A growing body of evidence provides biologic and clinical evidence that nonsteroidal anti-inflammatory agents are protective against colorectal cancer.
“It is fascinating for me as a medical oncologist and epidemiologist to see how the worlds of colorectal cancer treatment and epidemiology are intersecting,” said Charles S. Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston, at this year’s Gastrointestinal Cancers Symposium in San Francisco.
Key Research
Preclinical studies established the notion that aspirin might be protective against colorectal carcinogenesis. This led to two pivotal prospective observational cohort studies in humans, including the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study, which together followed almost 200,000 individuals over decades to better understand cancer biology and its influences. In the NHS, individuals who took two or more adult aspirin tablets (325 mg) per day had a 23% or greater reduction in subsequent colorectal cancer.1 A linear association was found between dose and risk, such that those in the highest quartile (> 14 tablets per week) had a 42% relative risk reduction.
“This indicated that—in contrast to cardiovascular prevention, where 81 mg/d is sufficient—325 mg/d would be the maximum recommendation for aspirin,” he said. “More aspirin does seem to be more protective.”
Subsequent prospective randomized trials further established a protective effect against adenoma recurrence. In four trials of persons with adenomatous polyps, regular aspirin use significantly reduced the risk of subsequent adenomas in a dose-response manner. Aspirin doses in these trials ranged from 81 to 325 mg/d, and hazard ratios ranged from 0.61 to 0.96.
Randomized trials then began to show aspirin to be as protective against colorectal cancer. The British Doctors Aspirin Trial followed more than 7,500 individuals for at least 20 years and showed that regular use of aspirin (≥ 300 mg/d) resulted in a 29% reduction in colorectal cancer risk.2
“We have what appears to be very compelling and consistent phase III literature to support the use of aspirin in reducing the risk of colorectal adenomas and colorectal cancer,” Dr. Fuchs indicated.
Mechanism of Protection
A theory “gaining traction” as to how aspirin influences cancer carcinogenesis is through inhibition of cyclooxygenase (COX)-1 and -2, which affect apoptosis, cell division, metastasis, and angiogenesis. Large trials of the selective COX-2 inhibitors celecoxib (Celebrex) and rofecoxib (Vioxx) after polypectomy demonstrated a 24% to 45% reduction in adenoma recurrence.
Numerous studies, however, also suggested that large doses of the COX-2 inhibitors raised the risk of cardiovascular events; rofecoxib was ultimately removed from the market because of these concerns. A meta-analysis was reassuring for the 400-mg/d dose of celecoxib, which was not associated with cardiovascular events.3 Furthermore, Dr. Fuchs maintained, risk of gastrointestinal bleeding should not be an overriding concern.
In spite of the evidence, however, the U.S. Preventive Services Task Force has recommended against the general use of nonsteroidal anti-inflammatory agents for colorectal cancer prevention,4 concluding that the potential for harm outweighs the potential for benefit in the general population.
Who Might Benefit?
Dr. Fuchs acknowledged, “We understand that giving these agents to the entire population may be of some concern, so we are therefore trying to define which persons may more selectively benefit from aspirin.”
The UGT1A6 genetic variant is related to impaired metabolism of aspirin. Persons with this genotype had a 34% reduction in the risk of adenoma recurrence and a 39% reduction if they took seven or more aspirin tablets per week, while those with the wild-type genotype derived no benefit.5 Such findings suggest the potential to use genotype in determining preventive utility, Dr. Fuchs said.
Systemic inflammation may be another marker of response. Persons with the highest quartiles of circulating inflammatory factors were found to have a 67% greater likelihood of developing colorectal cancer.6 Those with levels of inflammatory markers below the median derived little effect from aspirin, but those with levels above the median had a 60% reduction in the development of cancer. “The data suggest this may be an additional means of teasing out those who may benefit from aspirin for colorectal cancer prevention,” he said.
