flip side, glycolysis affects immature DCs (iDCs) [ 38 , 67 , 70 , 71 ]. mTOR is an effector target of AKT signaling that increases glycolysis and reduces lipid oxidation. This pathway is essential for the differentiation of CD4 + T cells into immunologically specific effector T cells (Teff) or the induction of regulatory T-cell (Treg) subsets [ 72 ]. As an energy sensor in cells, AMPK activation reduces the levels of mitochondrial aerobic glycolysis and oxidative phosphorylation, and inhibits the migration, invasion, and metastasis formation of CRC cells [ 38 , 73 , 74 , 75 , 76 ]. Targeting immunometabolism in the TME represents a highly promising therapeutic strategy [ 55 , 77 ].

The immunometabolism modulation. LKB1-AMPK signaling pathway and PI3K/AKT/mTOR signaling pathway are the main pathways regulating the metabolism of fatty acids and glucose. Consequently, the metabolic outcomes impact immune cells such as T cells, DCs, M1 and M2 macrophages, thereby influencing immunity. Furthermore, immune responses reciprocally recast metabolic regulation

Astragali Radix, Angelicae Sinensis Radix, and DGBX decoction advances

Astragali Radix (AR, Huang Qi in Chinese), the dried root of Astragalus membranaceus (Fisch.), Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge., and the components isolated and identified included polysaccharides, saponins, flavonoids, and amino acids [ 78 , 79 ]. As a traditional Chinese medicine employed in clinical treatment, AR exhibits diverse biological activities, including anti-inflammatory and anti-tumor functions [ 80 , 81 , 82 , 83 ]. Angelicae Sinensis Radix (ASR, Dang Gui in Chinese) is the root of Angelica sinensis (Oliv.) Diels [ 84 ]. The main chemical components of ASR include organic acids, volatile oil, polysaccharides, and flavonoids. It also has a variety of pharmacological activities, including anti-inflammatory activity, cardiac protection, antioxidant activity, and neuroprotection, as well as functioning in the cardiovascular and cerebrovascular systems [ 85 , 86 ]. As a Chinese classical prescription, DGBX decoction is recorded with AR and ASR, in a ratio of 5:1. It is a classic recipe to invigorate Qi and tonify the blood [ 87 , 88 ]. The main effective components in DGBX decoction are polysaccharides, calycosin, formononetin, astragaloside IV, ferulic acid, and ligustilide [ 89 ]. DGBX decoction exerts supporting Qi and enriches the blood, enhancing efficacy and reducing toxicity [ 90 ]. In recent years, traditional Chinese medicine and the classical prescriptions have been found to be widely used [ 83 , 91 ], such as AR, ASR, and DGBX decoctions, especially for their anti-cancer activities, immune regulation, and metabolic regulation, as shown in Tables  1 , 2 and 3 . Accordingly, the schema of the present study is shown in Fig.  2 .

The scheme. DGBX decoction is composed of AR and ASR with a ratio of 5:1. AR and ASR both have anti-inflammatory and anti-cancer effects. Inflammation plays a pivotal role in the pathogenesis and progression of IBD, while anti-cancer effects show significant potential for CRC treatment. Hence, this review aims to comprehensively explore the therapeutic implications of DGBX decoction in IBD-associated CRC. DGBX Danggui Buxue, AR Astragali Radix, ASR Angelicae Sinensis Radix, IBD inflammatory bowel diseases, CRC colorectal cancer

