Aspirin Use Not Associated With Survival in PIK3CA-Mutant Colorectal Cancer


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Nishi Kothari, MD

Aspirin in PIK3CA-Mutated Colorectal Cancer

Contrary to emerging data from other studies, the regular use of aspirin was not associated with improved survival in patients with PIK3CA-mutant metastatic colorectal cancer in a study reported at the 2014 Gastrointestinal Cancers Symposium in San Francisco.1

Large Dataset

“We did not validate survival benefits associated with aspirin in [patients with PIK3CA-mutant disease] across all stages, despite having a larger dataset” than previously reported studies, reported Nishi Kothari, MD, of Moffitt Cancer Center in Tampa, Florida.

“We were also not able to validate the recurrence-free survival benefits associated with aspirin in [patients with PIK3CA-mutant] stage II and III colorectal cancer,” she added.

In a meta-analysis of five randomized trials involving more than 14,000 patients followed for at least 20 years, published in the Lancet, the use of aspirin was associated with a 24% reduction in colorectal cancer occurrence and a 35% reduction in mortality associated with the disease.2

In the Nurses’ Health Study and the Health Professionals Follow-up Study, reported in The New England Journal of Medicine, patients with PIK3CA-mutated tumors who were regular aspirin users had an 82% reduction in colorectal cancer deaths and a 45% reduction in deaths from all causes.3

Most recently, in the VICTOR trial, aspirin use was associated with an 89% reduction in recurrence in patients with PIK3CA mutations.4

No Benefit in Current Study

The study reported at the Gastrointestinal Cancers Symposium involved a review of 1,019 colorectal cancer patients from the Royal Melbourne Hospital in Australia diagnosed between 1996 and 2009, and 468 similar patients from Moffitt Cancer Center and consortium sites diagnosed between 1998 and 2010. Genetic sequencing revealed 185 patients with mutations in the ­PIK3CA gene. Among these, 49 were regular aspirin users and 136 were not.

“To date this is the largest PIK3CA-mutant study population looking at aspirin therapy,” Dr. Kothari indicated.

At baseline, aspirin users had significantly fewer right-sided tumors (41% vs 64%, P = .006), were older (median age, 74 vs 70; P = .009), and tended to have more advanced cancers (stage IV in 26% vs 18%, P = .52), compared to nonusers.

“Unlike previous studies, we did not confirm a relationship between aspirin use and improved overall survival across the cohort,” Dr. Kothari reported. At 10 years, almost 50% of both groups were alive (hazard ratio [HR] = .96; P = .86).

Aspirin users had more medical comorbidities, which could worsen overall survival, and the researchers attempted to account for this by using cancer-specific survival as an outcome. “We still found no improvement in survival among aspirin users (HR = .60; P = .24),” she said.

“Because of the differences in our work and previously published data, we looked to ensure the validity of our study population,” she said. In the multivariate analysis, as expected, increasing age was associated with worse survival and increasing stage was associated with worse overall and cancer-specific survival. However, aspirin use was not associated with improved overall survival (HR = .94; P = .83) or cancer-specific survival (HR .64; P = .24).

“Because our population had a different stage breakdown than previously published work, we stratified patients by stage,” she continued, “but did not find decreased risk of recurrent disease for stage II and III patients who used aspirin. We did find a trend toward improved overall survival for stage IV patients (HR = .40; P = .06), but this trend was not sustained in the multivariate analysis.”

Potential Explanations

Dr. Kothari proposed that the differences between her findings and those of others could be attributed to the smaller proportion of right-sided cancers in this study (which were associated with worse survival), to the more advanced stage of the patients (which may have a different biology), and to the fact that this was a largely unselected community-based population. The follow-up is also shorter (46 months) than previous studies. “We may see different trends as the data mature,” she acknowledged.

As a retrospective study, the current research also lacks information about colorectal cancer treatment and duration of aspirin use. Moreover, the Moffitt population included mutations outside of exons 9 and 20, which have not yet been studied regarding their biologic relevance, she said.

“To help resolve these issues, we will contribute data to the individual patient analysis from the Oxford group, which will combine our data with the ­VICTOR trial as well as the study by Liao et al,” Dr. Kothari added. ■

Disclosure: Dr. Kothari reported no potential conflicts of interest.

References

1. Kothari N, Kim RD, Gibbs P, et al: Regular aspirin use and survival in patients with PIK3CA-mutated metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract 386. Presented January 18, 2014.

2. Rothwell PM, Wilson M, Elwin CE, et al: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741-1750, 2010.

3. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012.

4. Domingo E, Church DN, Sieber O, et al: Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol 31:4297-305, 2013.


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