Aspirin: More than a Pain Killer

Aspirin has been most commonly known as an effective pain reliever but more recently, its ability to reduce the risk of colorectal cancer has been unveiled by a research team led by Andrew Chan, Harvard professor and Chief of the Clinical and Translational Epidemiology Unit in the Department of Medicine and Vice Chair of Education in the  Division of Gastroenterology at the Massachusetts General Hospital. Analysing data from two large-scale, long-term epidemiological studies, Chan found that routine use of aspirin can significantly reduce the overall risk of cancer, specifically colorectal cancer and other tumours in the gastrointestinal tract. Scope invited Dr Chan to shed light on this important discovery.

SCOPE: Can you tell us more about your research findings and what they suggest? 

CHAN: Our team analysed 32 years of worth of data from nearly 136 000 participants in the Nurses' Health Study and the Health Professionals Follow-up Study. We found that participants who took aspirin regularly—either a standard or low-dose aspirin tablet at least twice a week—had a 3% absolute lower risk of any type of cancer, compared to those who did not report regular use of aspirin. In addition, regular aspirin use reduced the risk of colorectal cancer by 19% and the risk of any gastrointestinal cancer by 15%.

These findings imply that aspirin use would be expected to prevent a significant number of colorectal cancers above and beyond those that would be prevented by screening and may have even greater benefit in settings in which the resources to devote to cancer screening are lacking.

 Professor Chan discuss research with his team at MGH

SCOPE: Your findings definitely brings good news to the medical community. How did you come up with the hypothesis that aspirin could possibly prevent cancer?

CHAN: Several decades of studies have shown that people who use aspirins have a lower risk of cancer. That's been written in medical literature before our study. However, there has been relatively little work in understanding the mechanism by which aspirin actually prevents cancer.  Thus, we approached this from a molecular epidemiological approach to really leverage our ability to profile human biological samples to help understand what specific molecular markers either in blood, or tumour tissue or the normal colon might actually predict whether someone is going to respond to aspirin for cancer prevention. This work has helped us elucidate the molecular mechanism by which aspirin works and also helps define populations according to molecular characteristics that are more likely to benefit. This has been a relatively novel approach to traditional epidemologic research.

SCOPE: What have you discovered about the mechanism or the link between aspirin and cancer prevention?

CHAN: Based on studies in animals and in cell lines, it is already well known that aspirin reduces the synthesis of prostaglandins. These chemicals have also been linked to many pathways that promote cancer.  We have demonstrated that the link between aspirin and lower colorectal cancer risk is at least in part due to aspirin’s ability to inhibit prostaglandins. We have also extended these mechanistic studies in humans to understand what additional, perhaps less characterized pathways may also be relevant to help explain aspirin's anti-cancer benefits in human populations. In doing such studies we are learning more about the mechanism of aspirin's effects and using this as a way to help develop some molecularly specific biomarkers that could be used to risk stratify patients for aspirin chemoprevention in the future.

SCOPE: This specific focus on aspirin's molecular mechanism and the possibility of using it to risk stratify patients will make a significant contribution to the field. How is the medical community responding to this?

CHAN: There is a lot of interest in the scientific community in trying to understand more about precision medicine and how we can deliver more molecularly-tailored treatments to patients. Most of that focus has been in the field of cancer therapy while relatively little attention was paid to tailoring prevention. Thus, we are very motivated to demonstrate whether the precision medicine paradigm can be applied to cancer prevention which in the past was largely untargeted to large swaths of the population.

SCOPE: Has aspirin been recommended officially for the purpose of preventing cancer?

Chan: In 2016, the U.S. Preventive Services Task Force* unveiled its expert recommendation for the use of aspirin for the purposes of prevention of cardiovascular events and colorectal cancer in a large subset of the U.S. population. This has been a milestone in our field because there has been until now no recommendation for people at general risk of cancer to take a medicine to prevent cancer. Cancer prevention has always been focused on screening, and detection. This is now an example of how cancer prevention can get to the root of the problem and try to prevent tumors from ever developing.

Note：U.S. Preventive Services Task Force is an expert body of individuals assembled to review evidence and make recommendations to the general medical community to think about what preventative interventions are most relevant for their patients. This was an effort to provide a recommendation for doctors to provide to their patients who fit certain risk profiles, to help reduce their future risk of cancer.

SCOPE: Who is this recommendation for? Specifically, what populations are the ones most likely to benefit from aspirin?

CHAN: The recommendation is for the general population who has certain cardiovascular risk factors to use aspirin to prevent both heart disease and colorectal cancer. The benefits of aspirin probably cut across different ethnic and racial groups. However, our research does suggest there are specific genetic backgrounds that might have greater propensity to respond to aspirin than others. In addition, we also know that there are specific molecular biomarkers that are found in people's colon tissues that might predict whether they will respond to aspirin or not. We are still focused on some of the molecular features of someone's tissue or genes that really could be an explanation of why some people benefit more than others.

SCOPE: Do you recommend aspirin on a routine basis?

CHAN: We do recommend aspirin on a fairly routine basis, specifically for patients that have a high risk of colorectal cancer. For example, patients with a specific genetic syndrome called Lynch syndrome. These patients have about a 70% of lifetime risk of developing colorectal cancer. Amongst those patients, there has been a randomized clinical trials showing that aspirin is effective in reducing colon cancer risk over long-term follow-up.  There may be other less high-risk patient that are candidates if they are well informed about the potential side effects of regular aspirin treatment. Nonetheless, I remind people that aspirin should be not be regarded as a substitute for colonoscopy or other cancer screening tests.  