AR and ASR exhibit promising anti-inflammatory properties

By subcutaneous injection of air and Zymosan solution into the back of mice, a Zymosan air–pouch mouse model was established to induce inflammation. The higher dose of aqueous AR extract (100 mg/kg) effectively inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, indicating its anti-inflammatory effect through suppression of pro-inflammatory cytokines production. In addition, in lipopolysaccharide (LPS)-induced inflammation of RAW 264.7 cells, AR was found to inhibit the synthesis of inflammatory mediator nitric oxide (NO) and the expression of nitrite oxide synthase (iNOS) [ 111 ]. Astragalus polysaccharides and astragaloside IV are the primary bioactive compounds extracted from AR. Astragaloside IV enhances the tyrosine phosphatase activity of CD45 protein to induce T-cell activation, manages the balance of Teff/Treg cells to regulate immunity, and inhibits pro-inflammatory cytokines and nuclear factor-κB (NF-κB) pathways to enhance anti-inflammatory activity [ 112 , 113 ]. In an orthotopic implantation lung cancer model utilizing C57 BL/6 mice, which was established using 3LL-LUS-IDO cells, astragaloside IV, administered at a dosage of 40 mg/kg, has been demonstrated to effectively suppress the expression of indoleamine 2,3-dioxygenase in vivo. It also down-regulates the population of Tregs while concurrently up-regulating the activity of cytotoxic T lymphocytes to enhance the immune response, thereby showcasing anti-cancer activity [ 114 ]. By culturing human lung cancer cells and human mononuclear cells in vitro, it was found that astragaloside IV at a dosage of 40 mg/kg, significantly inhibits the M2 macrophage polarization of tumor-associated macrophages (TAMs) through the modulation of AMPK signaling pathway. This finding was corroborated through parallel experiments conducted on primary human macrophages, which further substantiate the immunomodulatory role of astragaloside IV in regulating macrophage function within the tumor microenvironment [ 115 , 116 ]. Astragalus polysaccharides, administered at a dosage of 3 mg/kg, exert comparable effects on a lung cancer subcutaneous model in vivo, enhancing the anti-cancer efficacy of cisplatin by modulating the activity of inflammation-associated macrophages. The anti-inflammatory effects of astragalus polysaccharides and astragaloside IV on bovine mammary epithelial cells induced by LPS were also studied. Bovine mammary epithelial cells stimulated with LPS were utilized as an in vitro model of inflammation to investigate the impact of astragalus polysaccharides (an efficacious concentration is 100 μg/mL) and astragaloside IV (an efficacious concentration is 1 mg/mL) on inflamed bovine mammary epithelial cells. It was found that both could significantly reduce the relative expression of IL-6, IL-8, and TNF-α, and activate the Wnt/β-catenin signaling pathway to inhibit inflammation [ 117 ]. Atragaloside IV also exerts inhibitory effects on the TLR4/NF-κB signaling pathway and the activation of autophagy, thereby attenuating cellular inflammation by reducing the release of inflammatory mediators [ 118 ]. CT26 cells were orthotopically implanted into BALB/c mice to establish a subcutaneous tumor model. Astragaloside III, administered at a dosage of 50 mg/kg in five bi-daily treatments, significantly activated NK cells in tumor environment, thereby enhancing the cytotoxic capacity of NK cells and leading to a notable inhibition of tumor growth. Further assay via co-culture of NK cells with CT26 cells revealed that astragaloside III up-regulated the expression of NK group 2D, Fas and IFN-γ in NK cells, thereby exerting a pronounced suppressive effect on the proliferation of CT26 colorectal tumor cells [ 119 ]. Flavonoids isolated from AR alleviate DSS-induced colitis by enhancing mitophagy levels, inhibiting NLRP3 inflammasome activation, and reducing the production of pro-inflammatory cytokines in colon tissue [ 120 ].

Calycosin is the predominant isoflavonoid in AR. Calycosin, administered at a dosage of 4.67 mg/kg, effectively reduces the levels of TNF-α and IL-1 in the serum of rats with heart failure induced by ligation of the left anterior descending artery, indicating that calycosin could alleviate the inflammatory response in rats with heart failure. In vitro cardiomyocyte cultures showed that calycosin exerts anti-inflammatory effects via the PI3K-AKT signaling pathway [ 121 ]. In glucocorticoid-induced osteonecrosis of the femoral head in rats, calycosin, administered at a dosage of 10 mg/kg, promotes bone formation, inhibits the TLR4/NF-κB pathway, and significantly regulates inflammation, thus effectively alleviating osteonecrosis of the femoral head. In addition, calycosin also inhibits LPS-activated inflammation in vitro by inhibiting the TLR4/NF-κB pathway [ 122 ]. Formononetin, a naturally occurring flavonoid derived from AR, has been reported to have immunomodulatory effects [ 123 ]. By pre-treatment of LPS-induced mastitis model mice with formononetin, administered at dosages of 10, 20 and 30 mg/kg, myeloperoxidase activity was reduced along with TNF-α and IL-1β production. In vitro experiments using EpH4-Ev cells from mouse mammary epithelial cells stimulated with LPS showed that formononetin, administered at dosages of 10, 20 and 30 μM, inhibits LPS-induced activation of the NF-κB signaling pathway [ 124 ]. Taken together, the active component from AR effectively modulates immune cells and cytokines to alleviate inflammatory symptoms.

