latest research on cancer prevention

10 new breakthroughs in the fight against cancer

Medical advances are continuing to help the world fight cancer. Image:  Unsplash/National Cancer Institute

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This article was originally published in May 2022, and most recently updated in May 2024 .

• Cancer is one of the world’s biggest killers, with around 10 million deaths per year due to the disease.
• Scientists are using artificial intelligence, DNA sequencing, precision oncology and other technologies to improve treatment and diagnosis.
• The Centre for the Fourth Industrial Revolution India, a collaboration with the World Economic Forum, hopes to accelerate 18 cancer interventions.

Cancer kills around 10 million people a year and is a leading cause of death globally, according to the World Health Organization.

Breast, lung and colon cancer are among the most common. Death rates from cancer were falling before the pandemic . But COVID-19 caused a big backlog in diagnosis and treatment .

There is some good news, however. Medical advances are accelerating the battle against cancer. Here are 10 recent developments.

Test to identify 18 early-stage cancers

Researchers in the US have developed a test they say can identify 18 early-stage cancers. Instead of the usual invasive and costly methods, Novelna's test works by analyzing a patient's blood protein. In a screening of 440 people already diagnosed with cancer, the test correctly identified 93% of stage 1 cancers in men and 84% in women. The researchers believe the findings "pave the way for a cost-effective, highly accurate, multi-cancer screening test that can be implemented on a population-wide scale". It's early days, however. With such a small sample screening and a lack of information on co-existing conditions, the test is currently more of "a starting point for developing a new generation of screening tests for the early detection of cancer".

Seven-minute cancer treatment jab

England's National Health Service (NHS) is to be the first in the world to make use of a cancer treatment injection , which takes just seven minutes to administer, rather than the current time of up to an hour to have the same drug via intravenous infusion. This will not only speed up the treatment process for patients, but also free up time for medical professionals. The drug, Atezolizumab or Tecentriq, treats cancers including lung and breast, and it's expected most of the 3,600 NHS patients in England currently receiving it intravenously will now switch to the jab.

Precision oncology

Precision oncology is the “ best new weapon to defeat cancer ”, the chief executive of Genetron Health, Sizhen Wang, says in a blog for the World Economic Forum. This involves studying the genetic makeup and molecular characteristics of cancer tumours in individual patients. The precision oncology approach identifies changes in cells that might be causing the cancer to grow and spread. Personalized treatments can then be developed. The 100,000 Genomes Project, a National Health Service initiative, studied more than 13,000 tumour samples from UK cancer patients , successfully integrating genomic data to more accurately pin-point effective treatment. Because precision oncology treatments are targeted – as opposed to general treatments like chemotherapy – it can mean less harm to healthy cells and fewer side effects as a result.

Artificial intelligence fights cancer

In India, World Economic Forum partners are using emerging technologies like artificial intelligence (AI) and machine learning to transform cancer care. For example, AI-based risk profiling can help screen for common cancers like breast cancer, leading to early diagnosis. AI technology can also be used to analyze X-rays to identify cancers in places where imaging experts might not be available. These are two of 18 cancer interventions that The Centre for the Fourth Industrial Revolution India, a collaboration with the Forum , hopes to accelerate.

Greater prediction capabilities

Lung cancer kills more people in the US yearly than the next three deadliest cancers combined. It's notoriously hard to detect the early stages of the disease with X-rays and scans alone. However, MIT scientists have developed an AI learning model to predict a person's likelihood of developing lung cancer up to six years in advance via a low-dose CT scan. Trained using complex imaging data, 'Sybil' can forecast both short- and long-term lung cancer risk, according to a recent study. "We found that while we as humans couldn't quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer," said co-author Jeremy Wohlwend.

Clues in the DNA of cancer

At Cambridge University Hospitals in England, the DNA of cancer tumours from 12,000 patients is revealing new clues about the causes of cancer, scientists say. By analyzing genomic data, oncologists are identifying different mutations that have contributed to each person’s cancer. For example, exposure to smoking or UV light, or internal malfunctions in cells. These are like “fingerprints in a crime scene”, the scientists say – and more of them are being found. “We uncovered 58 new mutational signatures and broadened our knowledge of cancer,” says study author Dr Andrea Degasperi, from Cambridge’s Department of Oncology.

Liquid and synthetic biopsies

Biopsies are the main way doctors diagnose cancer – but the process is invasive and involves removing a section of tissue from the body, sometimes surgically, so it can be examined in a laboratory. Liquid biopsies are an easier and less invasive solution where blood samples can be tested for signs of cancer. Synthetic biopsies are another innovation that can force cancer cells to reveal themselves during the earliest stages of the disease.

The application of “precision medicine” to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseases—and disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forum’s Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access – across borders – to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a “federated data system”: a decentralized approach that allows different institutions to access each other’s data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

CAR-T-cell therapy

A treatment that makes immune cells hunt down and kill cancer cells was declared a success for leukaemia patients in 2022. Known as CAR-T-cell therapy, it involves removing and genetically altering immune cells, called T cells, from cancer patients. The altered cells then produce proteins called chimeric antigen receptors (CARs), which can recognize and destroy cancer cells. In the journal Nature , scientists at the University of Pennsylvania announced that two of the first people treated with CAR-T-cell therapy were still in remission 12 years on.

However, the US Food and Drug Administration is currently investigating whether the process can in fact cause cancer , after 33 cases of secondary cancer were observed in patients receiving CAR-T therapies. The jury is still out as to whether the therapy is to blame but, as a precaution, the drug packaging now carries a warning.

Fighting pancreatic cancer

Pancreatic cancer is one of the deadliest cancers. It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years. At the University of California San Diego School of Medicine, scientists developed a test that identified 95% of early pancreatic cancers in a study. The research, published in Nature Communications Medicine , explains how biomarkers in extracellular vesicles – particles that regulate communication between cells – were used to detect pancreatic, ovarian and bladder cancer at stages I and II.

Have you read?

Cancer: how to stop the next global health crisis, how to improve access to cancer medicines in low and middle-income countries, why is cancer becoming more common among millennials, a tablet to cut breast cancer risk.

A drug that could halve the chance of women developing breast cancer is being tested out by England's National Health Service (NHS). It will be made available to almost 300,000 women seen as being at most risk of developing breast cancer, which is the most common type of cancer in the UK . The drug, named anastrozole, cuts the level of oestrogen women produce by blocking the enzyme aromatase . It has already been used for many years as a breast cancer treatment but has now been repurposed as a preventive medicine. “This is the first drug to be repurposed through a world-leading new programme to help us realize the full potential of existing medicines in new uses to save and improve more lives on the NHS," says NHS Chief Executive Amanda Pritchard.

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World Cancer Report: Cancer Research for Cancer Prevention

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Questions and answers, download pdf, what is the iarc world cancer report .

The new IARC World Cancer Report is the product of a collaboration between leading international scientists that describes multiple aspects of cancer research for cancer prevention. Starting with the latest trends in cancer incidence and mortality worldwide, this publication provides wide-ranging insights into cancer prevention based on the known causes of cancer, factors that determine how cancer develops, and the behaviour of different tumour types, and presents a broad scope of interventions to reduce the cancer burden from a global perspective. The scientific disciplines covered include descriptive epidemiology (the distribution of disease, and specifically cancer, within particular populations), cancer etiology (including infections, chemicals, radiation, metabolism and nutrition, and genetic factors), cellular and molecular biology, toxicology and pathology, behavioural and social sciences, public health, biostatistics, and informatics. Wild CP, Weiderpass E, Stewart BW, editors (2020). World Cancer Report: Cancer Research for Cancer Prevention. Lyon, France: International Agency for Research on Cancer. Available from: http://publications.iarc.fr/586 .

Who is this publication for?

World Cancer Report: Cancer Research for Cancer Prevention features the latest research from across multiple disciplines. It is aimed primarily at cancer researchers, academia, health professionals, and policy-makers, but this expert report remains accessible to a wider audience, including the general public, civil society, and the private sector.

What is the objective of the report?

The IARC World Cancer Report is the most comprehensive overview of relevant research yet available. This latest publication is part of a well-established series . Produced about every 5 years, World Cancer Report provides the latest evidence on cancer prevention and serves as an authoritative reference in the cancer research community. The volume editors of this new World Cancer Report are IARC Director Dr Elisabete Weiderpass, former IARC Director Dr Christopher P. Wild , and Professor Bernard W. Stewart of the University of New South Wales, Sydney, Australia.

What does the latest World Cancer Report include?

Based on how cancer is distributed worldwide, and differences between and within particular countries, this new assessment offers a comprehensive overview of the global cancer burden as a starting point for documenting all known options for cancer prevention through the latest research. The publication documents the causes of cancer, discussing infectious agents, alcohol consumption, metabolism and nutrition, physical activity, sedentary behaviour, and obesity as well as dietary carcinogens, occupational exposure, and the contamination of air, water, and soil, among other topics. The biological processes that affect cancer development are also presented, with a focus on sporadic cancer, genomics and susceptibility, gene–environment interactions, and DNA repair, as well as inflammation and its pivotal role in cancer pathogenesis, to name but a few. A full section is devoted to multiple chapters on the inequalities that affect the distribution of cancer within communities, clearly illustrating that in both high-income countries and low- and middle-income countries, there are groups of people in every community who are at a major disadvantage with respect to risk of cancer. Options for prevention include avoiding exposure to carcinogens, for example by smoking cessation, as well as vaccination, screening, monitoring those at high genetic risk, using therapeutics to reduce cancer risk, and emerging molecular technology for early diagnosis.

What’s new in this World Cancer Report ?

The impact of cancer on the global community can now be defined with greater precision than ever before. The causes of cancer are now better understood in terms of both the precise biological changes induced by causative agents and the characteristics of exposed people who prove to be susceptible to cancer development. This is the broad background against which both biological and sociological variables determine the distribution of cancer and, in many instances, its potential prevention. Factors determining cancer development and prevention The causes of cancer vary markedly in their character and impact. Cancer is just one of the diseases caused by tobacco smoking, but lung cancer and other cancer types caused by smoking are among the most lethal of such diseases. Millions of people are infected with human papillomavirus (HPV), Helicobacter pylori , or hepatitis B virus or hepatitis C virus, and are thus at risk of developing cervical cancer, stomach cancer, and liver cancer, respectively. Complex biological processes, including DNA repair, the occurrence of overweight or obesity, and the consequences of inflammation, are crucial determinants of cancer development. These processes are delineated in the new World Cancer Report . Although much is known about cancer causation, for many tumour types few, if any, relevant carcinogens have been identified. This applies to, for example, brain cancer and prostate cancer. For lung cancer, a broad spectrum of causes are known, beginning with active smoking and extending to second-hand smoke, certain occupations, and atmospheric pollution. Despite this, some individual cases of lung cancer have no evident cause. Such tumours, along with most cases of brain cancer and prostate cancer, are often described as sporadic. Another exciting first for the new World Cancer Report is a discussion of sporadic cancer and the biological principles that are thought to underpin the development of such cancer. Biological processes are common to all people, but the distribution of cancer in all countries is subject to socioeconomic differences. For the first time, inequalities as a determinant of cancer incidence and mortality are specifically addressed in a separate section of the new World Cancer Report . Previous World Cancer Reports described the disproportionately increasing burden of cancer in low- and middle-income countries, and this trend clearly persists. However, in all countries, irrespective of income grouping, sections of the communities are disadvantaged both in relation to circumstances of risk and with respect to prevention and treatment services. In the new World Cancer Report , separate chapters evaluate inequalities that affect cancer incidence in Africa, China, Europe, India, and the USA. Increasing options for cancer prevention Cancer prevention is often identified with community campaigns, such as those to promote smoking avoidance or cessation, to ensure that exposure to asbestos does not occur in the workplace and elsewhere, to prevent particular infections, and, particularly for fair-skinned people, to avoid deliberate sun exposure without sun protection. All these ways of preventing cancer remain relevant; they are proven to reduce cancer incidence, and research continues to demonstrate their efficacy. However, cancer prevention involves a far greater range of initiatives than avoiding exposure to known carcinogens. Perhaps the most effective means of cancer prevention, and one that has the prospect of eliminating one tumour type completely, is vaccination against human papillomavirus (HPV), which is the cause of cervical cancer. Vaccination against hepatitis B and C viruses also has a proven impact on the incidence of liver cancer in certain communities. The single greatest challenge to cancer prevention identified in the new World Cancer Report is overweight or obesity. Although the prevalence of overweight or obesity is readily identified with populations in high-income countries, this condition is now evident in many regions of the world. Multiple tumour types, including colorectal cancer and breast cancer, are attributable, at least in part, to overweight or obesity. The biological mechanisms by which overweight or obesity increases the risk of various tumour types are not yet fully explained. Altering community behaviour to reduce the prevalence of overweight or obesity is recognized as a means of preventing not only certain types of cancer but also other chronic diseases such as type 2 diabetes. For sporadic cancers in different organs (i.e. cancers for which no recognized exposure accounts for tumour development), options for prevention are emerging and are being evaluated by researchers. For multiple tumour types, World Cancer Report discusses population-based screening for detection of cancer at an early stage or of preconditions leading to cancer development. One chapter describes early diagnosis on the basis of tumour DNA detected in blood, and another describes how individual susceptibility to tumorigenesis may be determined using genomic data.

