For the more than 1.2 million colorectal cancer survivors living in the United States, identifying factors that might help them live longer after their diagnosis is an important public health priority. Of particular interest are modifiable lifestyle behaviors, such as diet or physical activity, which can be performed outside a clinical setting. Aspirin use has previously been suggested to improve survival, but the long-term impact was unknown. In a recent issue of the Journal of Clinical Oncology, Ms. Xinwei Hua and Dr. Polly Newcomb and colleagues in the Public Health Sciences Division report that regular use of aspirin was associated with improved survival among long-term colorectal cancer survivors with particular tumor mutations.
To evaluate this relationship, the authors utilized data from the Colon Cancer Family Registry (CCFR), an international consortium of population-based studies in the United States, Canada, and Australia. Patients diagnosed with colorectal cancer between 1997 and 2008 were identified from population-based cancer registries and asked to participate. Participants completed baseline questionnaires about various lifestyle factors before diagnosis, and then again five years after their diagnosis. These questionnaires measured the use, duration, and dose of both aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). As such, participants were classified as either continuing, discontinuing, starting, or never using these medications.
To explore this relationship in greater depth, the authors tested archived tumor tissue for several molecular characteristics: microsatellite instability status (MSI), mutations in the BRAF or KRAS genes, and the CpG island methylator phenotype (CIMP). Participants were followed over time to evaluate how different patterns of aspirin use were associated with colorectal cancer survival, with a median 10.8 years of follow-up after diagnosis. Delayed-entry Cox proportional hazards regression models were evaluated for both overall and colorectal cancer-specific survival, as well as subgroup analyses including tumor characteristics. Said senior author Dr. Newcomb, “several other studies have shown an association between NSAIDs and preventing CRC, but this is the first to look so thoroughly at how timing of NSAID use relative to diagnosis and tumor type could make a big difference in survival.”
Overall, regular use of any NSAIDs after colorectal cancer diagnosis was associated with 24% higher overall survival. In sensitivity analyses comparing tumor characteristics, this association between post-diagnostic NSAID use and overall survival depended on KRAS status (p-interaction = 0.02). The association was stronger in those without mutations in the KRAS gene (hazard ratio = 0.64), but was no longer statistically significant in those with KRAS-mutant tumors. For colorectal cancer-specific survival, regular users of aspirin alone had 56% higher survival compared to nonusers. For both overall and colorectal cancer survival, longer duration of aspirin-only or any-NSAID use was associated with better survival.
The authors also evaluated patterns of use over time. Compared to never-users, participants who started using NSAIDs after their diagnosis experienced significantly better overall survival (hazard ratio = 0.71) and colorectal cancer survival (hazard ratio = 0.39). Continuous aspirin-only users also had improved colorectal cancer survival versus never users, though this did not reach statistical significance.
Together, these results suggest that starting to take NSAIDs after a colorectal cancer diagnosis may help improve long-term survival for some patients with particular tumor characteristics. Lead author Hua, a doctoral student in the Department of Epidemiology at the University of Washington, reports she is enthusiastic about continuing this work: “We are just beginning to understand the biology underpinning NSAID use on the tumor’s molecular pathways, and it’s very exciting.” Future research will focus on further evaluating the best timing, dose, and duration of use, and further characterizing which patient subgroups would best benefit from taking NSAIDs.
Also contributing to this project from the Fred Hutch were Drs. Amanda Phipps, Andrea Burnett-Hartman, Scott Adams, Sheetal Hardikar, Stacey Cohen, and Jonathan Kocarnik.
Hua X, Phipps AI, Burnett-Hartman AN, Adams SV, Hardikar S, Cohen SA, Kocarnik JM, Ahnen DJ, Lindor NM, Baron JA, Newcomb PA. Timing of aspirin and other nonsteroidal anti-inflammatory drug use among patients with colorectal cancer in relation to tumor markers and survival. J Clin Oncol 2017: JCO2017723569. doi: 10.1200/JCO.2017.72.3569.
Funding for this study was provided by the National Cancer Institute, the National Institutes of Health.
Basic Sciences Division
Human Biology Division
Maggie Burhans, Ph.D.
Public Health Sciences Division
Vaccine and Infectious Disease Division
Clinical Research Division
Julian Simon, Ph.D.
Clinical Research Division
and Human Biology Division
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