ASR is also an herb used to regulate the immune system, and its active ingredient acts as an antioxidant and anti-inflammatory agent. Angelica sinensis polysaccharide, extracted from the roots of ASR, is a β-D-pyranoid polysaccharide. It is also a crucial herbal constituent in various traditional formulations utilized for the management of inflammatory responses [ 125 ]. Four polysaccharides extracted from different roots of Angelica sinensis have anti-inflammatory activity on intestinal epithelial system, and their activity varies with the difference of structure [ 126 ]. Angelica sinensis polysaccharide, administered at a dosage of 40 mg/kg, significantly reduced the levels of TNF, IF-2 and interferon-γ(IFN-γ) in L1210-bearing mice. In addition, angelica sinensis polysaccharide increased the number of lymphocytes, enhanced the ability of macrophages and natural killer cells, and induced a protective immune response [ 127 ]. Angelica sinensis polysaccharide, administered at a dosage of 6 mg/kg, significantly reduces the levels of TNF-α, IFN-γ, IL-2, and IL-6 in concanavalin A-induced mouse hepatitis models [ 128 ]. Both astragalus polysaccharides and angelica sinensis polysaccharide increase the levels of IL-2 and TNF-α in H22 tumor-bearing mice. Astragalus polysaccharides, administered at a dosage of 400 mg/kg, enhance the phagocytic function of peritoneal macrophages in H22 tumor-bearing mice, while angelica sinensis polysaccharide, administered at a dosage of 200 mg/kg, enhance the activity of T, B lymphocytes, and NK cells, and improve the proportion of lymphocyte subsets in the peripheral blood of H22 tumor-bearing mice. Both significantly inhibit tumor growth in mice [ 129 , 130 ]. Ligustilide is a bioactive phthalide derivative isolated from ASR, which significantly improves the infiltration of peripheral immune cells, inhibits Th1 immunity, increases Th2 immunity, and re-establishes Th1/Th2 balance [ 131 , 132 ]. Treatment of human umbilical vein endothelial cells with ligustilide, administered at dosages of 1, 3, 10 μM, significantly inhibits TNF-α and activates the Nrf2/HO-1 signaling pathway, alleviating vascular inflammation, and protecting the blood vessels [ 133 ]. Ferulic acid is a phenolic acid isolated from ASR, which has a variety of biological activities, including regulation of inflammation. Ferulic acid was found to improve hepatic oxidative stress and inflammation by activating AMPK in mouse hepatic fibrosis induced by carbon tetrachloride and LPS-induced macrophage inflammation [ 134 ]. At an efficacious concentration of 20 μM, ferulic acid inhibits LPS-induced expression of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and ROS production in macrophages by blocking NLRP3 inflammasome activation [ 135 ]. Furthermore, within the concentration range of 1, 2, 4 mM, ferulic acid dose-dependently down-regulates the expression of LC3-II, Beclin 1 and Atg12-Atg5 complex. This modulation of autophagy contributes to its efficacy as an anti-cancer agent by inhibiting the autophagic flux [ 136 ]. Additionally, tributyltin ferulate, a derivate of ferulic acid with an efficacious concentration of 400 nM, has been demonstrated to induce autophagic cell death in HCT-116 colon cancer cells, thereby exhibiting anti-tumor properties [ 137 ]. Therefore, ASR also effectively mitigates inflammation and modulates immune responses.

Regarding the aspect of inflammation modulation, DGBX decoction regulates immune responses and improves inflammatory symptoms, as shown in Fig.  3 . For T lymphocytes, DGBX decoction induces cytokines released from T cells, such as interleukin (IL), granulocyte–macrophage colony-stimulating factor (GM-CSF), IFN-γ, and TNF-α. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 is induced to stimulate T lymphocyte proliferation. For macrophages, DGBX decoction treatment increases phagocytosis [ 138 , 139 ]. Polysaccharides in DGBX decoction induce IκBα degradation, and activate NF-κB signaling pathways, stimulating the immune response. In macrophages, DGBX decoction exerts a pivotal role in host defense mechanisms by dose-dependent suppression of the expression of pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor at both mRNA and protein levels [ 140 ]. DGBX decoction significantly reduces the production of pro-inflammatory cytokines, and effectively improves the inflammatory state and pathological structure of DSS-induced IBD model, promoting inflammation resolution. MDSC inhibits the functional activity of CD8 + T activity and improves intestinal inflammation, and DGBX significantly increases the level of MDSC to change the composition of intestinal mucosal immune cells eventually. At the same time, it boosts the proliferation of intestinal epithelial cells and facilitates swift repair of damage to the intestinal mucosal barrier [ 141 , 142 ]. DGBX decoction attenuates tubulointerstitial fibrosis in rats with unilateral ureteral obstruction by inhibiting the expression of NOD-like receptor family Pyrin domain 3 (NLRP3) inflammasome and significantly reduces the expression of α-smooth muscle actin (α-SMA) representative protein [ 143 ]. In 2,4-dinitrochlorobenzene induced mice atopic dermatitis, DGBX decoction significantly inhibits excessive production of IL-4 and IL-5 by Th2 cells, along with a notable reduction in eosinophil and mast cell infiltration, thereby mitigating inflammation and swelling [ 144 ]. The potential impact of DGBX decoction on inflammation and immunity is supported by its anti-inflammatory and immunomodulatory effects, mediated by the AR and ASR constituents. Further experimental validation is required to substantiate the immunometabolism potential.