What is the difference between the WHO Report on Cancer and the IARC World Cancer Report ?

In May 2017, the cancer resolution ( WHA70.12 ) adopted at the Seventieth World Health Assembly requested WHO, in collaboration with IARC, to produce a comprehensive global report providing evidence-based public health- and policy-oriented guidance on cancer for WHO Member States. The outcome of this charge is the WHO Report on Cancer: Setting priorities, investing wisely and providing care for all . The WHO report complements the IARC World Cancer Report by synthesizing evidence to translate the latest knowledge into actionable policies to support governments to prevent and control cancer globally. These two complementary publications, launched jointly by WHO and IARC, will each contribute to an increased awareness, both professionally and in the wider community, of the lives affected by cancer, and what may be done, is being done, and should be done to decrease the impact of this disease.

What are the key messages in the IARC World Cancer Report ?

Cancer is the second most common cause of death worldwide, and the burden of cancer is increasing in all countries. This poses a rapidly growing threat to individuals, health systems, and economies globally. Countries must accelerate their multisectoral, evidence-based, and resource-appropriate responses now to avoid 7 million cancer deaths over the next decade. The cancer burden is predicted to nearly double over the next decade in low- and middle-income countries. If no additional action is taken, there will be millions of additional premature deaths from cancer over the next decade, and we will fail to achieve the United Nations Sustainable Development Goals target (Target 3.4) to reduce the total premature mortality from noncommunicable diseases, including cancer, by one third by 2030. The global cancer burden is expected to reach 29 million new cancer cases per year by 2040, a 62% increase on the estimated 18.1 million cancers in 2018. The increases in the cancer incidence burden will affect all countries, but the predicted increases will be proportionately greatest in low-income countries, due to known infectious agents, chemicals including tobacco, and obesity. World Cancer Report documents how the cancer burden continues to grow and emphasizes the need for urgent implementation of efficient prevention strategies to curb the disease. For cervical cancer, lung cancer, and most other cancer types, the relative incidence is greatest among those at socioeconomic disadvantage, particularly including ethnic and racial minorities and Indigenous populations. Cancer inequalities reflect the cultures and environments in which people are born, live, and work and the uneven application of preventive measures, both between and within countries. Vaccination and screening are effective for some cancer types but are differentially available. Most genomic data are from studies in individuals of European ancestry. In the future, the characterization of individual susceptibility to cancer and the closer identification of those at risk will enable precision cancer prevention.

Dr Elisabete Weiderpass, IARC Director, presents World Cancer Report: Cancer Research for Cancer Prevention

Professor bernard stewart presents world cancer report: cancer research for cancer prevention.

Published in section: Featured News

Publication date: 4 February, 2020, 6:50

Direct link: https://www.iarc.who.int/featured-news/new-world-cancer-report/

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AACR Cancer Progress Report Details Exciting Advances in Cancer Research and Treatment

Report includes call to action outlining steps congress must take to maintain momentum against cancer for all patients.

PHILADELPHIA – Today, the American Association for Cancer Research (AACR) released the 13th edition of its annual Cancer Progress Report , which chronicles how basic, translational, and clinical cancer research and cancer-related population sciences—primarily supported by federal investments in the National Institutes of Health (NIH) and the National Cancer Institute (NCI)—remain vitally important to improving health and saving lives.

In addition to providing the latest statistics on cancer incidence, mortality, and survivorship, the AACR Cancer Progress Report 2023 offers detailed updates and important context regarding the latest research in cancer etiology, early detection, diagnosis, treatment, prevention, and survivorship. Throughout the report, the personal stories of patients who have benefited from innovative, recently approved anticancer therapeutics highlight the real-world impact of cancer research.

This comprehensive report also features a spotlight on cancer immunotherapy and addresses persistent challenges in cancer research, including cancer disparities, slow progress against certain types of cancer, and the physical, psychosocial, and financial hardships faced by cancer patients, survivors, and their caregivers. A closing call to action outlines steps Congress and other stakeholders must take to ensure that the U.S. maintains its momentum against cancer for the benefit of all patients.

“The advances in cancer research, particularly in the last two decades, have been breathtaking,” said AACR President Philip Greenberg, MD, FAACR, faculty member at Fred Hutchinson Cancer Center. “We are in an era of unparalleled opportunity to make even more breakthroughs for patients. For the cancer research community to achieve these breakthroughs, however, our representatives in Congress must continue to prioritize funding for biomedical research, from basic research to clinical trials. Through the AACR Cancer Progress Report 2023 , we are sharing with the public and policy makers the progress that has been made, how that progress has been delivered to patients, how it’s changed people’s lives, and the unparalleled opportunities that now exist from scientific and technologic advances, so they understand how crucial it is that we maintain this momentum through continued support of NIH and NCI.”

PROMISING TRENDS AND ADVANCES IN CANCER CARE

The medical research community—including researchers in academia and industry, physician-scientists, patient advocates, regulators, and many other stakeholders—has maintained impressive momentum against cancer in recent years. As outlined in the AACR Cancer Progress Report 2023 :

• A new gene therapy-based immunotherapeutic for certain patients with bladder cancer
• A first-in-class antibody drug conjugate for patients with ovarian cancer
• Four new T-cell engaging bispecific antibodies for a range of hematologic malignancies
• The first approval of an immune checkpoint inhibitor for pediatric and adult patients with a rare form of sarcoma
• Due in large part to advances in prevention, early detection, and treatment, the age-adjusted overall cancer death rate in the U.S. fell by 33% between 1991 and 2020— an estimated 3.8 million cancer deaths averted .
• Breast cancer mortality declined by 43% between 1989 and 2020 , leading to an estimated 460,000 fewer breast cancer deaths.
• The decrease in lung cancer mortality has accelerated from 0.9% a year between 1995 and 2005 to nearly 5% a year between 2014 and 2020. This rapid decline is the result of a steep reduction in the U.S. smoking rate as well as the development of numerous highly effective molecularly targeted therapeutics and immunotherapeutics.
• More and better treatment options have led to notable progress against many pediatric cancers as well. Among children (14 and younger) and adolescents (15-19), overall cancer death rates declined by 70% and 64%, respectively, between 1970 and 2020.

THE IMMUNOTHERAPY REVOLUTION

Immunotherapy has revolutionized cancer care. Breakthroughs in this field have contributed to much of the progress noted above, such as declines in the death rates for previously intractable cancers like advanced lung cancer and melanoma. The AACR Cancer Progress Report 2023 contains a spotlight on the history of cancer immunotherapy, the current state of this treatment modality, and the immense promise of the next generation of immunotherapeutics. Highlights include:

• Since 2011, the FDA has approved 11 immune checkpoint inhibitors , which release “brakes” on the surface of certain immune cells—called T cells—so that the T cells are able to destroy cancer cells. Many of these drugs are approved for more than one type of cancer, making immune checkpoint inhibitors a treatment option for 20 cancer types and any tumor with certain specific molecular characteristics.
• Since 2017, the FDA has approved six CAR T-cell therapies to treat a range of hematologic malignancies. CAR T-cell therapy is a type of adoptive cell therapy, which is designed to dramatically increase the number of cancer-killing immune cells a patient has.
• The field is expanding in exciting ways, with researchers combining the power of other cells in the immune system with recent advances in gene editing to develop more personalized and effective versions of adoptive cell therapy for treatment of solid tumors; developing mRNA-based vaccines and therapeutics to treat cancer; and targeting the gut microbiome to increase the efficacy of cancer immunotherapy, among many other innovative approaches.

DESPITE PROGRESS, CHALLENGES PERSIST

Despite the extraordinary scientific progress against cancer in recent years, this complex disease remains a significant threat to human health around the world. In the U.S., it is estimated that nearly 2 million new cases of cancer will be diagnosed and more than 609,000 people will die from the disease in 2023.

Indeed, cancer research and patient care face numerous challenges, as outlined in the AACR Cancer Progress Report 2023 :

• Cancer disparities are a pervasive public health problem, with racial and ethnic minorities and other medically underserved U.S. populations shouldering a disproportionally higher burden of cancer. While advances have been made in identifying, understanding, and addressing some of these disparities, more research and policy solutions are urgently needed to ensure equitable progress against cancer.
• There has been uneven progress against different cancer types. Few treatment options exist for patients diagnosed with pancreatic cancer or glioblastoma, for example, and 5-year relative survival rates for these cancers are extremely low.
• Incidence rates for some cancers are increasing, including for early-onset colorectal cancer, pancreatic cancer, and uterine cancer, in part due to the rising rate of obesity.
• Financial toxicity is widespread, exacerbated by the rising cost of cancer care. In 2019, U.S. cancer patients paid an estimated $16.2 billion in out-of-pocket cancer care costs and lost an additional $5 billion in “time costs.”

FEDERAL FUNDING ESSENTIAL FOR CONTINUED PROGRESS

To confront these and other challenges, the AACR Cancer Progress Report 2023 calls on Congress to support robust, sustained, and predictable annual funding growth for NIH and NCI by providing increases of at least $3.465 billion and $2.6 billion, respectively, in their fiscal year 2024 base budgets. This funding is crucial to continued progress for patients. From 2010 to 2019, NIH funding contributed to the development of 354 out of 356 new drugs, including many cancer drugs, approved by the FDA.

The AACR also urges Congress to:

• Provide $1.7 billion in dedicated funding for Cancer Moonshot activities in FY 2024 across NCI, FDA, and Centers for Disease Control and Prevention (CDC) with the assurance that Moonshot funding will supplement rather than supplant NIH funding in FY 2024.
• Appropriate at least $472.4 million in FY 2024 appropriations for the CDC Division of Cancer Prevention to support comprehensive cancer control, central cancer registries, and screening and awareness programs for specific cancers.
• Allocate $50 million in funding for the Oncology Center of Excellence at FDA in FY 2024 to allow regulators with the capable staff and necessary tools to conduct expedited review of cancer-related medical products.

“We are proud to release the 13 th annual AACR Cancer Progress Report ,” said AACR CEO Margaret Foti, PhD, MD (hc). “It is our hope that this comprehensive resource will help to increase knowledge about the myriad diseases we call cancer as well as the innovative research that is improving and extending lives. The findings in this report, along with the personal stories of the featured patients, underscore the enormous impact that robust, sustained, and predictable funding for cancer research has had on Americans’ health, and why that support must continue.”

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Immune to Cancer: The CRI Blog

How CRI’s Immunotherapy Breakthroughs and Research are Shaping Cancer Treatment and Prevention

Today, cancer immunotherapy is the most forward-thinking and innovative form of cancer treatment for patients. Cancer immunotherapy is especially effective with treating melanoma, lung, breast, and several other types of cancer. When possible, however, there is a preferable option compared to treatment: the prevention of cancer entirely.

Want to do something big for cancer immunotherapy research? Make a donation today to the Cancer Research Institute .

CRI scientists are committed to groundbreaking cancer immunotherapy research that can benefit the lives of patients and potentially save lives. In addition to research regarding treating existing cancers, some CRI scientists are also working on forward-thinking research that can address cancer prevention and attack cancer at its roots.

CRI Scientists’ Innovative Work and Perspectives on Cancer Treatment and Prevention

1. Cancer Vaccine Discoveries

Elizabeth Jaffee, MD , deputy director of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and CRI Scientific Advisory Council associate director, serves on the panel for President Joe Biden’s Cancer Moonshot Initiative . Additionally, Dr. Jaffee’s research focuses on novel cancer vaccines, and she has patents for six of them.  Dr. Jaffee foresaw the immense potential of cancer vaccines long before others did. At the 2023 CRI Patient Immunotherapy Summit , she succinctly outlined the transformative power of these vaccines.

“Vaccines are the biggest success story of the 20 th century other than penicillin,” Dr. Jaffee says. “We have suggested developing new technologies and new computational approaches that can take all of the new data we are generating and put it into a framework, biologically, that tells us which signals a tumor is sending out to cells around it to cause it to protect the tumor. Through that information we can develop drugs that can intercept those signals. We can now take vaccines, combine them with drugs, and we can make a difference. We are seeing vaccines close to approval for cancers like melanoma. We are going to see this happening more and more over the next five years.”