“We also want to know whether aspirin prevents all colorectal cancers or those with a particular biology,” Dr. Fuchs said. In particular, intratumoral COX-2 expression might indicate susceptibility to the influence of aspirin, according to a study in which two aspirin tablets per week did not prevent tumors that were negative for COX-2 expression but did reduce by 36% the occurrence of tumors expressing COX-2.7 This offers yet another potential biomarker for defining the use of aspirin in the future, he said.
Furthermore, in persons with colorectal cancer, COX-2 expression was prognostic for survival in a study where individuals whose tumors were COX-2–positive had a 70% increase in colorectal cancer–related mortality.8 “Expression of this marker may influence the outcome, and perhaps interventions against this marker could change the natural history for these patients,” he suggested.
Interestingly, in the NHS, among the 1,279 patients with stage I–III colorectal cancer, aspirin use before diagnosis was not associated with colorectal cancer–specific survival or overall survival, but regular use after diagnosis reduced colorectal cancer mortality by 29% and overall mortality by 21%.9 The most robust effect was in aspirin-naive patients who initiated aspirin use after diagnosis, for whom mortality was reduced by 47%, and patients with COX2–positive tumors, whose mortality risk was reduced by 61% with postdiagnosis aspirin use.
Other pathways and mutations may also be influential with regard to aspirin use, including the PIK3CA pathway, which is downstream of COX-2. Dr. Fuchs and colleagues recently found that patients with colorectal cancer and activating mutations in PIK3CA experienced a protective effect from postdiagnosis use of aspirin that was not observed in the absence of the intratumoral mutation.10 Postdiagnosis aspirin use among patients with the mutation was associated with an 82% reduction in colorectal cancer–related mortality and a 46% reduction in overall mortality. “This suggests that PIK3CA may be a potential biomarker worthy of subsequent validation,” he said.
Next Step: Intervention Studies
“What’s needed now are intervention trials to test whether these strategies should enter clinical practice,” Dr. Fuchs said.
The ASCOLT trial is evaluating the effect of 3 years of aspirin, vs placebo, after adjuvant therapy in 2,660 patients with stage II/III colorectal cancer. The CALGB/SWOG 80702 trial is evaluating celecoxib at 400 mg/d after adjuvant therapy in 2,500 patients with stage III disease. Correlative studies will evaluate the influence of baseline circulating inflammatory factors, germline polymorphisms in COX-2 and inflammatory pathways, tumoral expression of COX-2, NFkB, IL-6, PIK3CA mutations, and other somatic events, and measures of tumor angiogenesis.
“We have new and exciting studies that will further investigate this intersection between aspirin and prevention, with the ultimate goal of informing our patients who are at risk for colorectal cancer or its recurrence,” Dr. Fuchs said. ■
Disclosure: Dr. Fuchs is a consultant for Amgen, Genentech, Pozen, Metamark Genetics, Momenta Pharmaceuticals, and Sanofi.
References
1. Chan AT, Giovannucci EL, Meyerhardt JA, et al: Long-term use of aspirin and non-steroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294:914-923, 2005.
2. Flossman E, Rothwell PM: Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies. Lancet 369:1603-1613, 2007.
3. Solomon SD, Wittes J, Finn PV, et al: Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 117:2104-2113, 2008.
4. U.S. Preventive Services Task Force: Routine aspirin and non-steroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 146:361-364, 2007.
5. Chan AT, Tranah GJ, Giovannucci EL, et al: Genetic variants in the UGT1A6 enzyme, aspirin use, and the risk of colorectal adenoma. J Natl Cancer Inst 97:457-460, 2005.
6. Chan AT, Ogino S, Giovannucci EL, et al: Inflammatory markers are associated with risk of colorectal cancer and chemopreventative response to anti-inflammatory drugs. Gastroenterology 140:799-808, 2011.
7. Chan AT, Ogino S, Fuchs CS, et al: Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131-2142, 2007.
8. Ogino S, Kirkner GJ, Nosho K, et al: Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res 14:8221-8227, 2008.
9. Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302:649-658, 2009.
10. Liao X, Lochhead P, Nichihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal cancer survival. N Engl J Med 367:1596-606, 2012.