Chan with faculty, fellows, and research associates of the MGH Clinical and Translational Epidemiology Unit

SCOPE: How long would a patient have to take aspirin in order to see the anti-cancer benefits?

CHAN: Cancer prevention requires long-term use of aspirin. It appears that you need to take a daily dosage for at least 5 to 10 years to see the anti-cancer benefits.

SCOPE: Are there significant side-effects associated with long-term use of aspirin?

CHAN: Long-term use of aspirin has been linked to gastrointestinal bleeding, which is the primary concern for patients who take this drug. So, we should be judicious in who we recommend aspirin to. We want to make sure that people will maximally benefit and have minimal side effects. This is the reason why understanding molecularly what aspirin is doing is important because if we can understand what molecular mechanisms tend to promote cancer we can better tailor who we recommend take the drug. For example, if some patients are predisposed to certain types of complications of aspirin based on their genetics, then we might avoid giving aspirins to such patients. In contrast, if we find that certain molecular markers predict a good response to aspirin, we might have a lower threshold to recommend it to patients with the appropriate molecular profile.  Thus, we won't have to rely on just clinical factors or demographics to tailor therapy.

SCOPE: Is there any evidence suggesting that aspirin can be used as a treatment for cancer?

CHAN: We were among the first to demonstrate, in a population-based cohort, that aspirin has promise as a treatment for cancer. We found that, among individuals with a history of colon cancer, regular use of aspirin after curative resection was associated with a lower risk of dying from colorectal cancer or dying from other cause.  This finding was confirmed by many other groups in other populations.  As a result, there is an increasing interest in using aspirin as a therapeutic agent. In fact, aspirin is currently being tested in several clinical trials of aspirin for the treatment of established cancer.

SCOPE: Your leadership in cancer prevention is pronounced in the field. Can you elaborate more on it?

CHAN: I do have a keen interest in precision chemoprevention and believe that aspirin provides a unique opportunity to develop a paradigm of a preventative intervention that can be molecularly targeted. As we think more about public health, we have to concede the notion of a one-size-fits-all preventative intervention is probably not ideal or resource efficient. We need to start focusing on understanding, on a molecular level, what some of our preventative interventions are really doing. If we can understand the molecular mechanisms of cancer prevention, for example, we can then exploit those mechanisms to develop novel biomarkers that will allow us to molecularly target our interventions. As a clinician and gastroenterologist, I understand that there are limits to screening and to early detection so we need better ways to actually prevent a tumor from ever developing. At the same time, I also understand that we have to be careful about potential side effects.  So, from the standpoint of a clinician, I have come to understand the importance of being able to provide very tailored therapy for patients.

SCOPE: What sparked your interest in cancer prevention?

CHAN: When I was a medical student at Harvard, I became interested in cancer. During medical school, I spent a year as a Luce Scholar, a fellowship awarded by the U.S. Henry Luce Foundation, to support intensive professional experiences in Asia.  I was based at the Cancer Centre at the Chinese University of Hong Kong where I did basic laboratory research into novel means of early detection of cancer. Coupled with seeing many patients with GI cancers, I became motivated when I returned to the U.S., to train in gastroenterology. At the same time, I also wanted to contribute to research on prevention of gastrointestinal cancers. Coming back to the U.S., I became more interested in public health and larger scale population studies. So I pursued a masters degree in public health after graduating from medical school, to really learn epidemiological methods.  These allowed me to develop expertise in molecular and genetic epidemiology. I have used these tools to study the role of aspirin in colorectal cancer prevention, which has been a terrific way to bridge my public health interest with my motivation to help individual patients.

Note：The Luce scholarship is given to 18 future leaders in different careers, young professionals in the U.S. It's given to those individuals that are the most promising people within their careers that are also interested in getting more exposure to Asia and try to understand how Asia can maybe inform their professional lives in the future.

ABOUT THE INTERVIEWEE

Andrew Chan is the Chief of the Clinical and Translational Epidemiology Unit within the Department of Medicine as well at the Vice Chair of Education in the Division of Gastroenterology at the Massachusetts General Hospital, Harvard Medical School's largest teaching hospital. He is an Associate Professor of Medicine at Harvard Medical School. As a clinical gastroenterologist, Dr. Chan specializes in familial gastrointestinal cancer syndromes and cancer prevention.  Dr. Chan is a leading investigator in the epidemiology of colorectal cancer and other digestive diseases. An elected fellow of the American Society of Clinical Investigation, his work is supported by the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Gastroenterological Association (AGA), the Damon Runyon Cancer Research Foundation, and the Crohn’s and Colitis Foundation of America.  He has published over 280 papers in the field of colorectal cancer and other chronic digestive diseases in leading journals, including the New England Journal of Medicine, Journal of the American Medical Association, Lancet, Science Translational Medicine, Gastroenterology and Gut.  In 2016, he was recognized with a Top Ten Clinical Research Achievement award by the Clinical Research Forum. Dr Chan is a section editor for Gastroenterology, serves on the editorial board of Cancer Prevention Research and Cancer Epidemiology Biomarkers and Prevention, and is vice-chair of the Gastrointestinal Oncology Section of the AGA.