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Aspirin reduced colorectal cancer recurrence in those with PIK3CA mutations
Low-dose aspirin reduced colorectal cancer recurrence in patients with PIK3CA mutations, according to study results.
“Our findings are consistent with those recently reported and suggest that prospective evaluation of aspirin as adjuvant therapy in this tumor molecular subtype is merited,” researchers wrote.
Prior studies have demonstrated regular aspirin use after colorectal cancer diagnosis is associated with better clinical outcomes. Recent data indicate this beneficial effect is limited to those with PIK3CA-mutant cancers.
Researchers in the current study set out to determine the predictive value of PIK3CA mutations for benefit from both cyclooxygenase-2 inhibition and aspirin in 896 patients enrolled in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial.
The large, randomized trial compared the effects of rofecoxib (Vioxx, Merck) with placebo after primary colorectal cancer resection.
Researchers compared RFS and OS between rofecoxib therapy and placebo, as well as between the use and nonuse of low-dose aspirin. The investigators evaluated results based on tumor PIK3CA mutation status.
Researchers observed no evidence of greater benefit with rofecoxib therapy in patients with PIK3CA mutations (multivariate adjusted HR=1.2; 95% CI, 0.53-2.72) compared with those with PIK3CA wild-type cancers (HR=0.87; 95% CI, 0.64-1.16).
Regular aspirin use post-diagnosis was associated with a decreased rate of colorectal cancer recurrence in those with PIK3CA-mutant cancers (HR=0.11; 95% CI, 0.001-0.832). Researchers did not observe the benefit in patients without PIK3CA mutations (HR=0.92; 95% CI, 0.60-1.42; P=.71).
“This is unlikely to be a result of modification of disease phenotype by aspirin use before colorectal cancer diagnosis because only three of 14 patients in this group were taking aspirin at the time of random assignment,” the researchers wrote. “Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant colorectal cancer.”
Disclosure: The researchers report consultant or advisory roles with Bayer.
Perspective
Back to TopRegular use of aspirin has been shown to impact on the natural history of colorectal cancer. Use of aspirin and similar agents that inhibit prostaglandin synthesis reduces polyp formation in individuals with familial adenomatous polyposis. Large population-based studies indicate that regular aspirin use reduces colorectal cancer mortality by 30% to 50%. A reduced risk for recurrent colon cancer and improved survival also is observed in patients who use aspirin after curative colorectal cancer treatment.
Because cyclooxygenases — and in particular cyclooxygenase-2 — are targets of aspirin, the expression of COX-2 as a predictive biomarker for aspirin’s preventive effect in colorectal cancer has been studied. Overexpression of COX-2 correlated with a preventive benefit for aspirin usage, with no benefit seen for normal COX-2 expression. Subsequent studies explored potential tumor mutations that might upregulate or enhance COX pathways. Activating mutations in PI3 kinase (PIK3CA), which may impact downstream on COX-2, identified patients who had a reduced risk for colorectal cancer with aspirin compared with no benefit for wild-type PIK3CA.
Results are now reported for the VICTOR study, which used high-dose rofecoxib — a specific COX-2 inhibitor — after adjuvant treatment of stage II or III colorectal cancer to potentially reduce recurrence. The trial was terminated due to the increased of rate of fatal cardiovascular events in the rofecoxib arm. The authors report the risk for recurrence of colorectal cancer as a function of rofecoxib use and aspirin use, and they explored PIK3CA mutation status as a potential molecular biomarker in the patients’ cancers.
Of the nearly 900 patients’ tumors studied, half of patients were treated with rofecoxib and half with placebo, and 14% of the study population reported regular aspirin use. PIK3CA mutations were observed in 11.6%, with the incidence irrespective of rofecoxib or aspirin use. In patients with PIK3CA mutation, rofecoxib had no impact on recurrence-free survival. However, with aspirin use in these patients, no recurrences were observed compared with a 26% rate of recurrence in nonaspirin users (HR=0.11). No impact of aspirin use was seen in PIK3CA wild-type tumors. An OS benefit also trended in aspirin users whose tumors harbored PIK3CA mutations (HR=0.44) without reaching statistical significance. A minority of the PIK3CA mutation patients were taking aspirin prior to a colorectal cancer diagnosis, arguing that the impact resulted from post-colorectal cancer treatment aspirin usage.
The results from the VICTOR trial are striking and agree with previous reports that indicate a protective benefit for aspirin therapy only seen for patients whose tumors contain a PIK3CA mutation. The authors argue for a prospective trial to evaluate the benefit for aspirin therapy specifically in PIK3CA-mutant patients. However, the huge magnitude of benefit — including no colorectal cancer recurrence in the patients taking aspirin, and an overall 82% to 89% rate of reduction in cancer recurrence with aspirin therapy compared with no aspirin therapy over two studies — argues that such a trial might not be ethical. Current practice is to recommend regular aspirin use to patients with Lynch syndrome, and aspirin therapy is already considered for use in patients after curative treatment of colorectal cancer. In the VICTOR trial, it is notable that the supplemental use of a specific COX-2 inhibitor did not convey any benefit about aspirin use alone. The negative results of the VICTOR trial could potentially impact on the ongoing CALGB trial 80702 (NCT01150045) in stage III colorectal cancer, using celecoxib (Celebrex, Pfizer) vs. placebo postoperatively as a preventive therapy.