The anti-inflammatory activities of DGBX decoction. DGBX decoction contains polysaccharide, calycosin, formononetin, astragaloside IV, ferulic acid, and ligustilide. These active ingredients interfere with immune cells and modulate cytokines through various signaling pathways to attenuate inflammation

Metabolism modulation aspect

Abnormal metabolism of cancer has highlighted therapeutic targets in recent years. Glucose and amino acids uptake, nutrition acquisition preference, the metabolic intermediates, even the metabolite-driven gene regulation, have been highlighted to explore the novel treatments or targets [ 57 ]. AR and ASR both interfere with cell metabolism and improve blood lipids and blood glucose by regulating abnormal cellular metabolic pathways, including fatty acid metabolism and glucose metabolism. AR extract significantly reduces HFD-induced lipid storage, increases the processes of lipolysis and lipid β-oxidation, and alleviates acquired hyperlipidemia in HFD-fed mice by regulating lipid metabolism [ 170 ]. Based on pharmacology network analysis and experimental verification, it was found that AR water extract stimulates fat cells and promotes fatty acid metabolism to maintain fatty acid homeostasis [ 171 ]. Astragalus polysaccharides at a dosage of 0.25 g/kg regulate cholesterol homeostasis by reducing plasma total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemia hamsters [ 172 ]. Meanwhile, astragalus polysaccharides (700 mg/kg) regulates blood glucose in insulin resistant C57BL/6 J mice by alleviating ER stress [ 173 ]. Astragaloside IV, administered at a dosage of 80 mg/kg, alleviates hepatic injury in type 2 diabetes mellitus rats by modulating the AMPK/mTOR pathway, also attenuating dyslipidemia, oxidative stress, and inflammation [ 174 ]. Additionally, astragaloside IV, administered at a dosage of 50 mg/kg, exerts hypoglycemic effects in a rat model of diabetes induced by a high-sugar diet combined with streptozotocin by modulating intestinal microbiota [ 175 ]. Calycosin-7-glucoside, administered at a dosage of 0.05 mg per mouse, inhibits glycolysis in the db/db mouse model of diabetes mellitus through the activation of AMPK pathway in an inflammatory environment, reducing the inflammatory response and promoting healing of diabetic wounds [ 176 ]. Abnormal metabolism in cancer results in different phenotypic characteristics from normal cells, including cell proliferation, migration, invasion, and angiogenesis [ 177 ]. Calycosin and Astragaloside IV both inhibit transforming growth factor-β (TGF-β). Calycosin inhibits colorectal cancer cell growth through the PI3K/AKT pathway, upregulates basic leucine zip-ATF-like transcription factor 2 (BATF2) and downregulates plasminogen activator inhibitor-1(PAI-1), and inhibits TGF-β-induced cell migration and enhances the effect of TGF-β induction on cell apoptosis. The mechanism of regulating autophagy is related to the PI3K/AKT/mTOR signaling pathways. Astragalus polysaccharides reduce the levels of p-AKT and p-mTOR in cells, block PI3K/AKT/mTOR signaling pathways, increase autophagy, and alleviate inflammation, to effectively suppress gastric cancer [ 178 , 179 , 180 , 181 ]. Angelica sinensis polysaccharide ameliorates the inflammatory response in PC12 cells induced by LPS, attenuates cellular apoptosis, and mitigates cellular damage by down-regulating COX-1 expression and the activation of PI3K/AKT signaling pathway [ 182 ]. In addition, Astragaloside IV regulates AMPK, NF-κB, and signal transducer and activator of transcription (STAT) signaling pathways, inhibits the polarization of M2 macrophages, and reduces the progression and metastasis of liver cancer cells and lung cancer cells [ 116 , 183 , 184 ]. Both Astragaloside IV and ligustilide alleviates experimentally DSS-induced colitis. Astragaloside IV, administered at dosages of 50 and 100 mg/kg, effectively inhibits the polarization of M1 macrophages and ameliorates colitis through modulation of STAT signaling pathway. Astragalus saponins reduces the expression level of glycolytic enzymes to attenuate aerobic glycolysis and inflammation, inhibiting colitis eventually. Ligustilide, administered at dosages of 15, 30 and 60 mg/kg, activates peroxisome proliferator-activated receptor γ (PPARγ) and inhibits NF-κB and AP-1 signaling, controlling the expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α to alleviate experimental colitis in mice. [ 156 , 185 , 186 ]. ROS are byproducts of cellular metabolism, and the ROS level of cancer cells is higher than that of non-tumor cells. Formononetin mitigates cisplatin-induced nephrotoxicity in LLC-PK1 porcine kidney epithelial cells by suppressing intracellular ROS accumulation and oxidative stress [ 187 ]. Similarly, angelica sinensis polysaccharide also inhibits oxidative stress in vivo and in vitro, decrease superoxide dismutase (SOD) activity, and improve acetaminophen-induced acute liver injury to achieve liver protection. Ferulic acid has antioxidant activity, while tributyltin ferulate stimulates ROS production, leading to autophagy activation, showing an obvious anti-tumor effect in colon cancer cells [ 137 , 187 , 188 ]. Astragalus polysaccharides, administered at a dosage of 200 mg/kg, regulate the intestinal microenvironment, including regulating the composition of the intestinal microbiota and its metabolic function, changing the composition of fecal metabolites, reducing the expression levels of IL-1β and IL-6 in serum, weakening the immunosuppressive activity of MDSC, and inhibiting the growth of melanoma in mice [ 189 ]. DGBX decoction induces ROS production in the mitochondria of osteoblasts, thereby activating the AMPK pathway, affecting glycolytic capacity, and improving bioenergy [ 190 ]. In addition, the potent cardioprotective effect of DGBX decoction is mediated by the regulation of mitochondrial bioenergetics to improve the health status of H9C2 cardiomyoblasts [ 191 ]. In conclusion, DGBX decoction and its principal constituents actively participate in metabolic regulation, modulate immune pathways, exerting a therapeutic effect.