2. Measuring Immunotherapy Response in a Single Drop of Blood

  Valsamo (Elsa) Anagnostou, MD, PhD , director of the thoracic oncology biorepository at Johns Hopkins, leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board, co-director of the Lung Cancer Precision Medicine Center of Excellence, CRI Torrey Coast Foundation GEMINI CLIP Investigator, and CRI Clinical Accelerator is at the forefront of leveraging cutting-edge technologies to advance diagnosis and therapy response. Her pioneering work has unleashed the power of liquid biopsies to test ctDNA (circulating tumor DNA) in patient blood, revolutionizing our ability to gauge patient responses to treatment.  Liquid biopsies involve drawing small samples of blood from patients for testing. “ctDNA response is particularly informative to understand the complexity of stable disease on imaging, which represents a sizable fraction of patients in whom imaging fails to timely and accurately detect the magnitude of therapeutic response,” Dr. Anagnostou says. “ctDNA response correlated with tumor size seen on imaging, which is the gold standard for monitoring response to cancer treatments and seemed to be better correlated with survival.”

Liquid biopsies could be the first step in preventing excessive follow-up procedures and scans. This is a technology that can further be developed to test for markers in blood that can indicate presence of undetectable tumors or the presence of cancer cells even before they become large enough tumors to be detected using traditional scans.

3. The Tumor Microenvironment Holds the Answer to Cancer

Max Krummel, PhD, Robert E. Smith Endowed Chair in Experimental Pathology at the University of California San Francisco (UCSF), Professor, Department of Pathology at UCSF, and former CRI Investigator Award recipient, emphasizes the need to broaden our perspective on cancer prevention beyond the current focus on boosting T cell responses through checkpoint blockade. While acknowledging the significance of enhancing T cell activity, Dr. Krummel sees an equally promising avenue in understanding and targeting the tumor microenvironment (TME). The TME is comprised of the non-cancerous cells, blood vessels, and molecules that surround and sustain a tumor cell. He highlights, “We have started to think about the fundamental biology of the tumor and how to target [that].” This shift in focus towards comprehending the intricacies of the tumor microenvironment underscores the importance of exploring diverse approaches in our efforts to combat cancer effectively.

In the U.S. alone, about 600,000 people die from cancer annually. While treatment methods have improved in recent years, particularly with immunotherapy, there is no silver bullet for cancer prevention, there are several measures people can take to try and safeguard against a potential cancer diagnosis (via the Mayo Clinic).

Measures That can Help Prevent Cancer

1. Screen Early

Different populations are at greater risk of diagnosis depending on the type of cancer. For former and current smokers, screening against lung cancer is critical. Another example is that for women between 40-75 years old, having a mammogram every two years is greatly encouraged to guard against breast cancer .

Additionally, there are also tests that can detect specific cancer-related mutations that are routinely performed to determine if someone is at risk for cancer.

2. Limit Exposure to Harmful UV Rays

Limiting the amount of time your skin is exposed to the sun and avoiding tanning booths is a good way to safeguard against skin cancer.   If you are going to be in the sun, applying sunscreen and covering your skin as best you can be good safety measures.

3. Consider Cancer Vaccines

There are currently four distinct preventative cancer vaccines for HPV and HBV-associated cancers that have been approved by the FDA. Viral infections have proven responsible for several cancers, and preventative cancer vaccines are an important tool to help thwart off cancer before it can develop.

Additionally, there are two approved therapeutic cancer vaccines for bladder and prostate cancers. These vaccines help the immune system identify cancer cells so they can be eliminated.

4. Maintain a Healthy Diet

Certain dietary measures, such as reducing one’s intake of red meat, can help reduce an individual’s risk of a cancer diagnosis . A healthy diet is one that is focused on fruits and vegetables, while avoiding refined sugars and excess animal fat.

Between new developments in cancer immunotherapy on the horizon and greater education of the public regarding preventative measures, there is potential for a greater collective focus on cancer prevention, and therefore, a world immune to cancer.

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What to Know About the HPV Vaccine and Cancer Prevention

New research shows many eligible people are not getting the shots.

By Dani Blum

Nearly 20 years after the first vaccine against human papillomavirus became available, many eligible Americans still are not getting the shot — even though it provides powerful protection against the leading cause of cervical cancer and a strong risk factor for anal cancer.

HPV is the most common sexually transmitted infection in the United States, and while most infections are asymptomatic and clear up on their own within two years, a small number persist and can cause cancer. HPV causes nearly all cases of cervical cancer, and can also lead to penile, anal, oral, vulvar and vaginal cancers .

The HPV vaccine, delivered as two or three doses, can significantly cut the risk of infection. It “is really one of the most effective vaccines we have,” said Dr. Lauri Markowitz, the HPV team lead in the Centers for Disease Control and Prevention’s division of viral diseases. But uptake remains stubbornly low: A report released by the C.D.C. this month showed that in 2022, only 38.6 percent of children ages 9 to 17 had received at least one dose of the HPV vaccine. Other new research suggests that HPV vaccination rates stalled in the wake of the coronavirus pandemic.

A study published this week laid out some of the primary reasons cited by parents in the United States who don’t plan to vaccinate their children against HPV, including safety concerns, a lack of knowledge about the vaccine and a belief that it isn’t necessary.

“We are still facing an uphill battle from what I would call inappropriate messaging or incomplete messaging when the vaccine rolled out about why this is so important,” said Karen Knudsen, chief executive of the American Cancer Society.

How does the vaccine work?

The HPV vaccine fools the body into thinking it has come into contact with the virus, marshaling antibodies in defense. Those antibodies can help clear the virus and prevent infection if someone is later exposed, which can happen through oral, anal and vaginal sex .

The vaccine offers protection from the types most likely to cause cervical and anal cancers and genital warts. Since the vaccine was introduced in 2006, infections with the types of HPV that cause most HPV-related cancers and genital warts have fallen by 88 percent among teen girls and by 81 percent among young adult women, according to the C.D.C.

One reason doctors are so enthusiastic about the vaccine is that it is one of very few tools to combat HPV: Condoms do not entirely prevent transmission, and there is no treatment for the virus itself. Researchers believe HPV is responsible for more than 90 percent of cervical and anal cancers and a majority of vaginal, vulvar, and penile cancers.

Who should get it? And how?

Children can be vaccinated starting at age nine. The C.D.C. recommends the vaccine for all preteens from the age of 11 or 12 and anyone up to age 26. It’s most effective before people are exposed to the virus, and “the assumption is that most people have started having sexual intercourse by age 26,” said Dr. Ban Mishu Allos, an associate professor of medicine at Vanderbilt University Medical Center.

The vaccine may still provide some benefit for people over age 26, and is approved up until age 45. The C.D.C. says that people between the ages of 27 and 45 might get the vaccine after talking to their doctors about their risk for new HPV infections.

You can ask your primary care doctor or local health centers for the vaccine. Most insurance plans fully cover it through age 26. Children and adolescents who are uninsured or underinsured can get the shots for free through the Vaccines for Children program. After age 26, insurance may not fully cover the shot, which can cost hundreds of dollars per dose. Merck, which makes the HPV vaccine Gardasil 9, has a patient assistance program for eligible people.

Why are vaccination rates still low?

Researchers believe much of the hesitation stems from a key misunderstanding: “More people perceive it as a sexually transmitted infection prevention vaccine, as opposed to a cancer prevention vaccine,” said Kalyani Sonawane, an associate professor of public health sciences at the M.U.S.C. Hollings Cancer Center and an author of the new paper on parental attitudes toward HPV vaccination.

Dr. Sonawane’s research has also found that many parents are concerned about side effects. But doctors say many people do not experience side effects, and for those that do, the issues are generally mild and can include arm soreness, nausea, dizziness or, in some cases, fainting.

Doctors urge parents to vaccinate their children before they’re likely to become sexually active, which gives some parents pause, said Dr. Monica Woll Rosen, an obstetrician-gynecologist at the University of Michigan Medical School.

“You’re doing something to prevent them from getting cancer in 30 years,” she said, “and the disconnect might be too large for some people to really wrap their heads around.”

Dani Blum is a health reporter for The Times. More about Dani Blum

The Fight Against Cancer

We asked experts what to know about melanoma symptoms, treatment and prevention. Here’s how to avoid one of the deadliest forms  of skin cancer.

Colon and rectal cancers are increasing among people younger than 50. Experts have a few ideas about why .

Should alcoholic beverages have cancer warning labels? Ireland will require them starting in 2026, and there are nascent efforts elsewhere .

Risk calculators can offer a more personalized picture of an individual patient’s breast cancer risk. But experts warn that the results need to be interpreted with the help of a doctor .

The human papillomavirus vaccine provides powerful protection against the leading cause of cervical cancer and against a strong risk factor for anal cancer. Here’s what to know about the shot .

A recent study adds to growing evidence that exercise is an important part of preventing prostate cancer , the second most common and second most fatal cancer in the United States for men.

Cancer Prevention Overview (PDQ®)–Patient Version

What is prevention.

Cancer prevention is action taken to lower the chance of getting cancer. In 2023, about 1.9 million people will be diagnosed with cancer in the United States. In addition to the physical problems and emotional distress caused by cancer, the high costs of care are also a burden to patients, their families, and to the public. By preventing cancer, the number of new cases of cancer is lowered. Hopefully, this will reduce the burden of cancer and lower the number of deaths caused by cancer.

Cancer is not a single disease but a group of related diseases. Many things in our genes , our lifestyle, and the environment around us may increase or decrease our risk of getting cancer.

Scientists are studying many different ways to help prevent cancer, including the following:

• Ways to avoid or control things known to cause cancer.
• Changes in diet and lifestyle.
• Finding precancerous conditions early. Precancerous conditions are conditions that may become cancer.
• Chemoprevention (medicines to treat a precancerous condition or to keep cancer from starting).
• Risk-reducing surgery.

Carcinogenesis

Carcinogenesis is the process in which normal cells turn into cancer cells., changes (mutations) in genes occur during carcinogenesis..

Carcinogenesis is the series of steps that take place as a normal cell becomes a cancer cell. Cells are the smallest units of the body and they make up the body's tissues. Each cell contains genes that guide the way the body grows, develops, and repairs itself. There are many genes that control whether a cell lives or dies, divides (multiplies), or takes on special functions, such as becoming a nerve cell or a muscle cell.

Changes ( mutations ) in genes can cause normal controls in cells to break down. When this happens, cells do not die when they should and new cells are produced when the body does not need them. The buildup of extra cells may cause a mass (tumor) to form.

Tumors can be benign or malignant (cancerous). Malignant tumor cells invade nearby tissues and spread to other parts of the body. Benign tumor cells do not invade nearby tissues or spread.

Risk Factors

Cigarette smoking and tobacco use, immunosuppressive medicines after organ transplant, physical activity, environmental risk factors.

Scientists study risk factors and protective factors to find ways to prevent new cancers from starting. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.

Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Risk factors that a person can control are called modifiable risk factors.

Many other factors in our environment, diet , and lifestyle may cause or prevent cancer. This summary reviews only the major cancer risk factors and protective factors that can be controlled or changed to reduce the risk of cancer. Risk factors that are not described in the summary include certain sexual behaviors, the use of estrogen , and being exposed to certain substances at work or to certain chemicals .

Factors that are known to increase the risk of cancer

Tobacco use is strongly linked to an increased risk for many kinds of cancer. Smoking cigarettes is the leading cause of the following types of cancer:

• Acute myelogenous leukemia (AML).
• Bladder cancer .
• Cervical cancer .
• Esophageal cancer .
• Kidney cancer .
• Lung cancer .
• Oral cavity cancer .
• Pancreatic cancer .
• Stomach cancer .

Not smoking or quitting smoking lowers the risk of getting cancer and dying from cancer. Scientists believe that cigarette smoking causes about 30% of all cancer deaths in the United States.

See the following PDQ summaries for more information:

• Lung Cancer Prevention
• Lung Cancer Screening
• Cigarette Smoking: Health Risks and How to Quit

Certain viruses and bacteria are able to cause cancer. Examples of cancer-causing viruses and bacteria include:

• Human papillomavirus (HPV) increases the risk for cancers of the cervix , penis , vagina , anus , and oropharynx .
• Hepatitis B and hepatitis C viruses increase the risk for liver cancer .
• Epstein-Barr virus increases the risk for Burkitt lymphoma .
• Helicobacter pylori increases the risk for gastric cancer .

Two vaccines to prevent infection by cancer-causing agents have been developed and approved by the US Food and Drug Administration (FDA). One is a vaccine to prevent infection with hepatitis B virus. The other protects against infection with strains of human papillomavirus (HPV) that cause cervical cancer . Scientists continue to work on vaccines against infections that cause cancer.

