Aspirin cuts risk of BRAF wild-type colorectal cancer

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Benefits must outweigh risks

Chemoprevention to reduce the incidence of future colorectal cancer is a laudable goal so long as the benefits outweigh risks of the drug or drugs utilized. Aspirin, used mainly for cardiovascular disease prevention, has been shown in randomized controlled trials to also reduce risk for colorectal neoplasia, and mechanisms that drive that reduced risk might be COX-2 dependent or independent. The RAS/RAF/MAPK pathway, normally regulated via upstream receptor pathways such as EGFR, can upregulate COX-2 expression but becomes autonomous when KRAS or BRAF is mutationally activated to provide incessant signaling and perhaps high persistent levels of COX-2 that might not be diminished with aspirin.

Nishihara and colleagues surmised that wild-type BRAF tumors might be more sensitive and be prevented with regular aspirin usage, and in two large cohorts yielding 1226 incident colorectal cancers, demonstrated a lower risk of developing wild-type BRAF tumors but not mutant BRAF tumors. Increased weekly dose of aspirin and longer duration of aspirin usage were associated with reduced risk of wild-type BRAF cancers.

The clinical utility of this is unknown. Mutant BRAF segregates with sporadic CIMP-positive, microsatellite unstable tumors, which are often right-sided flat serrated lesions in the colon that may proliferate faster, are more resistant to 5-fluorouracil chemotherapy, but have an overall better survival prognosis compared to CIMP-negative or microsatellite stable tumors Theoretical selection for these tumors could occur with aspirin use. Tumors from Lynch syndrome patients demonstrate wild-type BRAF, and might explain this group's response to reduction of colorectal cancer risk with aspirin.

John M. Carethers, M.D., is the John G. Searle Professor and chair of the department of internal medicine, University of Michigan, Ann Arbor. He had no conflicts to disclose.



Regular aspirin use has been linked to a lower risk of BRAF wild-type, but not BRAF mutated, colorectal cancer, according to a report in the June 26 issue of JAMA.

The absolute difference in risk was considered modest, so further investigation is required to clarify the clinical implications of these study findings. But the results do indicate that BRAF status may someday serve as a marker of sensitivity to aspirin therapy, said Reiko Nishihara, Ph.D., of the Dana-Farber Cancer Institute and Harvard University, Boston, and her associates.

Activating mutations in the BRAF oncogene occur in 10%-15% of colorectal cancers, and are thought to play a role in the upregulation and synthesis of certain prostaglandins. Since aspirin is an antiprostaglandin, "we hypothesized that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin, whereas BRAF wild-type neoplastic cells might be more susceptible to its antitumor effects," they said.

© Photo by Aubrey Calo/Courtesy of Harvard School of Public Health

Dr. Reiko Nishihara

The study findings also could lead to new treatment strategies that are better tailored to tumor characteristics. And they "enhance understanding of the molecular pathogenesis of colorectal neoplasia and the mechanisms through which aspirin may exert its antineoplastic effects," the investigators noted.

Dr. Nishihara and her colleagues examined the association between aspirin use and colorectal cancer’s BRAF mutation status using data from two large national prospective cohort studies that tracked participants’ aspirin use beginning in the 1980s. They analyzed data on 82,095 women in the Nurses' Health Study (NHS) and 45,770 men in the Health Professionals Follow-Up Study (HPFS), in which numerous dietary and other exposures were monitored in detail at 2-year intervals.

"Our detailed, updated exposure data allowed us to control for the effects of potential confounding by other dietary and lifestyle factors implicated in colorectal carcinogenesis," they said.

The study participants used aspirin primarily to prevent cardiovascular disease and to treat arthritis, other musculoskeletal pain, and headache.

During 28 years (more than 3 million person-years) of follow-up, 1,226 of these subjects developed colorectal cancer. As expected, both men and women who used aspirin regularly showed a significantly lower risk of developing the disease than did aspirin nonusers.

DNA tissue was extracted from stored samples of tumor tissue so that BRAF status could be determined.

Aspirin use was associated with a significantly lower risk of BRAF-wild-type cancer. For this tumor, the age-adjusted incidence was 40.2 per 100,000 person-years among aspirin nonusers, compared with 30.5 per 100,000 person-years for aspirin users.

In contrast, aspirin use showed no relation to the risk of BRAF-mutated cancer. The age-adjusted incidence was 5.0 per 100,000 person-years among nonusers and 5.7 per 100,000 among aspirin users (JAMA 2013;309:2563-71).

In a sensitivity analysis that accounted for the concomitant use of cholesterol-lowering agents, antihypertensive medications, and NSAIDs, the results were unchanged.

Further investigation showed that the risk of BRAF-wild-type colorectal cancer decreased as the weekly dose of aspirin increased. In addition, this risk decreased as the duration of aspirin therapy increased.

In contrast, neither dose nor duration of aspirin therapy affected the risk for BRAF-mutated cancer.

"These findings support the hypothesis that BRAF-mutated cells may show resistance to the anticancer effects of aspirin due to upregulation of the [prostaglandin] pathway," Dr. Nishihara and her associates said.

This study was supported by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the National Colorectal Cancer Research Alliance. Dr. Nishihara reported no financial conflicts. An associate reported ties to Bayer Healthcare, Millenium Pharmaceuticals, Pfizer, and Pozen.

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