Anti-cancer aspect

AR is a traditional tonic herb widely used in the treatment of various cancers. AR aqueous extracts were applied to different cancer cell lines and were found to inhibit a variety of cancer cell growths [ 211 ]. AR and its four major bioactive compounds, including calycosin, formononetin, astragaloside IV, and astragalus polysaccharides, were found to have effects on breast cancer cells. Calycosin, at efficacious concentrations of 200 and 400 μM, impedes the migration and invasion of breast cancer cells by suppressing the epithelial-mesenchymal transition process. Formononetin reduces autophagy by regulating mTOR, promotes apoptosis of paclitaxel-resistant triple-negative breast cancer cells, and overcomes paclitaxel resistance [ 212 ]. The combination treatment involving formononetin at efficacious concentrations of 40 and 80 μM, in conjunction with metformin, exerts synergistic inhibition of MCF-7 breast cancer cells proliferation and induces apoptosis. Through MDA-MB-231 breast cancer cells in vitro experiments and orthotopic mouse tumor models for in vivo experiments, astragaloside IV was found to inhibit cell viability and invasion of breast cancer cells. Astragalus polysaccharides, administered at concentrations of 100, 200, 500 and 1000 μM, did activate the macrophage-like RAW 264.7 cells in in vitro models to induce apoptosis, thereby inhibiting the viability of MCF-7 cells [ 78 , 213 , 214 , 215 , 216 ]. Calycosin and astragaloside IV shows anti-tumor activity against CRC and gastric cancer cells. Calycosin, administered at concentrations of 25, 50 and 100 μM, significantly induces apoptosis in HCT116 cells and inhibits cell proliferation and invasion in a dose-dependent manner. Calycosin exhibits significant cytotoxicity against AGS cells, with an IC50 value of 47.18 ± 1.27 μM, while demonstrating minimal toxicity towards normal cells. Astragaloside IV exhibits a dose-dependent inhibition of proliferation in both SW620 and HCT116 cells, while it had no significant effect on the proliferation of normal colonic fetal human cells. N-methyl-N'-nitro-N-nitrosoguanidine was used to induce gastric precancerous lesions (GPL) in a model. Astragaloside IV, at efficacious concentrations of 50 and 100 mg/kg, has been demonstrated to modulate autophagy and apoptosis, thereby exerting a protective effect on gastric mucosal injury and improving both intestinal metaplasia and dysplasia within precancerous gastric lesions [ 98 , 217 , 218 , 219 ]. Astragalus polysaccharides have been shown to participate in a variety of biological processes, encompassing inflammation, metabolism, and carcinogenesis. Cell experiments have shown that astragalus polysaccharides reduce prostate cancer cell proliferation and lipid metabolism in a dose-dependent manner. Utilizing a tumor xenograft model, astragalus polysaccharides, administered at a dosage of 100 mg/kg, have been shown to exert an inhibitory effect on tumor growth via modulation of the miR-138-5p/SIRT1/SREBP1 signaling pathway [ 220 ]. Angelica sinensis polysaccharides obtained from ASR are primarily composed of arabinose, glucose, and galactose. Angelica sinensis polysaccharide, at efficacious concentrations of 25, 50, and 100 mg/kg, significantly inhibits tumor growth in H22 tumor-bearing mice by suppressing the production of hepcidin, thereby reducing intracellular iron concentration [ 221 ]. Ferulic acid shows inhibitory effects on both Hela and Caski cervical cancer cell lines. By downregulating the expression of MMP-9, ferulic acid suppresses cell invasion in cervical cancer cells. Moreover, ferulic acid inhibits autophagy by decreasing the levels of related proteins LC3-II, Beclin-1, and Atg12-Atg5 in a dose-dependent manner [ 136 ]. Ligustilide and two other phthalides extracted from ASR have cytotoxic and anti-proliferative effects on HT-29 [ 108 ]. Ligustilide can alter the immunosuppressive function of cancer-associated fibroblasts. Cellular experiments show that ligustilide significantly inhibits prostate cancer and prostate cancer-associated fibroblasts and induces apoptosis of prostate cancer-associated fibroblasts through the TLR4 pathway [ 222 , 223 ].