• Cervical Cancer Causes, Risk Factors, and Prevention
• Cervical Cancer Screening
• Liver Cancer Causes, Risk Factors, and Prevention
• Stomach Cancer Causes and Risk Factors
• Oral Cavity, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancers Prevention

Being exposed to radiation is a known cause of cancer. There are two main types of radiation linked with an increased risk of cancer:

• Ultraviolet radiation from sunlight: This is the main cause of nonmelanoma skin cancers .
• Medical radiation from tests to diagnose cancer such as x-rays , CT scans , fluoroscopy , and nuclear medicine scans .
• Radon gas in our homes.

Scientists believe that ionizing radiation causes leukemia , thyroid cancer , and breast cancer in women. Ionizing radiation may also be linked to myeloma and cancers of the lung , stomach , colon , esophagus , bladder , and ovary . Being exposed to radiation from diagnostic x-rays increases the risk of cancer in patients and x-ray technicians . Diagnostic radiation in children and adolescents has been linked with a higher risk of cancers at a young age.

The growing use of CT scans over the last 20 years has increased exposure to ionizing radiation. The risk of cancer also increases with the number of CT scans a patient has and the radiation dose used each time.

• Breast Cancer Prevention
• Breast Cancer Screening
• Skin Cancer Prevention

Immunosuppressive medicines are used after an organ has been transplanted from one person to another. These medicines stop an organ that has been transplanted from being rejected. These medicines decrease the body's immune response to help keep the organ from being rejected. Immunosuppressive medicines are linked to an increased risk of cancer because they lower the body's ability to keep cancer from forming. The risk of cancer, especially cancer caused by a virus, is higher in the first 6 months after organ transplant, but the risk lasts for many years.

Factors that may affect the risk of cancer

The foods that you eat on a regular basis make up your diet . Diet is being studied as a risk factor for cancer. It is hard to study the effects of diet on cancer because a person's diet includes foods that may protect against cancer and foods that may increase the risk of cancer.

It is also hard for people who take part in the studies to keep track of what they eat over a long period of time. This may explain why studies have different results about how diet affects the risk of cancer.

Some studies have shown that a diet high in fat, proteins , calories , and red meat increases the risk of colorectal cancer , but other studies have not shown this.

It is not known if a diet low in fat and high in fiber , fruits, and vegetables lowers the risk of colorectal cancer.

Studies have shown that drinking alcohol is linked to an increased risk of the following types of cancers:

• Oral cancer .
• Breast cancer.
• Colorectal cancer (in men).

Drinking alcohol may also increase the risk of liver cancer and female colorectal cancer.

• Colorectal Cancer Prevention
• Esophageal Cancer Prevention

Studies show that people who are physically active have a lower risk of certain cancers than those who are not. It is not known if physical activity itself is the reason for this.

Some studies show that physical activity protects against postmenopausal breast cancer and endometrial cancer .

• Endometrial Cancer Prevention

Studies show that obesity is linked to a higher risk of the following types of cancer:

• Postmenopausal breast cancer.
• Colorectal cancer.
• Endometrial cancer.
• Esophageal cancer.
• Kidney cancer.
• Pancreatic cancer.

Some studies show that obesity is also a risk factor for cancer of the gallbladder and liver cancer.

Studies have shown that people who lose weight decrease their risk of these cancers.

Some studies show that having diabetes may slightly increase the risk of having the following types of cancer:

• Bladder cancer.
• Breast cancer in women.
• Liver cancer.
• Lung cancer.
• Oral cancer.
• Oropharyngeal cancer .
• Ovarian cancer .

Diabetes and cancer share some of the same risk factors. These risk factors include the following:

• Being older.
• Having obesity.
• Not eating a healthy diet.
• Not exercising.

Because diabetes and cancer share these risk factors, it is hard to know whether the risk of cancer is increased more by diabetes or by these risk factors.

Studies are being done to see how medicine that is used to treat diabetes affects cancer risk.

Being exposed to chemicals and other substances in the environment has been linked to some cancers:

• Links between air pollution and cancer risk have been found. These include links between lung cancer and secondhand tobacco smoke , outdoor air pollution, and asbestos .
• Drinking water that contains a large amount of arsenic has been linked to skin , bladder, and lung cancers.

Studies have been done to see if pesticides and other pollutants increase the risk of cancer. The results of those studies have been unclear because other factors can change the results of the studies.

Interventions That Are Known to Lower Cancer Risk

Chemoprevention is being studied in people who have a high risk of developing cancer., studies have shown that weight loss surgery lowers cancer risk..

An intervention is a treatment or action taken to prevent or treat disease, or improve health in other ways. Many studies are being done to find ways to keep cancer from starting or coming back.

Chemoprevention is the use of substances to lower the risk of cancer, or keep it from recurring. The substances may be natural or made in the laboratory. Some chemopreventive agents are tested in people who are at high risk for a certain type of cancer. The risk may be because of a precancerous condition, family history , or lifestyle factors.

Taking one of the following agents may lower the risk of cancer:

• Selective estrogen receptor modulators (SERMS) such as tamoxifen or raloxifene have been shown to reduce the risk of breast cancer in women at high risk. SERMS may cause side effects , such as hot flashes , so they are not often used for prevention of cancer. For more information, see Breast Cancer Prevention .
• Finasteride has been shown to lower the risk of prostate cancer . For more information, see Prostate Cancer Prevention .
• COX-2 inhibitors may prevent colon and breast cancer. COX-2 inhibitors may cause heart problems. Because COX-2 inhibitors may cause heart problems there have not been many studies on their use to prevent cancer. For more information, see Colorectal Cancer Prevention and Breast Cancer Prevention .

Weight loss surgery, also called bariatric surgery , is a procedure that people with obesity can have to lose weight and improve their overall health and quality of life. The surgery changes the anatomy of the stomach or changes the way the body absorbs nutrients. A person who undergoes this procedure will lose a lot of weight and as a result, will have a decreased risk of cancers that are linked to being overweight.

See the NCI website for more information about cancer prevention.

Interventions That Are Not Known to Lower Cancer Risk

Aspirin has not been shown to prevent most cancers., vitamin and dietary supplements have not been shown to prevent cancer., new ways to prevent cancer are being studied in clinical trials..

Aspirin has been studied as chemoprevention . The studies show mixed results but most have shown that aspirin does not prevent cancer. However, there is evidence that taking aspirin for long periods of time may prevent colorectal cancer in certain people. For more information, see Colorectal Cancer Prevention .

Results from a randomized trial suggest that taking aspirin may make cancer grow more quickly in the elderly, but longer follow up is needed to confirm these results.

Bleeding in the gastrointestinal tract or brain is a side effect of aspirin. Even though aspirin has not been shown to reduce the risk of most cancers, it has many uses, including helping to lower the chances of dying from heart disease. Before beginning long-term aspirin use, it is important to talk with your doctor about the related benefits and harms.

An intervention is a treatment or action taken to prevent or treat disease, or improve health in other ways.

There is not enough proof that taking multivitamin and mineral supplements or single vitamins or minerals can prevent cancer. The following vitamins and mineral supplements have been studied, but have not been shown to lower the risk of cancer:

• Vitamin B6 .
• Vitamin B12 .
• Vitamin E .
• Vitamin C .
• Beta carotene .
• Folic acid .
• Vitamin D .

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) found that vitamin E taken alone increased the risk of prostate cancer . The risk continued even after the men stopped taking vitamin E. Taking selenium with vitamin E or taking selenium alone did not increase the risk of prostate cancer.

Vitamin D has also been studied to see if it has anticancer effects. Skin exposed to sunshine can make vitamin D. Vitamin D can also be consumed in the diet and in dietary supplements . Taking vitamin D in doses from 400–1100 IU / day has not been shown to lower or increase the risk of cancer.

The VITamin D and OmegA-3 TriaL (VITAL) is under way to study whether taking vitamin D (2000 IU/ day) and omega-3 fatty acids from marine (oily fish) sources lowers the risk of cancer.

The Physicians' Health Study found that men who have had cancer in the past and take a multivitamin daily may have a slightly lower risk of having a second cancer .

• Prostate Cancer Prevention

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

About This PDQ Summary

Physician Data Query (PDQ) is the National Cancer Institute's (NCI's) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish .

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about cancer prevention. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary ("Updated") is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board .

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become "standard." Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI's website . For more information, call the Cancer Information Service (CIS), NCI's contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Cancer Prevention Overview. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/causes-prevention/patient-prevention-overview-pdq . Accessed <MM/DD/YYYY>. [PMID: 26389424]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online . Visuals Online is a collection of more than 3,000 scientific images.

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us .

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Breast Cancer Prevention: Current Approaches and Future Directions

The topic of breast cancer prevention is very broad. All aspects of the topic, therefore, cannot be adequately covered in a single review. The objective of this review is to discuss strategies in current use to prevent breast cancer, as well as potential approaches that could be used in the future. This review does not discuss early detection strategies for breast cancer, including breast cancer screening. The breast is the most common site among women worldwide of noncutaneous cancer. Many clinical and genetic factors have been found to increase a woman’s risk of developing the disease. Current strategies to decrease a woman’s risk of developing breast cancer include primary prevention, such as avoiding tobacco, exogenous hormone use and excess exposure to ionizing radiation, maintaining a normal weight, exercise, breastfeeding, eating a healthy diet and minimizing alcohol intake. Chemoprevention medications are available for those at high risk, though they are underutilized in eligible women. Mastectomy and/or bilateral oophorectomy are reasonable strategies for women who have deleterious mutations in genes that dramatically increase the risk of developing cancer in either breast. There are a variety of strategies in development for the prevention of breast cancer. Personalized approaches to prevent breast cancer that are being developed focus on advances in precision medicine, knowledge of the immune system and the tumor microenvironment and their role in cancer development. Advances in our understanding of how breast cancer develops are allowing investigators to specifically target populations who are most likely to benefit. Additionally, prevention clinical trials are starting to evaluate multi-agent cancer prevention approaches, with the hope of improved efficacy over single agents. Finally, there is a push to increase the use of chemopreventive agents with proven efficacy, such as tamoxifen and raloxifene, in the prevention of breast cancer.

Introduction

While breast cancer death rates increased by 0.4% per year in the United States (U.S.) between 1975 and 1989, between 1989 and 2015 they decreased by 39%, averting 322,600 deaths ( 1 ). There has not been a similar decrease in breast cancer incidence. The incidence of breast cancer is increasing in the developing world due to increased life expectancy, increased urbanization and the adoption of western lifestyles ( 2 ). There is an emerging epidemic of obesity related cancers, including breast cancer, in many parts of the developed and developing world. The incidence of obesity related cancers (other than those of the colon and rectum) increased in the U.S. by 7 percent between 2005 and 2014, while the rates of non-obesity related cancers declined during that time ( 3 ). About 631,000 people in the U.S. were diagnosed with a cancer associated with overweight and obesity in 2014 ( 3 ).

The prevention of breast cancer depends on targeting factors that increase risk. Many, but not all of these risk factors can be modified. Those that can be modified include diet; exercise; avoidance of certain things such as tobacco, exogenous female hormones, ionizing radiation, and alcohol in excess; pregnancy and nursing. An important question when discussing breast cancer prevention is which individuals to target. In general, greater focus has been placed on strategies to decrease risk among those at the greatest risk of developing breast cancer. For high risk women, two chemoprevention medications have been approved by the U.S. Food and Drug Administration (FDA), and a third recommended by some governing bodies for use. Surgery has also been recommended for certain subsets of women who are genetically at increased breast cancer risk.

Risk factors are inherited, histopathologic or environmental, each of which is important. Strategies to decrease environmental risks generally focus on directly addressing the environmental factor, whereas genetic and histopathologic risks, which cannot so easily be altered directly, are addressed indirectly, such as through altering known drivers to breast cancer, such as estrogen and its receptor through chemoprevention, or by surgical extirpation of the organ(s) at risk. Mammographic breast density (MBD) also influences breast cancer risk. MBD is appears to be influenced by genetics ( 4 ), age and body mass index ( 5 ).

There are a variety of risk assessment tools available, some of which require information on breast cancer ( BRCA ) gene mutation status, and others which do not but rather focus on clinical and histopathologic factors which influence risk ( 6 ). The Gail breast cancer risk assessment tool (BCRAT) is the tool most commonly used in the U.S. to estimate a woman’s risk of developing breast cancer. This tool was used to determine eligibility in two large U.S. breast cancer prevention trials (the first evaluating tamoxifen, the second tamoxifen vs. raloxifene) ( 7 ). It incorporates a variety of clinical and histopathologic factors. Two European breast cancer prevention trials (the first evaluating tamoxifen, the second anastrozole) used the Tyrer-Cuzick risk assessment tool, which incorporates genetic and clinical breast cancer risk factors ( 7 ).

