Published OnlineFirst November 27, 2013; DOI: 10.1158/2159-8290.CD-ND2013-027

NEWS IN DEPTH

A Role for Aspirin in Cancer Prevention? Researchers try to pinpoint populations that might benefit—and find out why For more than two decades, observational studies and randomized trials have generated evidence that using aspirin daily for several years—even at low doses—may significantly reduce the risk of developing colorectal cancer. Published in 2011 and 2012, pooled analyses of randomized trials of aspirin, originally designed to examine cardiovascular disease, have suggested that aspirin might also lower the risk of developing or dying from other types of solid tumors (Lancet 2011;377:31–41 and Lancet 2012;379:1602–12). Aspirin, or acetylsalicylic acid, “is ubiquitous and cheap and has the longest safety record of any drug in widespread use,” writes Sir John Burn, MD, professor of clinical genetics at the UK’s Newcastle University. Burn has spoken in favor of aspirin use to combat cancer, especially among those with a family history of solid tumors, most recently at the American Association for Cancer Research’s Frontiers in Cancer Prevention meeting on October 30. Even so, “the American Cancer Society does not currently recommend use of aspirin specifically to help prevent cancer,” says Eric Jacobs, PhD, strategic director of pharmacoepidemiology at the Society. The U.S. Preventive Services Task Force (USPSTF) recommends against taking aspirin to prevent colorectal cancer in people at average risk for the disease, citing the potential harm from aspirin-induced bleeding, especially of the gastrointestinal tract. However, the USPSTF is reviewing its recommendation, which was issued in 2007. As recent findings are evaluated, the guidelines may change, Jacobs says. In the 2011 Colorectal Adenoma/Carcinoma Prevention Programme’s CAPP2 placebo-controlled trial conducted by Burn and his colleagues, for example, patients with hereditary cancer (Lynch syndrome) who took two aspirin a day for 2 years cut their risk of colorectal and other cancers by more than half after a mean of nearly 56 months (Lancet 2011;378:2081–7). That finding, says Raymond DuBois, MD, PhD, a professor and executive director of the Biodesign Institute at Arizona State University in Tempe, speaks to the need to personalize cancer prevention. “In the past, we thought one size would fit everybody, but it’s becoming clear that for toxicity and other reasons, whatever the preventive recipe is for each individual person, it’s going to need to be tailored to their risk factors and other genomic factors,” he says. Further supporting the idea of aspirin use in specific populations, Shuji Ogino, MD, PhD, an associate professor of pathology and epidemiology at Boston’s Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard School of Public Health, and Andrew Chan, MD, an associate professor of medicine at Massachusetts General Hospital, also in Boston, and their colleagues reported

in June that aspirin decreased the risk of BRAF–wild-type colorectal cancer—but not BRAF-mutated colorectal cancer— in two prospective cohorts (JAMA 2013;309:2563–71). Because molecular pathology testing is becoming routine in clinical practice, Ogino says the next step is for institutions to pool patient data to build large-scale databases that include use of aspirin and other medications, lifestyle factors, molecular pathology results, and clinical outcomes. “Such databases can generate novel information on potential chemopreventive benefits of drugs,” he says.

MULTIPLE MECHANISMS Researchers don’t yet know exactly how aspirin exerts its protective effect, information that “would give us more solid ground upon which to make the recommendation for it to be used clinically,” says Chan. Most researchers believe that aspirin exerts its anticancer effects in part by modulating COX-1 and COX-2. These enzymes produce prostaglandins involved in inflammation. One such prostaglandin, PGE2, increases cellular proliferation, promotes angiogenesis, and increases resistance to apoptosis, hallmarks of both inflammation and cancer, points out Asad Umar, DVM, PhD, chief of the National Cancer Institute’s Gastrointestinal and Other Cancers Research Group in the Division of Cancer Prevention. Umar, Dubois, and Chan agree that aspirin’s effect on cancer is complex and probably not restricted to COXdependent pathways alone. Some evidence suggests that NF-κB, acetylation of platelets, polyamine metabolism, WNT signaling, and DNA repair may also play a role. “It’s likely the collection of all of these effects that causes the dramatic reduction in cancer risk,” says DuBois. –Suzanne Rose, with reporting by Michele Hartsough ■

ASPIRIN ON TRIAL Data on aspirin use to reduce cancer risk come largely from observational studies, with relatively few data from randomized controlled trials. Furthermore, cardiovascular disease prevention has been the primary endpoint in most trials, limiting knowledge about the best timing and dose for cancer risk reduction. A phase III, randomized, placebo-controlled trial of multiple aspirin regimens in the general population would be difficult to mount. It would need to accrue tens of thousands of participants—and run for many years—before effects on cancer incidence would be evident. Plus, given that aspirin is a generic drug, no pharmaceutical company is eager to bear the expense. Data from trials of aspirin in patients with specific genetic abnormalities, such as CAPP3, which will test different doses in 3,000 patients with Lynch syndrome over 7 years, may offer some insight, but “I don’t know that we’re ever going to have an ideal study of aspirin for cancer prevention,” says Massachusetts General Hospital’s Andrew Chan, MD.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

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Published OnlineFirst November 27, 2013; DOI: 10.1158/2159-8290.CD-ND2013-027

A Role for Aspirin in Cancer Prevention? Cancer Discovery 2013;3:1324. Published OnlineFirst November 27, 2013.

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A role for aspirin in cancer prevention?

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