DGBX decoction influences tumor development, including inducing cell apoptosis and inhibiting metastasis, enhancing immune function, improving chemotherapy sensitivity, and reducing bone marrow suppression, as shown in Fig.  4 . Myelosuppression is a frequently encountered adverse effect of most chemotherapy drugs. In gemcitabine-induced myelosuppression mice, DGBX decoction enhances the anti-cancer effect of gemcitabine by regulating the expression of stress response protein Hu antigen R (HuR), deoxycytidine kinase (dCK), and nuclear factor erythroid 2-related factor (Nrf2). Meanwhile, it inhibits the proliferation of cancer cells, increases the number of bone marrow nucleated cells and the level of hematopoietic cytokine thrombopoietin to alleviate myelosuppression induced by gemcitabine, and improves hematopoietic function [ 224 ]. In addition, the combination of DGBX decoction and gemcitabine enhances anti-cancer activity, represented by the increased level of granulocyte–macrophage colony-stimulating factor (GM-CSF), the enhanced immune ability, increased deoxycytidine kinase (dCK), and decreased P-glycoprote in a murine lewis lung carcinoma model [ 225 ]. Polysaccharide-depleted DGBX decoction partially inhibits the cell viability of colorectal adenocarcinoma cells, enhances the proliferation inhibition effect of 5-fluorouracil (5-FU), induces apoptosis, and increases sensitivity to chemotherapy or radiotherapy [ 105 ]. In addition, phase II clinical studies have shown that DGBX decoction prevents chemotherapy-induced myelosuppression in breast cancer patients [ 226 ]. According to network pharmacological analysis, 28 active compounds of DGBX decoction were predicted to hit 61 common targets. CT26 cells were employed to develop a murine model of metastatic colon cancer in BALB/c mice. In vivo experiments showed that DGBX decoction alleviates the progression of metastatic breast cancer by upregulating the expression of pro-apoptotic proteins Bax, inducing the activation of Caspase-3, and downregulating the expression of anti-apoptotic protein Bcl-2 to induce apoptosis [ 106 ]. DGBX decoction induces autophagic death of colorectal cancer cells and inhibits the growth of colorectal adenocarcinoma by regulating the mTOR/P70 S6K signaling pathway and upregulating autophagy related protein 7 (Atg7) [ 227 ]. DGBX decoction, particularly its polysaccharide-depleted fraction, potentiates the growth inhibitory effects of 5-fluorouracil and radiation treatment, possibly by inducing autophagy [ 105 ]. DGBX decoction also regulates intestinal flora, enhances immunity of mice by regulating Lactobacillus and Odoribacter , and reduces cancer-related bacteria such as Helicobacter and Lactococcus , showing anti-tumor activity [ 228 ].

The anti-tumor activity of DGBX decoction. DGBX decoction regulates apoptotic proteins to induce apoptosis of breast cancer cells. Modulation of HuR, dCK and Nrf2 proteins alleviates the suppression of gemcitabine and enhances the anti-cancer effect of gemcitabine. Modulation of autophagic pathways has been shown to induce autophagic cell death in colorectal cancer cells

Immunometabolism potential of DGBX decoction in IBD-related CRC

Promoting intestinal mucosal repair.