Scientists have identified some of the genetic mutations which drive the development of breast cancer, but we know relatively little of genetic alterations which work together, or in concert with environmental alterations, to promote breast cancer development. Some of the proven or potential driver genetic alterations, including BRCA 1 and 2, TP53, PTEN, STK11, CDH1, PALB2, CHECK2, ATM, NBN, and NF1 ( 8 ), are included in commercially available risk assessment panels. Genetic counseling can be provided to discuss detection of one or more alterations in a driver mutation, as well as the implications of an identified deleterious mutation and a patient’s options.

Male breast cancer (MBC) accounts for fewer than 1% of all cancers in men and is less than 1% as common as female breast cancer ( 9 ). Due to the relative rarity of MBC, far less is known about what causes the disease, and chemoprevention studies have generally excluded men from enrollment. Nonetheless, limited studies have provided evidence for the causes of MBC. A report which pooled data from 11 case-control and 10 cohort studies, including 2,405 men with and 52,013 men without breast cancer, demonstrated that risk factors for MBC include obesity (odds ratio-OR=1.3), diabetes (OR=1.19), Klinefelter syndrome (OR=24.7), and gynecomastia (OR=9.78) ( 10 ). Many of these factors lead to elevated levels of circulating estrogen. Family history is also an important risk factor for MBC. Deleterious mutations in BRCA1 and 2 are known to significantly increase the risk of MBC. Lifetime risk of developing MBC is 1–5 % for BRCA1 and 5–10 % for BRCA2 mutation carriers, compared with a risk of 0.1% in the general male population ( 9 ).

Currently Accepted Targets for Breast Cancer Prevention

1. primary prevention, a. dietary modification.

Obesity is a common cause of many cancers, including those of the breast, endometrium, ovary, prostate, liver, gallbladder, kidney and colon ( 11 ). How specific foods influence breast cancer risk, independent of weight gain or loss, is less certain ( 12 ). Obesity is associated with a higher risk of premenopausal estrogen receptor negative breast cancer and triple negative breast cancer (TNBC), with two meta-analyses of women with TNBC demonstrating an 80% and 43% higher risk of developing TNBC, respectively, in obese than in non-obese premenopausal women ( 13 ). Between 2011–2014 over one third (36.5%) of U.S. adults were reported to be obese (BMI≥30) ( 14 ), with rates higher among women than men. The prevalence of obesity was lowest among Asian (11.7%) and highest among black (48.1%) adults ( 14 ). The prevalence of obesity among children aged 2–10 years was 17% ( 14 ). The prevalence of obesity continues to increase among adults (from 30.5% in 1999 to 37.7% in 2014), though youth obesity may be leveling off ( 14 ).

Many U.S. adults who are not obese are overweight (BMI 25–29.9). Estimates in 2015 suggested that 40% of men (36.3 million) and 29.7% of women (almost 28.9 million) were overweight. Combined with the percent of obese individuals, in 2015 more than two thirds of U.S. adults were overweight or obese ( 15 ). These trends are also seen in other parts of the world, and worldwide obesity has nearly tripled since 1975 ( 11 ). In 2016, the World Health Organization reported that 1.9 billion adults and 381 million children aged 2–19 years were overweight or obese ( 11 ).

B. Exercise

Exercise appears to be safe for most breast cancer patients, and improves their physiological and psychological well-being ( 16 ). Assessment of the benefits of exercise in the prevention of breast cancer are often confounded by the effects of concomitant weight loss or gain. A meta-analysis of prospective studies which evaluated the association between physical activity and breast cancer risk involving 63,786 individuals demonstrated a 12% reduction in risk among those who were physically active vs. those who were not ( 17 ). Stronger associations with physical activity and breast cancer risk were found for subjects with a BMI <25 (hazard ratio: HR=0.72), premenopausal women (HR=0.77), and estrogen and progesterone receptor-negative breast cancer (HR=0.80).

C. Tobacco and alcohol

Tobacco use is a leading cause of cancer incidence and death from cancer ( 18 ). Tobacco use causes cancer of the lung, larynx, mouth, esophagus, throat, bladder, kidney, liver, stomach, pancreas, colon and rectum, and cervix, as well as acute myeloid leukemia. Studies evaluating a possible association of tobacco use with breast cancer have demonstrated mixed results. This may be due to the confounding of alcohol use. Most reports indicate that alcohol use increases breast cancer risk ( 19 ). A longitudinal study was conducted by the American Cancer Society involving over 70,000 women with a median follow-up of 13.8 years in which concomitant alcohol use was considered. The analysis demonstrated that breast cancer incidence was 24% higher among smokers than non-smokers and 13% higher in former smokers than non-smokers ( 20 ), with a stronger association between smoking and breast cancer risk among women who started smoking before the birth of their first child. The positive association between smoking and breast cancer risk was seen in current or former alcohol drinkers, but not in those who never drank.

D. Exogenous use of estrogens and progestins

The role of exogenous female hormones in the development of breast cancer remains uncertain, though most reports of the use of combined estrogen and progesterone formulations after menopause report an increased risk of breast cancer. The use of estrogen alone after menopause, which is only safe among women who have undergone hysterectomy (for estrogen alone use increases the risk of endometrial cancer), does not appear to increase a woman’s risk of developing breast cancer ( 21 ).

Findings regarding birth control pill (BCP) use and breast cancer risk are mixed, but the bulk of evidence suggests that BCPs increase risk during active use, which decreases over time once BCP use is stopped ( 22 ). Many have believed that the mixed findings regarding BCPs and breast cancer risk are related to the BCP dose, suggesting that higher doses of estrogens and progestins are more likely to increase breast cancer risk. Higher doses of female hormones were more commonly present in BCPs that were prescribed in the past than in BCPs in current use. However, a recent study which followed 1.8 million women in Denmark who used contemporary hormonal contraceptives demonstrated that BCPs and IUDs which release progestins increased a woman’s risk of breast cancer on average by 20%. Different hormonal formulations did not appear to significantly alter the increase in risk ( 23 ).

E. Ionizing radiation

Most cancers can be induced by ionizing radiation, with a linear dose-response noted for most solid cancers ( 24 ). As there is generally a time lag of five or more years between exposure and the development of radiation induced cancer, many of the most revealing studies have been performed in children and young adults who received radiation for the diagnosis and treatment of cancer. The most radiosensitive organ sites in children, in order of sensitivity, are the thyroid gland, breasts, bone marrow, brain and skin ( 25 ). At one time, infants received radiation to treat certain benign lesions (hemangioma and an enlarged thymus). Infants who received on average 30 cGy to treat an hemangioma had a 40% increased risk of breast cancer while those who received 70 cGy to treat an enlarged thymus had a 250% excess risk of developing breast cancer ( 25 ). The excess risk persisted for up to 50 years after the radiation exposure.

Studies of radiation exposure from multiple chest X-rays used to monitor treatment for tuberculosis (TB) in adolescent girls and young women and a study of multiple X-ray examinations to monitor curvature of the spine in girls with scoliosis have reported increased mortality from breast cancer with increasing radiation dose, with the increased breast cancer risk appearing 15 years after radiation exposure and the risk remaining elevated up to 50 years later ( 24 ).

Young women who receive computerized tomography (CT) scans of the chest or heart may also be at increased breast cancer risk. The records of almost a quarter of a million women, who underwent imaging between 2000 and 2010, were reviewed and breast cancer risk determined. Those who underwent CT or nuclear medicine scans which exposed breast tissue to radiation were compared to National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) breast cancer risk data (control). The authors concluded that a child or young adult under the age of 23 who received two or more chest or cardiac CTs had more than double the normal 10 year risk of developing breast cancer ( 26 ).

Therapeutic radiation to treat a childhood cancer is also associated with increased breast cancer risk. An assessment of 1,230 female childhood cancer survivors treated with chest irradiation demonstrated that by age 50 years the incidence of breast cancer was 30% overall, and 35% among those receiving radiation to treat Hodgkin’s lymphoma ( 27 ). This is compared to a lifetime breast cancer risk of 12.4% in otherwise healthy women ( 28 ).

F. Pregnancy and nursing

Immediately following childbirth there is an increased risk of breast cancer observed for women of all age groups. Over the long term, parity is protective for women whose first full term pregnancy (FFTP) was completed at a young age (<26), and increased in parous women whose FFTP occurred after 35 years of age ( 29 ). Breast cancer diagnosed shortly after childbirth tends to be aggressive. It is more likely to be hormone-insensitive, higher grade, with a higher proliferative rate ( 30 ) and a higher likelihood of bone marrow metastases ( 31 ).

Observational studies have demonstrated inconsistent findings regarding nursing, length of nursing and risk of premenopausal breast cancer. A prospective cohort study, part of the Nurses’ Health Study II, involving 60,075 women demonstrated an inverse association (HR=0.75) between having ever breastfed and risk of premenopausal breast cancer ( 32 ). There was no association between length of lactation and risk. Subset analysis demonstrated that the influence of lactation on premenopausal breast cancer risk was limited to women at increased breast cancer risk because of a first degree relative who had developed breast cancer (HR=0.41). There was no association between lactation and breast cancer risk among women of normal risk.

2. Chemoprevention

A. overview.

Two selective estrogen receptor modular (SERM) medications, tamoxifen and raloxifene, are approved by the FDA to prevent breast cancer in high risk women. In the studies which helped support FDA approval, high risk was defined as women 60 years or older, 5-year risk of invasive breast cancer ≥1.67% or lifetime breast cancer risk of at least 20% of developing invasive breast cancer based on the BCRAT ( 7 ). SERMs act as an anti-estrogen in some organ systems, and in a pro-estrogenic fashion in others. Tamoxifen was the first agent to be approved, and the only one approved for use in both pre- and post-menopausal women. The Breast Cancer Prevention Trial, started in 1992 and funded by the U.S. National Cancer Institute, enrolled 13,388 pre- and post-menopausal women deemed to be at increased breast cancer risk. Approximately equal numbers of women received tamoxifen or placebo. Tamoxifen reduced the risk of invasive breast cancer by 49% overall and in all age subgroups by over 40% ( 33 ). It also reduced the incidence of ductal carcinoma in situ (DCIS) by 50%, lobular carcinoma in situ (LCIS) by 56% and atypical hyperplasia by 86%. Tamoxifen also reduced the number of hip, radius and spine fractures. On the other hand, there was an increased risk of developing endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis. The risk of developing one or more of these side effects was higher in women over age 50. The International Breast Cancer Intervention Study (IBIS)-I clinical trial based in Europe, used the Tyrer-Cuzick risk assessment tool and required that women have a 10 year risk of developing breast cancer of at least 5% ( 7 ). The study enrolled 7.154 pre- and post-menopausal women deemed to be at increased risk of developing breast cancer. They were randomized to tamoxifen or placebo. Long term follow-up (median 16 years) demonstrated that tamoxifen decreased the risk of breast cancer (HR=0.71) overall, estrogen receptor (ER) positive invasive breast cancer (HR=0.66) and DCIS (HR=0.65), but not invasive ER negative breast cancer ( 34 ).

Raloxifene was approved based in part on findings from a prospective, randomized trial that by compared the agent to tamoxifen. At the time the trial started, raloxifene was already FDA approved to treat osteoporosis in postmenopausal women. Therefore, the trial comparing raloxifene to tamoxifen enrolled only postmenopausal women. Among the 19,747 women enrolled, median age was 58.5 years. The risk of developing invasive breast cancer was similar between the two agents, though there were 40% fewer cases of DCIS in the tamoxifen group ( 35 ). There was a 38% lower incidence of uterine cancers (HR=0.62), thromboembolic events (HR=0.70) and cataracts (HR=0.79) in the raloxifene group.

In 2013 the American Society of Clinical Oncology issued and updated guideline on interventions to reduce the risk of breast cancer in women at increased risk for the disease. The guideline was the third addressing the use of chemopreventive medications in women at increased breast cancer risk, and the first to recommend discussing the option of exemestane, an aromatase inhibitor, as an alternate to tamoxifen or raloxifene in postmenopausal high risk women ( 36 ). In the MAP.3 trial, exemestane was compared with placebo or celecoxib plus exemestane in 4.560 postmenopausal women deemed to be at increased breast cancer risk ( 37 ). Exemestane (plus or minus celecoxib) decreased the risk of ER positive (HR=0.27) but not ER negative (HR=0.80, but p>0.05) invasive breast cancer. DCIS incidence was lower with exemestane (HR=0.65), but the difference did not reach statistical significance. The IBIS II trial recruited postmenopausal women from 18 countries in a prospective randomized study comparing another aromatase inhibitor, anastrozole, vs. placebo. After a median follow-up of 5 years, anastrozole decreased the risk of developing breast cancer (HR=0.47) ( 38 ).

