For those diagnosed with colorectal cancer, regular use of nonsteroidal anti-inflammatory drugs, or NSAIDs, is tied to longer survival, a new observational study shows. But that potentially protective link only holds up for patients with the most common genetic subtype of tumor.
About 70 percent of colorectal cancer patients have a normal copy of a gene known as KRAS in their tumors. The other 30 percent carry mutations in that gene. And it’s in this larger group — those without KRAS mutations in their cancer — that NSAID use is linked to longer survival, said Fred Hutchinson Cancer Research Center epidemiologist Dr. Polly Newcomb, senior author on the study published Thursday in the Journal of Clinical Oncology.
The study included all types of NSAIDs — the most well-known of which are aspirin, ibuprofen and naproxen. Aspirin (at low doses) is the most commonly used on a daily, long-term basis, Newcomb said. That’s because it’s well known to prevent heart disease for those at high risk.
Aspirin is also linked to reduced risk of developing certain types of cancer, colorectal cancer included. But for those already diagnosed with cancer, it’s less clear whether those links extend to a reduced risk of recurrence or increased survival. Fred Hutch epidemiologist and doctoral student Xinwei Hua, who is lead author on the study, teamed up with Newcomb to delve into that area.
Photo by Robert Hood / Fred Hutch News Service
The researchers took data from 2,419 patients who were part of the Colon Cancer Family Registry, an international consortium that collects lifestyle, family history and medical information from patients diagnosed with colorectal cancer in the U.S., Canada and Australia. Hua, Newcomb and their colleagues looked for patients in the registry who had survived at least five years past their diagnosis, surveyed them on their NSAID use and other lifestyle factors, and then followed them for another five years to track their survival. On the whole, the researchers found that regular NSAID use was linked to an increase of about 25 percent in overall survival in these patients — similar to what previous studies had found.
Precision prevention for survivors
Because the group of survivors was so large, the researchers were able to slice up the data in multiple ways. They split the patients who regularly used NSAIDs according to the type of NSAID they used, the timing of NSAID use (before or after diagnosis or both), and by the particular genetics of their tumors, comparing all these different groups to survivors who didn’t use NSAIDs.
Many of these groupings didn’t yield statistically significant differences in survival, Newcomb said, but one group showed a very clear difference: NSAID use among survivors without KRAS mutations in their tumors. Compared to those who had never used aspirin or other NSAIDs, survivors who didn’t carry the KRAS mutation and who used NSAIDs regularly had 40 percent higher survival rates. For those whose tumors bore KRAS mutations, NSAID use wasn’t associated with a difference in survival. The researchers looked at two other mutations commonly found in colorectal tumors but didn’t see significant differences in survival tied to NSAID use.
Research such as this falls under the heading of “precision prevention,” a form of the broader precision medicine approach and one that aims to tailor prevention strategies to a person’s (or their tumor’s) unique molecular makeup. This is the first report linking KRAS subtype to NSAID use and survival, Newcomb said. One previous small study had found an association between aspirin use and increased survival in colorectal cancer patients whose tumors carry mutations in the gene known as PIK3CA. Now, with the additional information that the protective benefit of NSAIDs may be limited to those without KRAS mutations — the most common colorectal tumor subtype — researchers have another piece in the puzzle of who might benefit most from NSAID use.
Patients whose tumors bear KRAS mutations already tend to fare worse than those with normal versions of the genes, Newcomb said. She was half-hoping the study would yield information to benefit this population in particular, “but it didn’t work out that way,” she said.
The researchers also saw a stronger link to increased survival for patients who used aspirin over other NSAIDs. But it’s not clear if that’s because daily, ongoing use of aspirin is much more common than prolonged use of medicines like ibuprofen and naproxen, Newcomb said. That is, they don’t know if it’s the specific drug, the dose or the frequency that made a difference.
Photo by Robert Hood / Fred Hutch News Service
Correlation vs. causation — what does it mean for patients?
The goal of the study — and much of Newcomb’s work — was to uncover factors that could lead to longer survival for cancer patients.
“Everybody wants to consider what lifestyle options might be available to them to improve their longevity after diagnosis,” she said. “This study gives us insight into how great the benefits of NSAID use might be.”
Because the study was observational — the researchers didn’t assign survivors to take or not take the medicines, but rather observed their normal use — it can’t definitively answer the question of whether aspirin and other NSAIDs can prolong survival.
“I think this is compelling evidence, but this is an observational study,” said Hua. “All kinds of things could be happening” that could potentially explain the results they saw.
Because the study was observational and because Hua and Newcomb are not clinicians, they can’t make specific recommendations for survivors, they said. And regular aspirin use is not completely benign — NSAIDs are blood thinners and can increase the risk of certain kinds of stroke. The epidemiologists recommended that any colorectal cancer survivor interested in the potentially protective effects of aspirin talk to their doctors first before starting on a regular NSAID dose.
“It’s always a good idea to talk to your health care provider about whether or not aspirin or other NSAIDs might help enhance your survival,” Newcomb said.
There is an ongoing, randomized clinical trial looking at whether treatment with a very strong NSAID known as Celecoxib can improve survival in those with stage 3 colorectal cancer after primary treatment. That study will provide a more definitive answer — but to a much narrower question, Newcomb said.
Epidemiology can’t prove causality of a given medicine or other lifestyle factor. But the advantage to studies like Newcomb and Hua’s is that they can look at multiple factors over a longer span of time, Newcomb said. That’s why for many cases, medical research can benefit from both types of studies.
“Clinical trials can establish causality, but only in the one way you’ve defined exposure and in a limited population who is eligible,” she said. “Whereas in an epidemiology study, we study the disease as it occurs in the population.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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