The intestinal mucosal barrier is essential to prevent bacterial invasion and maintaining intestinal homeostasis. Intestinal epithelial cells and the tight junction complex between epithelial cells serve as mechanical barriers. The disruption of the intestinal mucosal barrier may result in bacteria and toxins invading normal colon tissue, causing local inflammation, and promoting its carcinogenic transformation [ 229 ]. AR has the effect of reducing intestinal inflammation. AR extract, administered at dosages of 5, 10, 50 and 100 μg/mL, reduces the expression of TNF-α and the activation of NF-κB, alleviates the inflammatory response of intestinal epithelial cells, and inhibits the destruction of the intestinal mucosal barrier and the increase of permeability caused by inflammation [ 230 ]. AR decoction reduces the levels of inflammatory factors, improves the intestinal mucosal injury induced by lipopolysaccharides in mice, and promotes tissue repair [ 94 ]. In addition, astragalus polysaccharides promote the proliferation of intestinal epithelial cells in vitro in a dose-dependent manner. Astragalus polysaccharides stimulates the ornithine decarboxylase (ODC) gene to synthesize polyamine organisms and promote the proliferation, migration, and differentiation of intestinal epithelial cells [ 231 ]. Astragaloside IV, administered at a dosage of 3 mg/kg, has been demonstrated to attenuate intestinal mucosal injury induced by sepsis through the downregulation of the RhoA/NLRP3 inflammasome signaling pathway [ 232 ]. When administered at the early stage of an AOM/DSS model, ASR extract was found to reduce DNA damage and exert an antioxidant effect in epithelial tissues [ 107 ]. In rats with 2,4-dinitrobenzene sulphonic acid (DNBS)-induced acute UC, the content of glutathione was decreased by angelica sinensis polysaccharide, and the protective effect on the intestinal mucosa may be attributed to oxidative stress [ 110 ]. Ferulic acid, administered at a dosage of 1 μM, can reduce the LPS-induced inflammatory response in human intestinal epithelial model Caco-2 cells, inhibit the activation of MAPK p38 and ERK1/2, inhibit the expression of iNOS, and alleviate intestinal inflammation [ 233 ]. DGBX decoction was found to repair intestinal mucosal barriers and improve IBD. DGBX decoction inhibits the activity of CD8 + T cells by increasing the number of MDSC immune cells, to improve intestinal inflammation. DGBX decoction treatment not only regulates immunity, but also promotes the repair of intestinal mucosal damage by accelerating the proliferation of intestinal epithelial cells [ 141 , 142 ]. Therefore, DGBX decoction exhibits the potential to enhance the restoration of intestinal mucosal injury, alleviate local inflammation, and prevent carcinogenicity, as shown in Fig.  5 .

Effects of DGBX decoction and its principal constituents on intestinal barrier. DGBX decoction increases MDSC immune cells and inhibits the activity of CD8 +T cells. Ferulic acid inhibits the expression of MAPK p38, ERK1/2 and iNOS. Astragalus polysaccharides stimulates ODC gene synthesis of polyamine organisms, which promotes the proliferation of intestinal epithelial cells and improves inflammatory symptoms

Balancing intestinal microbiota

Intestinal microbes and their metabolites influence not only the immune response but also the occurrence and development of CRC. Traditional Chinese medicines and their natural compounds are typically administered orally, inevitably interacting with the gut microbiota [ 234 , 235 ]. Studies have demonstrated that astragalus polysaccharides effectively ameliorate colonic mucosal injury, restore immune homeostasis, and modulate the overall composition of the intestinal microbiota in mice with DSS-induced acute colitis. Furthermore, it normalizes the levels of Firmicutes and Bacteroides to their physiological states. In addition, astragalus polysaccharides after honey processing could increase the proportion of dominant bacteria such as Lactobacillus and Bacteroides , and significantly inhibit the upregulation of Firmicutes and Verrucomicrobia , thereby protecting the intestinal mucosa, affecting the diversity of microbiota, and alleviating the symptoms of colitis in mice. Honey-processed astragalus polysaccharides exhibited superior anti-inflammatory efficacy compared to astragalus polysaccharides in mice with colitis [ 100 , 103 ]. The main components of Astragalus mongholicus Bunge- Curcuma aromatica Salisb. include calycosin, formononetin, and three astragalosides. The treatment effectively suppresses the proliferation of opportunistic pathogenic gut bacteria, such as Shigella , Streptococcus , and Enterococcus, while promoting the growth of beneficial probiotic gut microbiota including Lactobacillus, Roseburia, and Mucispirillum. At the same time, significant growth of colon cancer in tumor-bearing mice is inhibited and the intestinal barrier damage is repaired [ 236 ]. Interestingly, using human gut microbiota to mimic the gut environment, 4-vinylguaiacol (2-methoxy-4-vinylphenol), a metabolite of ferulic acid, exhibits stronger anti-cancer effects than ferulic acid on both chemo-resistant HT-29 and chemotherapy-sensitiveHCT116 cells. Therefore, oral ferulic acid provides a potential method for CRC treatment [ 237 ]. DGBX was found to partially restore the balance of intestinal microbiota destroyed by antibiotics and improve the abundance of intestinal microbiota by increasing the prevalence of Bacteroides , Alistipes and Ruminiclostridium [ 238 ]. Therefore, the utilization of DGBX decoction for gut microbiota modulation not only ameliorates colitis but also exerts inhibitory effects on colon cancer progression, thus exhibiting promising prospects in the management of IBD-associated CRC.