B. Specific subgroups: histopathologic alterations and breast density findings which increase risk

There are many benign breast disease alterations identified on needle or excisional breast biopsy which have been associated with increased breast cancer risk. In general, these alterations can be separated into hyperplasia (usual or atypical) and LCIS. The risk of developing breast cancer in women with usual hyperplasia is increased 50–100%, whereas atypical hyperplasia of the breast increases risk 4–5 fold ( 39 ), or 1.5–2% per year ( 40 ). The risk of breast cancer development in patients with LCIS is 2% per year, compared to the risk in otherwise healthy women of < 0.4% per year ( 41 ). Women with atypical hyperplasia or LCIS have a greater than 30% lifetime risk of developing breast cancer ( 42 ). There are few indicators in these high-risk women which assist the treating healthcare provider in determining if the patient will develop invasive breast cancer, with the possible exception of the extent of disease. Greater disease extent increases risk both for women diagnosed with atypical hyperplasia ( 43 ) and LCIS ( 41 ). The lack of clarity regarding which individuals with atypical hyperplasia and LCIS will go on to develop breast cancer is a problem when counseling women regarding risk reduction, since chemoprevention and surgical strategies have the potential for side effects. Moreover, while bilateral mastectomy is an option for those with LCIS, it is not generally recommended when one is diagnosed with atypical hyperplasia.

Women with dense breasts on mammogram have an increased risk of developing breast cancer, and increased density makes breast cancer detection when reading two dimensional mammograms more difficult ( 44 ). However, it is not clear if reducing MBD reduces risk. The chemopreventive agent tamoxifen was evaluated for its potential ability to reduce MBD in women at increased breast cancer risk. MBD measurements were obtained before starting tamoxifen or placebo and on treatment at 12- to 18-month intervals. A reduction in MBD was noted within 18 months of tamoxifen treatment, which lasted for at least 54 months. After 54 months on tamoxifen, MBD decreased on average 13.4% in women 45 years or younger at entry vs. 1.1% in women over 55 years at entry ( 45 ). it is not clear that this risk reduction is due to tamoxifen’s effect on MBD, on other breast cancer risk factors, or both ( 44 ). It appears that the influence of MBD on breast cancer risk is primarily in women with non-proliferative breast disease, with little influence on future risk among women with atypical hyperplasia ( 46 ).

3. Surgical approaches to breast cancer prevention: mastectomy and/or oophorectomy

Among the breast cancer driver genetic mutations that have been identified, including BRCA 1 and 2, TP53, PTEN, STK11, CDH1, PALB2, CHECK2, ATM, NBN, and NF1 ( 8 ), each alteration imparts its own unique implications regarding future breast cancer risk. Guidelines as to which therapies are reasonable are based on known risk implications. Guidelines are updated from time to time based on the latest available information. Current recommendations from the American Society of Breast Surgeons is that risk reducing bilateral mastectomy is a reasonable approach for women without breast cancer who have a known deleterious mutation in BRCA 1, BRCA2, TP53, PALB2, CDH1, or PTEN . Risk-reducing mastectomy is recommended for consideration for patients with deleterious mutations in CHEK2 or ATM if the patient has a family member with breast cancer ( 8 ). Increased surveillance with breast MRI and mammogram, but not bilateral risk-reducing mastectomy, is recommended for patients with mutations in STK11, NF1, and NBN . Screening is recommended to start at age 30 for STK11 and NF1 , and at age 40 for NBN ( 8 ).

Bilateral risk-reducing mastectomy is also recommended for consideration in women with a history of prior therapeutic mantle radiation ( 47 ) and with a diagnosis of LCIS. An additional option for risk reduction in those diagnosed with LCIS is chemoprevention, as tamoxifen was shown to decrease the risk developing breast cancer in this population of women ( 33 ). Mastectomy is not recommended as a routine procedure for risk reduction in the contralateral breast of women diagnosed with cancer in the ipsilateral breast, but may be discussed with the patient based on individual risks and benefits, such as a strong family history and a known deleterious genetic mutation which increases breast cancer risk ( 48 ). Alternatives include chemoprevention, which reduces the risk of contralateral breast cancer in women diagnosed with cancer in the ipsilateral breast, including women demonstrated to carry a deleterious BRCA1 or BRCA2 mutation ( 49 ).

Bilateral salpingo-oophorectomy (BSO) can be considered for risk reduction in genetically high-risk women. BSO reduces breast cancer risk in premenopausal BRCA 1 and 2 mutation carriers by approximately 50%, similar to tamoxifen, compared to a 90% reduction in similar women who undergo bilateral mastectomy ( 50 ). BSO also reduces the risk of ovarian cancer in these women by 90% ( 51 ).

The Future of Breast Cancer Prevention

Innovations have greatly advanced our understanding of breast cancer. These innovations have driven a precision based, patient focused approach to the treatment of breast cancer. These same and similar innovations are driving the future of breast cancer prevention.

1. Precision medicine

The ability to sequence a patient’s entire genome from a blood or tissue sample has dramatically improved in recent years. Multiple companies and cancer centers now offer whole genome sequencing of a patient’s tumor to identify targetable mutations for treatment, and increasingly treatment trials are being designed based on a given genetic alteration rather than on the site of tumor origin. The NCI has launched a clinical trial called NCI-Match, in which patients are assigned treatment based on the genetic changes found in their tumors rather than on disease site ( 52 ). The origin of cancer can be from a variety of tumor sites, including the breast. Gene sequencing laboratories that are participating in the study including Foundation Medicine, Caris Life Sciences, MD Anderson Cancer Center, and Memorial Sloan-Kettering Cancer Center.

Studies have been reported in a variety of cancers addressing how gene alterations may guide chemopreventive strategies. For example, EGFR mutations have been identified in the histologically normal epithelium of patients with lung cancer, and PI3K/AKT activation has been identified in the airways of smokers with precancerous lesions ( 53 ). A cancer prevention trial using myo-inositol in patients with bronchial dysplasia demonstrated significant reductions in the inflammatory cytokine IL-6, though other cancer-associated biomarkers did not significantly change with treatment. Among participants with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation (p=0.002) ( 54 ). Investigators of the study suggest that a more detailed assessment of molecular alterations in the bronchial tissue may identify additional alterations which could be targeted and hopefully increase the efficacy of myo-inositol as a chemopreventive agent. Future studies which emphasize molecular approaches to breast cancer chemoprevention are likely.

The NCI has issued a request for applications (RFA) for Pre-Cancer Atlas Research Centers (RFA –CA-17-035) ( 55 ). This call is a companion to CA-17-034, Human Tumor Atlas Research Centers. In the pre-cancer atlas RFA, the NCI is looking for proposals that focus on a multidimensional cellular, morphological and molecular mapping of human pre-malignant tumors, complemented with critical spatial information (at the cellular and/or molecular level) that facilitates visualization of the structure, composition, and multiscale interactions within the tumor ecosystem over time resulting in tumor progression or regression. The RFA posits that a deeper understanding of the transition from the pre-malignant to the malignant state as a function of time will allow the development of more precise risk stratification methods and effective early intervention strategies.

2. Immunoprevention

The immunoprevention of cancer has been in place for some time with the use of cancer vaccines. A vaccine to the hepatitis B virus produced an 80% reduction in the development of hepatocellular cancer in Taiwan ( 56 ). A three-dose prophylactic vaccine to human papilloma virus (HPV) is 90–100% effective in preventing HPV infection and associated anogenital malignancies ( 53 ). Fewer doses may be as effective as the three-dose regimen.

Vaccines to prevent non-viral induced cancers is an attractive approach to cancer prevention. A validation study is underway targeting MUC1 for the primary prevention of colon cancer based on initially promising results ( 57 ). Preliminary results evaluating a HER2 vaccine for the prevention of recurrence in women with a history of HER2 positive breast cancer were also encouraging ( 58 ). Vaccines which induce immunity to multiple antigens are in development as well, and may be more effective than single agent vaccines in activating the immune system to target premalignant lesions of the breast ( 59 ).

3. Tumor microenvironment (TME)

The TME appears to be altered early on in the development of cancer ( 53 ). The microenvironment becomes immunosuppressive such that immunoprevention strategies are less effective. Checkpoint inhibitors (targeting CTLA-4, PD-1, PD-L1 and PD-L2), have been effective in decrease the immunosuppressive TME when cancer is present. These agents are rather toxic, however, and therefore other strategies, such as depleting suppressive T cells (Tregs), may be better ( 53 ) for enhancing vaccine and other immunoprevention strategies.

4. Targeting specific populations

Cancer prevention currently targets high risk individuals, based on known risk factors such as evidence of a deleterious mutation in a breast cancer oncogene (e.g. BRCA1 and 2 ), family history, and breast biopsy premalignant changes. A high-risk population that has been targeted to a lesser degree are individuals who are obese. This is starting to change. The NCI is funding a study to determine if metformin, an FDA approved medication for the treatment of diabetes which has shown preliminary promise as a cancer preventive agent, will decrease the risk of obesity related postmenopausal breast cancer (NIH grant no. R01CA172444-05).

5. Single vs. multiple agents

Demonstration and validation of the safety and efficacy of a single agent, or at least preclinical evidence for synergy among two or more agents with evidence of clinical safety, is generally a pre-requisite to the initiation of a multiple agent clinical study. It is therefore perhaps not surprising that the vast majority of chemoprevention clinical trials conducted thus far have evaluated single agents. Cancer treatment is generally more effective when targeting multiple driver pathways with multiple agents, as opposed to only one. It is likely that this is also true for precancers. Findings from a lung cancer prevention trial involving the administration of myo-inositol vs. placebo in smokers with bronchial dysplasia demonstrated an effect on the targeted PI3K/Akt pathway, but limited to no effect on other affected pathways, leading to no overall improvement in response with active agent vs. placebo ( 54 ). A recent randomized clinical trial showed increased efficacy of combination chemoprevention in patients with familial adenomatous polyposis which targeted two pathways, Wnt/EGFR and COX, using sulindac and erlotinib vs. either agent alone ( 60 ).

6. Increasing the use of agents proven effective in preventing breast cancer

As previously mentioned, there are two agents (tamoxifen and raloxifene) currently approved for the prevention of breast cancer in postmenopausal high-risk women. Two aromatase inhibitors, exemestane and anastrozole, also demonstrate promise in preventing breast cancer in this population. Tamoxifen is also FDA approved for the prevention of breast cancer in premenopausal high-risk women. The percentage of eligible women taking a chemoprevention medication to decrease their risk of breast cancer is less than 10% ( 61 ). There are a variety of reasons for this. For many women, consideration of chemoprevention is not discussed with them by a healthcare provider ( 62 ). Moreover, many are concerned about the potential side effects such as endometrial cancer and blood clots with tamoxifen, others stop the medication because they have experienced a side effect, most commonly hot flashes. Indeed, for individuals who initiate a medication, the most common reason to stop is due to side effects ( 63 ). Women less likely to take chemoprevention are older, smokers and those with depression ( 62 ).

How to overcome this? There are newer SERMs (arzoxifene, bazedoxifene and lasofoxifene) with evidence of efficacy with a lower risk of side effects than tamoxifen ( 64 ). Lowering the dose or intermittent dosing of tamoxifen appears to decrease side effects while maintaining biologic efficacy ( 7 ). In a short term pre-surgical window trial, transdermal 4-hydroxytamoxifen applied directly to the breast skin showed promising preliminary evidence of efficacy comparable to oral tamoxifen ( 65 ). Transdermal delivery appeared to reduce the systemic effects on endocrine and coagulation parameters, though the incidence of hot flashes was similar in both groups.

We are already aware of important risk factors that lead to cancer (smoking, obesity, lack of exercise, high alcohol intake) which are being addressed, with some success. To increase our impact on cancers that are caused by these behaviors, we need to overcome the inertia at a personal and social level with regard to adopting healthy behaviors. Equally important, we need to encourage activities such as breastfeeding that are associated with lower risk of breast cancer, at least among women with a family history of the disease. We need to continue to educate clinicians on the hazards of ionizing radiation, and the adoption of imaging approaches which mitigate this.

Vaccines which prevent cancer must continue to be promoted, and new preventive vaccines developed. We should encourage more women with pathologically precancerous lesions and who are genetically at high risk to consider cancer prevention strategies. This requires that we educate their healthcare providers. It also requires that our interventions be safe, easy to use and with limited side effects.

