The benefit of taking aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) after colorectal cancer (CRC) diagnosis depends on tumor subtype, new research suggests.
Among long-term CRC survivors, regular use of NSAIDs after diagnosis was significantly associated with improved overall survival (OS) only in patients with KRAS wild-type tumors. That subtype accounts for a majority of CRCs.
"This study is unique in examining the previously observed benefits of NSAIDs on colorectal cancer survival according to tumor subtype," study investigator Polly Newcomb, PhD, president, American Society of Preventive Oncology, told Medscape Medical News.
"We found that patients who had tumors that didn't have mutation in KRAS (about 70% of all colorectal cancers) experienced improved survival — about a 40% reduction in mortality. In our study there was no survival benefit of these common medications in patients that had KRAS mutation," said Dr Newcomb, from the Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
"The results of this study support the hypothesis that mutations in KRAS activate pathways that may lead to pro-proliferative/antiapoptotic effects that cannot be inhibited by NSAIDs," she added.
Timing also seems to matter. Patients who started aspirin therapy after diagnosis had improved OS, while both aspirin initiators and continued users seemed to be associated with more favorable CRC-specific survival.
The study was published online June 15 in the Journal of Clinical Oncology.
Regular use of aspirin is associated with improved survival for patients with CRC, but until now, the timing of and the subtype of CRC that would provide the most survival benefit have been unclear, the authors note.
To investigate, they used population-based cancer registries in the United States, Canada, and Australia to identify 2419 patients aged 18 to 74 years diagnosed with incident invasive CRC from 1997 to 2008.
After a median of 10.8 years of follow-up since diagnosis, 381 of the patients had died (100 due to CRC).
Overall, compared with nonusers, patients who used aspirin-only after CRC diagnosis had more favorable OS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59 - 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 - 0.71).
The association between aspirin use and OS and CRC-specific survival was more pronounced in those who initiated aspirin therapy after diagnosis. For OS, the HR was 0.64 (95% CI, 0.47 - 0.86) and for CRC-specific survival, it was 0.40 (95% CI, 0.20 - 0.80).
The association between any NSAID use after diagnosis and OS differed significantly by KRAS mutation status (P interaction = .01). Use of any NSAID after diagnosis was associated with improved OS in patients with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 - 0.80) but not in those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 - 1.96).
"Although both observational and randomized studies provided convincing evidence of aspirin as an effective chemopreventive agent for CRC, aspirin is not generally recommended for primary prevention of CRC for people at average risk of [cardiovascular disease] CVD because of the potential risks," Dr Newcomb and colleagues note in their article.
"Aspirin for secondary prevention of CRC, particularly in subgroups such as those with KRAS wild-type tumors, is supported by our study. Future studies are needed to find the best timing, dose, and duration of aspirin use and to identify subgroups of patients with CRC for whom the benefits of aspirin outweigh its risk," they conclude.
"Very Interesting" Study
Gerrit Jan Liefers, MD, PhD, and Martine Frouws, MD, PhD candidate, from Leiden University Medical Centre in the Netherlands, who reviewed the study for Medscape Medical News, called it "very interesting" and said it generally supports their own research.
In a 2012 retrospective cohort study in the Journal of the American Geriatrics Society, Dr Liefers and colleagues reported that aspirin use after colon cancer diagnosis in older adults was associated with longer survival.
At the 2015 European Cancer Congress, Dr Frouws reported an analysis of prescribing data of almost 1400 patients with gastrointestinal cancer that found low-dose daily aspirin almost doubled survival among those patients. Almost half of the patients in the analysis had colon cancer.
However, determining the subtype of CRC that benefits most from aspirin in relation to survival is "difficult" to do in a retrospective cohort, Drs Liefers and Frouws commented. "This year, in PLOS One, one of our studies could not confirm an effect of KRAS or BRAF mutations on the effect of aspirin on survival. This contradiction has been the case in many retrospective studies in the past decade, and no decisive answers have been found."
In their view, the current study "confirms two very important issues" in this field of research: (1) the necessity for large, worldwide cohorts and (2) the importance to study this in a randomized, placebo-controlled setting."
Currently, Dr Liefers and Dr Frouws are performing a large randomized controlled trial (RCT) on the effect of aspirin on survival in 1588 patients with colon cancer in the Netherlands, and very soon also in Belgium. "This RCT is being done in close cooperation with other RCT's worldwide (UK, India, Singapore, Sweden, Switzerland) in order to pool these cohorts in the future, so we will be able to perform further studies in the future on molecular mechanisms involved in the effect of aspirin on cancer survival," the researchers said.
Dr Newcomb has disclosed no relevant financial relationships. One author holds a use patent for the colorectal chemopreventive use of aspirin.
J Clin Oncol. Published online June 15, 2017. Abstract