Clinical research

A formulation developed from the DGBX decoction significantly ameliorates postoperative immunosuppression in cancer patients, sustainably bolsters immune function, and possesses anti-tumor properties, thereby promoting postoperative recovery [ 239 ]. In individuals sustaining severe abdominal trauma, there is a notable diminishment in cellular immunity. Clinical trials have evidenced that the administration of Astragalus injection as an adjuvant therapy is efficacious in the restoration of cellular immune function [ 240 ]. A Phase II clinical trial was conducted involving a cohort of healthy, naturally postmenopausal women. The study intervention involved the administration of escalating doses of oral DGBX decoction for a period of 12 weeks. Throughout the trial, physiological parameters and adverse events were closely monitored, with blood samples analyzed for a spectrum of health indicators. Notably, no significant alterations were observed in serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol in either intra-group or inter-group comparative analyses. Further research is warranted to ascertain the potential therapeutic effects of DBT on blood lipid profiles in comparable populations [ 241 ]. Clinical studies also have demonstrated the efficacy of Astragalus extract TA-65 in ameliorating conditions associated with metabolic syndrome, including a significant elevation in high-density lipoprotein (HDL) cholesterol levels accompanied by a concurrent reduction in the low-density lipoprotein (LDL) to HDL cholesterol ratio, and a marked decrease in plasma TNF-α level [ 242 , 243 ]. Some clinical trials of DGBX decoction and its main components are shown in Table  4 .

Immunometabolism, the intricate interplay between immune cell metabolism and immune function, has emerged as a promising field with potential therapeutic utility in various pathophysiological conditions. The anti-inflammatory and anti-cancer properties of AR and ASR within the traditional Chinese prescription DGBX decoction, prefigures its immunometabolism potential utility in the context of inflammation-cancer transformation, particularly in the setting of IBD-related CRC. It is evidenced by promoting intestinal mucosal repair and balancing intestinal microbiota. While the field of immunometabolism has made significant strides, it is important to acknowledge the limitations inherent in current research methodologies, such as the choice of experimental models, the fundamental biological differences between mice and humans, and clinical verification in the future. Further investigation into the therapeutic application of DGBX decoction for colorectal cancer is imperative, with a particular focus on elucidating its underlying mechanisms of immunometabolism modulation. Concurrently, it is crucial to implement stringent quality control measures and to standardize the production process of DGBX decoction to ensure its safety and reliability for clinical use.

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Acknowledgements

We would like to thank all our colleagues and friends for their sincere and generous help.

This research was funded by the Gansu Province Science Fund for Distinguished Young Scholars (20JR10RA650), and the Outstanding Youth of the Fundamental Research Funds for the Central Universities (lzujbky-2021-ey21). This study was also supported by the Macao Science and Technology Development Fund (FDCT 001/2023/ALC, 0123/2022/A and 0006/2020/AKP), Natural Science Foundation of Guangdong Province, China (2020A1515010922), Traditional Chinese Medicine Bureau of Guangdong Province, China (20201183), Shenzhen–Hong Kong-Macau S&T Program (Category C) (SGDX2020110309420200), and Research Fund of the University of Macau (CPG2023-00028-ICMS).

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Yang Zhang, Qianming Kang, Luying He, Hui Gu, Wenjing Xue & Wen Tan

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YZ wrote and revised this manuscript. QK, LH, KC, HG and WX participated in the revision guidance of the manuscript. WT and ZZ conceived and organized this study. All authors have read and agreed to the published version of the manuscript.

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Zhang, Y., Kang, Q., He, L. et al. Exploring the immunometabolic potential of Danggui Buxue Decoction for the treatment of IBD-related colorectal cancer. Chin Med 19 , 117 (2024). https://doi.org/10.1186/s13020-024-00978-y

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DOI : https://doi.org/10.1186/s13020-024-00978-y

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