We need to develop new technologies to better identify women at the greatest risk of developing breast cancer. Atypical hyperplasia places women at significantly increased risk, but we lack clear evidence of which women with this diagnosis will have their disease progress to invasive breast cancer. Surgical risk reduction is currently not recommended for most women who are at increased risk and chemoprevention uptake is not used by most women due to the risk of side effects. We need to develop tools that can better predict which women are at the greatest risk of developing breast cancer so that healthcare providers can better counsel them, and that women can better weigh the risks and benefits of active intervention, such as chemoprevention, vs. observation.

Risk assessment needs to be personalized. There have been many paradigm-changing advances in cancer prevention, and many more to come. Developing safe and effective agents, personalizing preventive therapy, and harnessing technology will be increasingly important in getting public buy-in and achieving greater participation in cancer prevention trials.

Peer-review: Externally peer-reviewed.

Conflict of Interest: No conflict of interest was declared by the author.

Financial Disclosure: The author declared that this study has received no financial support.

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Clinical trials: A significant part of cancer care

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Editor's note: May is National Cancer Research Month.

By Mayo Clinic staff

A cancer diagnosis is an emotional experience. Learning that you have cancer can create feelings of hopelessness, fear and sadness. This is especially true if your cancer is advanced or available treatments are unable to stop or slow its growth.

"Often, when patients are diagnosed with cancer , they feel hopeless and scared. Clinical trials are one way patients can be proactive. They can make a choice in how their care is going to be," says Matthew Block, M.D., Ph.D. , a Mayo Clinic medical oncologist.

Cancer clinical trials help physician-scientists test new and better ways to control and treat cancer. During a clinical trial, participants receive specific interventions, and researchers determine if those interventions are safe and effective. Interventions studied in clinical trials might be new cancer drugs or new combinations of drugs, new medical procedures, new surgical techniques or devices, new ways to use existing treatments, and lifestyle or behavior changes.

Clinical trials provide access to potential treatments under investigation, giving options to people who otherwise may face limited choices. "Clinical trials open the door to a new hope that maybe we can fight their cancer back and give them a better quality of life," says Geoffrey Johnson, M.D., Ph.D. , a Mayo Clinic radiologist, nuclear medicine specialist and co-chair of the Mayo Clinic Comprehensive Cancer Center Experimental and Novel Therapeutics Disease Group.

You will receive cancer treatment if you participate in a clinical trial. "I think one common misperception about clinical trials is that if you enter a clinical trial, you may not get treatment (receive a placebo). And that's actually very much not true. Most clinical trials are looking at one treatment compared to another treatment," says Judy C. Boughey, M.D. , a Mayo Clinic surgical oncologist, chair of Breast and Melanoma Surgical Oncology at Mayo Clinic in Rochester, Minnesota, and chair of the Mayo Clinic Comprehensive Cancer Center Breast Cancer Disease Group.

"I think one common misperception about clinical trials is that if you enter a clinical trial, you may not get treatment (receive a placebo). And that's actually very much not true. Most clinical trials are looking at one treatment compared to another treatment." Judy C. Boughey, M.D.

Watch this video to hear the experiences of people who have participated in cancer clinical trials and to hear Drs. Block, Johnson and Boughey discuss the importance of clinical trials in cancer care:

Clinical trials are a significant part of cancer care at Mayo Clinic Comprehensive Cancer Center. Cancer care teams work together across specialties to make sure the right clinical trials are available to serve the needs of people with cancer who come to Mayo Clinic.

"We are very particular in how we select the clinical trials that we have available for patients," says Dr. Boughey. "We want to have the best trials available for our patients. Some of the clinical trials are evaluating drugs — we are so excited about those drugs, but we can't prescribe those drugs for patients without having that trial. And so we will actually fight to try to get that trial open here to have it available as an opportunity for our patients."

If you choose to participate in a clinical trial, you will continue to receive cancer care. "For most patients that we evaluate, there's always the standard of care treatment option for those patients. And then, in many situations, there's also a clinical trial that the patient can participate in," says Dr. Boughey.

People who participate in clinical trials help make new and better cancer care available for future patients. The treatments available for cancer patients today exist because of the clinical trial participants of yesterday. "We couldn't advance medicine if it wasn't for people volunteering for trials. And the promise from our side is to say we're not going to put patients on trials or offer trials for them to consider unless we think there's a good chance that they'll get a benefit or that society at large will get a benefit," says Dr. Johnson.

"We couldn't advance medicine if it wasn't for people volunteering for trials. And the promise from our side is to say we're not going to put patients on trials or offer trials for them to consider unless we think there's a good chance that they'll get a benefit or that society at large will get a benefit." Geoffrey Johnson, M.D., Ph.D.

Participating in a clinical trial may give you access to cutting-edge treatment, improve your quality of life and extend your time with loved ones.

"It's definitely worth reaching out to your healthcare provider and asking, 'What clinical trials could I be a potential candidate for?'" says Dr. Boughey. "And remember, you can ask this of your surgical oncologist, your medical oncologist, your radiation oncologist, or any of the physicians you're seeing because there are trials in all disciplines. There are also ongoing trials that require the collection of tissue or the donation of blood. They can also be important in trying to help future generations as we continue to work to end cancer."

Participating in a clinical trial is an important decision with potential risks and benefits. Explore these FAQ about cancer clinical trials, and ask your care team if a clinical trial might be right for you.

Learn more about cancer clinical trials and find a clinical trial at Mayo Clinic.

Join the Cancer Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Read these articles about people who have participated in clinical trials at Mayo Clinic:

• A silent tumor, precancerous polyps and the power of genetic screening
• Mayo Clinic’s DNA study reveals BRCA1 mutations in 3 sisters, prompts life-changing decisions

Read more articles about Mayo Clinic cancer research made possible by people participating in clinical trials.

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Blood proteins ‘warn of cancer seven years before diagnosis’

It is hoped that in the future, the findings could be targets for cancer prevention..

Researchers have discovered proteins in the blood that could warn people of cancer more than seven years before it is diagnosed.

The scientists identified 618 proteins linked to 19 types of cancer including bowel, prostate and breast cancers.

Some 107 of the proteins were found in a group of people whose blood was collected at least seven years before diagnosis.

It is hoped the proteins could one day be targets for cancer prevention – instead of detection – and with further research lead to drugs to help stop the disease before it starts.

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The two Cancer Research UK-funded studies from Oxford Population Health suggest the proteins could be involved at the earliest stages of cancer, and could be linked to being at risk of the disease.

Some could be used to detect cancer earlier than is currently possible, potentially making it possible to treat the disease at a much earlier stage, or prevent it altogether.

Professor Ruth Travis, senior molecular epidemiologist at Oxford Population Health and a senior author of both studies, said: “To be able to prevent cancer, we need to understand the factors driving the earliest stages of its development.

“These studies are important because they provide many new clues about the causes and biology of multiple cancers, including insights into what’s happening years before a cancer is diagnosed.

“We now have technology that can look at thousands of proteins across thousands of cancer cases, identifying which proteins have a role in the development of specific cancers, and which might have effects that are common to multiple cancer types.”

Dr Iain Foulkes, executive director of research and innovation at Cancer Research UK, said: “Preventing cancer means looking out for the earliest warning signs of the disease.

“That means intensive, painstaking research to find the molecular signals we should pay closest attention to.

“Discoveries from this research are the crucial first step towards offering preventative therapies which is the ultimate route for giving people longer, better lives, free from the fear of cancer.”

In the first study, scientists analysed blood samples from UK Biobank taken from more than 44,000 people, including 4,900 who subsequently had a cancer diagnosis.

​The team used proteomics – the study of proteins to help learn how cancer develops and spreads – to analyse a set of 1,463 proteins from a single sample of blood from each person.

They compared the proteins of people who were later diagnosed with cancer and others who were not, allowing them to identify differences and establish which were linked to cancer risk.

The scientists also identified 182 proteins that differed in the blood three years before a cancer diagnosis.

​In the second study, the researchers looked at genetic data from more than 300,000 cancer cases to analyse which blood proteins were involved in cancer development and could be targeted by new treatments.

Some 40 proteins in the blood were found to influence someone’s risk of getting nine different types of cancer: bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney and malignant non-melanoma.

According to the findings, although altering these proteins may increase or decrease the chances of someone developing cancer, in some cases it may lead to unintended side-effects.

The researchers stress that further research is needed to find out the exact role the proteins play in cancer development, which are the most reliable ones to test for, what tests could be developed to detect the proteins in a clinic, and which drugs could target the proteins.

A test called the Galleri test is being trialled in the NHS, but it works by detecting tumour DNA circulating in the blood.

Researchers suggest the proteins they have discovered could be targets for cancer prevention.

Prevention and early detection are needed to keep improving cancer survival.

The findings are published in the Nature Communications journal.

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• Published: 23 February 2023

Clinical Studies

Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?

• Simon R. Lord   ORCID: orcid.org/0000-0001-7946-5609 1 &
• Adrian L. Harris   ORCID: orcid.org/0000-0003-1376-8409 1  

British Journal of Cancer volume  128 ,  pages 958–966 ( 2023 ) Cite this article

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• Clinical trial design

Over the past 15 years, there has been great interest in the potential to repurpose the diabetes drug, metformin, as a cancer treatment. However, despite considerable efforts being made to investigate its efficacy in a number of large randomised clinical trials in different tumour types, results have been disappointing to date. This perspective article summarises how interest initially developed in the oncological potential of metformin and the diverse clinical programme of work to date including our contribution to establishing the intra-tumoral pharmacodynamic effects of metformin in the clinic. We also discuss the lessons that can be learnt from this experience and whether a further clinical investigation of metformin in cancer is warranted.

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Introduction.

A drug is described as being ‘repurposed’ when it exhibits clinical benefit for the treatment of cancer patients, despite being initially developed for an unrelated indication. As drug development costs rise for new entities, there is a growing attraction in looking to off-patent medicines that have established safety and pharmacokinetic profiles potentially reducing the time to entry into the oncology clinic. Indeed, a recent estimate suggested that the median cost to develop a single cancer drug is $648 million [ 1 ], although other analyses have suggested far higher sums [ 2 ]. This outlay directly results in the great expense of drug therapy for patients and health systems, often more than $100,000 per year for new cancer drugs, and contributes to inequality of access to cancer treatment. For rare cancers, where low commercial returns may be prohibitive for drug development, repurposing may be of particular value.

Metformin is the most widely prescribed medicine for type 2 diabetes worldwide and on the World Health Organisation’s list of essential medicines. A series of epidemiological studies which suggested that metformin may reduce cancer incidence in diabetic populations sparked great interest in its potential as a cancer treatment. However, there remains some debate as to its pharmacodynamic effects in tumours and recent randomised trials have not clearly demonstrated clinical benefit for any cancer indication to date. In this perspective article, we present a summary of the history of preclinical and clinical studies that informed the repurposing of metformin, discuss how this programme of work could have been better focused and coordinated and lastly describe oncological indications where there remains a strong rationale for investigation.

Metformin’s mechanism of action

As has typically been the case drug repurposing programmes, the interest in metformin was serendipitous. Two decades ago, researchers trying to understand the metabolic effects of metformin in diabetic patients discovered that it inhibits Complex 1 of the mitochondrial respiratory transport chain, the consequence of which was the activation of the cellular regulator of energy homoeostasis, AMP-activated protein kinase (AMPK) [ 3 , 4 ]. AMPK is known to be a tumour suppressor that regulates a number of downstream anabolic pathways critical to tumour cell proliferation. On this basis, a pilot epidemiological case–control study was carried out and the analysis suggested that patients with Type 2 Diabetes Mellitus on metformin were less likely to develop cancer compared to patients on other diabetes drugs [ 5 ]. This finding led to a host of preclinical studies, which suggested that under laboratory conditions and with doses substantially greater than peak plasma level in patients, metformin possessed a number of anti-cancer properties including synergy with cytotoxic chemotherapy and radiotherapy.

Despite great effort and multiple published preclinical studies, the actual mechanism of action of metformin in tumour cells remains a topic of debate. As described above it is clear, at least when cells are treated with high doses, that metformin inhibits Complex-1 activity and cellular respiration. This was demonstrated in a series of elegant experiments in which metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In the same study the administration of metformin to mice inhibited the growth of control xenografts but not those expressing NDI1 [ 6 ]. In models, the consequences of inhibiting Complex 1 and hence the tricarboxylic acid cycle has been shown to check the funnelling of carbon from glucose to the anabolic building blocks needed for cell proliferation [ 7 ]. However, in patients, it remains unclear as to the degree to which the disruption of carbon metabolism or induction of energy stress and subsequent AMPK activation might be most critical to any antiproliferative effects. The further preclinical investigation has suggested a host of pleiotropic effects of metformin in cancer cells but it seems likely that many if not all of these are downstream consequences of metformin inhibiting complex 1 and subsequent AMPK activation, rather than the drug engaging multiple targets. For example, metformin has been shown to inhibit AKT/mTOR signalling and suppress fatty acid synthesis in an AMPK-dependent manner [ 8 , 9 , 10 ]. Metformin-induced AMPK activation has also been shown to reduce cancer cell proliferation through several other mechanisms, including activation of cMYC, HIF-1α and DICER1 [ 11 ].

However, an alternative hypothesis focussed on metformin’s effects on systemic ‘host’ metabolism has been proposed. Within the liver, activation of AMPK has been shown to reduce gluconeogenic gene expression in hepatocytes [ 12 ], increase insulin receptor activity and enhance translocation of glucose transporters [ 13 ]. It has also been proposed that biguanides inhibit glucagon signalling in the liver in an AMPK-independent manner, possibly by increasing AMP levels secondary to inhibition of Complex 1. AMP then by binding to adenylate cyclase downregulates cAMP-PKA activity suppressing gluconeogenesis [ 14 ]. Activation of the insulin receptor promotes downstream PI3K-AKT-mtor signalling and growth in tumour models [ 15 ] and increased insulin levels are associated with higher cancer incidence and mortality [ 16 ]. Hence, by reducing circulating insulin and glucose levels it is postulated that metformin may reduce insulin-mediated tumorigenesis and cancer progression, perhaps most relevant to patients with metabolic syndrome or type 2 diabetes although metformin has been shown to reduce insulin levels in cancer patients without these conditions [ 17 ].

Pharmacodynamic clinical studies

In the clinic, metformin’s anti-cancer effects were initially evaluated in several small pharmacodynamic clinical trials. These typically used ‘window of opportunity’ designs often prior to surgery and compared assays using the diagnostic and surgical tumour sample with a course of metformin in between to assess the drug’s effects on cancer biology. The endpoints and findings of these studies are described in Table  1 but in summary almost all of these early studies designated the well-validated marker of proliferation, Ki67, as the primary endpoint. Other immunohistochemical markers were often assayed, in particular for immunohistochemical markers of apoptosis, AMPK and mTOR pathway activation, however detailed characterisation of metformin’s effects on tumour biology was not evaluated. To address this, we undertook a radiogenomic ‘window-of-opportunity’ study in 40 non-diabetic patients with primary breast cancer, linking FDG–PET tumour uptake to tumour transcriptomic and metabolomic profiling. Here, we observed the upregulation of several transcriptomic pathways linked to mitochondrial metabolism and change in the levels of a number of mitochondrial metabolites suggesting that metformin disrupted mitochondrial metabolism at clinical dosing. A reactive increase in mitochondrial oxidative phosphorylation gene transcription linked to metformin resistance and two distinct metabolic responses in breast cancer were observed. Furthermore, we showed that metformin increases 18-FDG flux in primary breast cancer concomitant to the increased expression of multiple genes regulating glycolysis, glucose transport and glutamine metabolism. This was consistent with breast tumours upregulating well-described mitochondrial metabolic resistance pathways in response to metformin adding weight to the potential of previously proposed strategies to target these pathways, in combination with metformin [ 17 , 18 ].

Efficacy studies

Results have now been presented from a number of randomised trials in different settings which in most cases have not demonstrated clinical benefit for metformin as a cancer treatment. These studies have assessed the combination of metformin with chemotherapy, endocrine and other targeted therapy in a number of different tumour types as summarised in Table  2 . Most notably, the MA.32 study was a Phase III randomised trial that recruited over 3600 patients with high-risk operable breast cancer randomised to 850 mg metformin or placebo for 5 years. The investigators concluded that the addition of adjuvant metformin did not lead to an improvement in disease-free survival for either oestrogen receptor-positive or negative breast cancer [ 19 ]. An exploratory analysis did suggest that there might be some benefit in patients with HER2-positive disease and who genotyped for the C allele of the rs11212617 single-nucleotide polymorphism although the authors concluded that this would need to be confirmed with further prospective study [ 19 , 20 ]. Tumour hypoxia is strongly linked to radiotherapy resistance and metformin has been shown to improve tumour oxygenation and radiotherapy response in xenograft models [ 21 ]. Hence, the combination of metformin and chemoradiotherapy has been investigated in patients with non-small lung cancer in two randomised trials but again with no evidence of benefit [ 22 , 23 ]. A handful of studies have had encouraging results but with insufficient sample sizes to be firmly conclusive [ 24 , 25 , 26 , 27 , 28 ].

Can lessons be learnt from the metformin experience?

When the MA.32 study commenced recruitment in 2010 there was very limited information regarding the pharmacodynamic effects of metformin in breast cancer at therapeutic doses from the clinic. This impacted on the ability to develop rationale clinical trial designs that took into account markers of selection, resistance, treatment combination and dosing. As has been frequently been demonstrated in drug development without appropriate patient selection clinical benefit may be masked.

Initially, there was little effort to establish the tolerability and possible advantage of higher dose levels of metformin in the context of treatment for cancer where a greater risk/side effect profile might be acceptable. Efforts have now been made to evaluate different dose levels for metformin and its biguanide cousin phenformin in various therapeutic combinations [ 29 , 30 , 31 ]. However, to our knowledge, a well-designed dose escalation study of metformin with detailed tumour pharmacodynamic assessment is still awaited.

An example of a well-structured programme of work that could be taken as template to repurpose an anti-mitochondrial agent for cancer therapy is the ongoing evaluation of the anti-parasitic drug atorvaquone as a radio-sensitiser. A decade ago, a group of investigators carried out a high throughput screen for drugs that reduced oxygen consumption and hence, potentially tumour hypoxia. Atovaquone is an anti-malarial agent and ubiquinone analogue that inhibits mitochondrial complex III and was identified as a ‘top hit’ in this screen. In vivo, atovaquone reduced tumour hypoxia and sensitised xenograft models to radiotherapy [ 32 ]. To determine whether atovaquone could reduce tumour hypoxia in patients, a pharmacodynamic clinical study compared 15 atovaquone treated versus 15 untreated non-small cell lung cancer (NSCLC) patients, recruited sequentially. Here, [18F]-fluoromisonidazole (FMISO) PET-CT demonstrated a significant reduction in hypoxia in the atovaquone group and this was corroborated using a transcriptomic hypoxia gene expression signature [ 33 ]. An ongoing dose escalation study, the ‘ARCADIAN trial’ is designed to ascertain the recommended phase 2 dose of atovaquone in combination with concurrent chemoradiotherapy in locally advanced NSCLC.

The contrast here with the approach to metformin is clear. The work was led by a team of collaborators who worked together throughout each stage of the drug development project to ensure that each step was informed by the prior. At an early point during clinical evaluation detailed pharmacodynamic assessment of the drug was carried out at several dose levels. We believe this stepwise approach to pharmacodynamic characterisation prior to Phase II/III efficacy trials optimises the chances of success in a drug repurposing programme.

Future directions: is further clinical investigation of metformin in cancer warranted?

Given the results of the randomised efficacy trials enthusiasm to develop further clinical studies of metformin as a treatment for established cancers is waning. However, preclinical and clinical pharmacodynamic data obtained since the design of early clinical efficacy studies has now informed new avenues of investigation.

Markers are now being established that may define response to Complex-1 inhibitors such as mutations in the SWI-SNF complex [ 34 ]. Mitochondrial mutations in genes encoding for Complex 1 have also been proposed as markers of sensitivity for biguanide therapy [ 35 ] although mitochondrial heteroplasmy and the dynamic negative and positive enrichment of mitochondrial mutations may prevent their application as biomarkers. The transcription factor STAT3 is frequently activated in a variety of malignancies and emerging data points toward STAT3-mediated upregulation of OXPHOS as a mechanism of survival in drug-resistant tumours and a potential marker for drugs targeting mitochondrial metabolism [ 36 , 37 , 38 ]. The biobanking of translational samples from the trials already carried out to date may facilitate exploratory research to evaluate some of these emerging markers of susceptibility to anti-mitochondrial therapy with the opportunity for future trials with appropriate stratification. We suggest ‘window’ studies over short time frames for selected tumours may allow stratification of patients by evaluating dynamic response and highlight additional drug combination opportunities. If these had been performed a priori for metformin it may have aided trial design and outcome.

A number of animal and human studies have shown that metformin can alter the metabolism of gut microbiota [ 39 , 40 ]. Transfer of faeces from obese mice treated with metformin into untreated mice inhibited tumour growth independently of changes in body mass, blood glucose or serum insulin. The study authors proposed that metformin treatment led to a proportionate increase in short-chain fatty acid-producing microbes and faecal transfer then led to reprogramming of tumour metabolism specifically changes in lipid homoeostasis [ 41 ]. To date, these approaches have been unexplored in the clinic.

Metformin, by inhibiting oxidative respiration and hence oxygen consumption has been shown to reduce hypoxia in tumour models [ 6 ] and more recently in a clinical study of patients with advanced cervical cancer using fluoroazomycin arabinoside (FAZA) PET-CT [ 42 ]. Via a number of mechanisms, hypoxia has been shown to suppress the anti-tumour immune response and this may be a significant mechanism of resistance to immune checkpoint immunotherapy [ 43 ]. Preclinical data have suggested that by remodelling the hypoxic tumour microenvironment metformin could potentiate the effect of anti PD-1 immunotherapy [ 44 ]. Metformin may enhance tumour immunosurveillance in ways other than reducing hypoxia in the tumour microenvironment. AMPK activation in immune cells leads to phosphorylation of PD-L1, subsequent PD-L1 glycosylation and its accumulation in the endoplasmic reticulum and degradation [ 45 ]. In syngeneic in vivo cancer models metformin enhanced the anti-tumour effect of anti-CTLA-4 therapy [ 45 ]. In another model metformin-induced AMPK activation was shown to inhibit PD-1 gene expression in CD8 +  T lymphocytes and in metformin-treated lung cancer patients there was an increase in the frequency of memory stem and central memory T cells [ 46 ]. Metformin-induced AMPK activation may downregulate CD39 and CD79 gene expression thereby reducing myeloid-derived suppressor cell-driven immunosuppression [ 47 ]. Tumour-associated macrophages have been shown to be immunosuppressive through production of specific immunomodulatory cytokines promoting tumour growth. The preclinical investigation has shown that metformin can alter macrophage polarisation from an M2 to M1-like phenotype inhibiting tumour growth and angiogenesis and that this may be driven by activation of AMPK/ NF-κB signalling [ 48 , 49 ].

Metformin and its role in cancer prevention is an area that has been underexplored in prospective studies. Indeed, the epidemiological data provide a strong rationale for testing this hypothesis in selected groups of patients, for example, obese or insulin-resistant individuals and now early clinical trial data is emerging in support. One clinical study investigated metformin’s potential utility in preventing tamoxifen-induced endometrial hyperplasia showing reduced endometrial thickness on transvaginal ultrasound for metformin-treated patients compared to the placebo control group [ 50 ]. Metformin has been shown to suppress intestinal polyp growth in a murine model of familial adenomatous polyposis coli [ 51 ] and a subsequent randomised clinical trial showed that metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy following 12 months of treatment with metformin [ 52 ].

However, prevention studies designed to identify differences in cancer incidence are notoriously difficult to execute given the numbers of patients needed to properly power such a trial and the length of time it takes to complete adequate follow-up. However, opportunity lies in investigating the potential of metformin as cancer preventative for patients with cancer predisposition syndromes which will allow for smaller studies and shorter follow-up. For example, Li-Fraumeni syndrome (LFS) is a rare inherited cancer predisposition syndrome with a lifetime risk of cancer close to 100% by age 60 years in women and 73% in men. LFS is caused by germline pathogenic variants in the TP53 tumour suppressor gene [ 53 ] and in studies of mice carrying a knock-in missense mutation of TP53 , metformin increases their cancer-free survival [ 54 , 55 ]. This has been attributed to metformin’s direct anti-mitochondrial effect, supported by clinical evidence of attenuated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from metformin-treated mTP53 carriers. On this basis, randomised clinical trials are now moving forward to evaluate whether metformin can reduce cancer incidence in this high-risk population.

In summary, outcomes from late-phase efficacy studies testing metformin as a repurposed cancer therapeutic have been disappointing. In a rush to establish its potential utility, such trials were designed prior to due diligence with regard to patient selection, mechanism of action and appropriate combination. New avenues of investigation in selected populations including the assessment of combination with immunotherapy, and potential as a cancer preventative agent still warrant well-designed clinical investigation.

Data availability

Not applicable.

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SL is funded by Cancer Research UK, National Institute for Health and Care Research and Against Breast Cancer.

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Lord, S.R., Harris, A.L. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?. Br J Cancer 128 , 958–966 (2023). https://doi.org/10.1038/s41416-023-02204-2

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DOI : https://doi.org/10.1038/s41416-023-02204-2

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