Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with dramatically improved survival in a subset of patients with head and neck squamous cell carcinoma (HNSCC), researchers say.
Among patients with PIK3CA mutations or amplification, regular NSAID use conferred markedly prolonged disease-specific survival (DSS) that was three times higher than was seen in patients who did not use NSAIDs, according to an observational study of a cohort of 266 HNSCC patients treated at a single center.
For PIK3CA-altered HNSCC patients, the predicted 5-year DSS was 72% for NSAID users vs 25% for nonusers; the predicted 5-year overall survival was 78% vs 45%.
"Our results suggest that the use of NSAIDs could significantly improve outcomes for not only head and neck cancer patients but also patients with other cancers that contained the PIK3CA mutation," said senior author Jennifer R. Grandis, MD, a professor of otolaryngology and head and neck surgery at the University of California, San Francisco.
"The magnitude of the apparent advantage is strong and could potentially have a positive impact on human health," Grandis said in a statement.
The article was published online January 25 in the Journal of Experimental Medicine.
Confirmation Needed
Although not conclusive, a growing number of studies have found that regular long-term use of aspirin may lower the risk for certain cancers, adding to the growing evidence that aspirin may play a role as a chemopreventive agent.
Regular use of aspirin or NSAIDs has been associated with improved outcomes in a number of malignancies, including ovarian cancer, colorectal cancer (only KRASwild-type tumors), and lung cancer in men.
"It is provocative to see that there was a survival benefit, but this isn't in any way conclusive," said Richard Bakst, MD, an associate professor of radiation oncology at the Icahn School of Medicine at Mount Sinai in New York City. "Nor does it identify a clear role for NSAIDs."
He also pointed out that this was a retrospective study, not a prospective one. Nevertheless, the survival benefit that was observed was quite significant. "They did break it down by who had the mutation or amplification and who didn't," said Bakst. "And interestingly, there was no survival difference for patients with unaltered PIK3CA. This probably means that this difference was NSAID related and mutation related."
Although this isn't going to change clinical practice, "it does make one wonder if we should screen for the mutation and think about a trial for people who harbor this mutation," he said. "Another interesting point was that this study was done across a variety of cancer sites, and the results were irrespective of HPV [human papillamovirus] status and other factors — it was not anatomically or risk-factor driven."
The data need confirmation, either in a prospective trial or at least in a study conducted at a different center with a different sample, Bakst added.
Improved Survival Seen in Subset
In this study, Grandis and colleagues evaluated the impact of NSAIDs on survival in HNSCC patients. A correlation between regular NSAID use and improved survival in patients harboring PIK3CA mutations had been described in patients with colorectal cancer. In the current study, the investigators tested the hypothesis that regular NSAID use would be associated with improved DSS and overall survival in HNSCC patients with PIK3CA-mutated or -amplified disease.
Patients were classified as regular NSAID users if the patients' electronic medical records indicated ≥6 months of regular use; regular use was defined as taking NSAIDs ≥2 days a week.
About two thirds of patients (67%) received adjuvant chemotherapy, radiotherapy, or both (CRT). Treatment with CRT was equally distributed among patients with PIK3CA mutation/amplification (66% received CRT) and among long-term NSAID users (69% received CRT).
Administration of CRT had no effect on DSS and overall survival between groups, suggesting that adjuvant CRT did not affect or confound the conclusion regarding the impact of PIK3CA mutation/amplification and long-term NSAID use, the authors note. Smoking history also did not have an effect.
One third (n = 25 of 75, 33%) of patients with PIK3CA-altered tumors were regular NSAID users, as were 39% (74 of 191) of those with wild-type, unamplified PIK3CA,independent of PIK3CA status (chi-square, P = .48). The authors observed no association between either regular NSAID use or PIK3CA status with any clinical or pathologic variable except age (regular NSAID users tended to be slightly older) and disease status (regular NSAID users with altered PIK3CA were more likely to present with recurrent disease; P = .27).
The median DSS was not reached in the cohort but was at least 6 years. Median overall survival was 66 months; the median follow-up was 40 months (range, 3 – 106 months) among survivors.
Aspirin was a component of the NSAID regimen in 93% of regular users; 73% used aspirin exclusively. Most of the regular users (86%) began NSAID therapy after being diagnosed with HNSCC. There was no indication that the diagnosis of HNSCC informed the decision to take NSAIDs.
In multivariable analysis that was adjusted for confounders that included cancer type (primary vs recurrence), pathologic N (nodal) stage, and HPV status, DSS in patients with wild-type PIK3CA was unaffected by regular NSAID use (P = .61). Conversely, regular use was strongly associated with improved DSS for those with mutated and/or amplified PIK3CA (P = .0032).
Patients with altered PIK3CA who used NSAIDs regularly had an absolute 5-year DSS advantage of 47% (72% in regular users vs 25% for nonregular users; hazard ratio [HR], 0.24; P = .0032). But for the cohort with wild-type PIK3CA, the disease-specific HR for regular vs nonregular NSAID use did not reach significance (HR, 0.86).
The authors point out that altered PIK3CA in nonregular NSAID users was associated with worse DSS (P = .047), which is consistent with the known oncogenic properties of PIK3CA.
Similar to the findings for DSS, overall survival for regular NSAID users with unaltered PIK3CA was similar to that for nonregular users (P = .95). But among patients with altered PIK3CA, regular NSAID use conferred a 5-year overall survival advantage of 33% (78% in regular users vs 45% for nonregular users; P = .0043).
PIK3CA alteration was also associated with poorer overall survival among patients who did not regularly use NSAIDs (P = .014).
Mechanisms Explored
Grandis and colleagues tested their findings using in vivo HNSCC models of mice harboring six distinct patient-derived xenografts that endogenously expressed either wild-type or mutated PIK3CA. They found that NSAIDs also reduced the growth of tumors in mice harboring a mutant PIK3CA gene. In analysis, they found that NSAIDs likely inhibited tumor growth by reducing the production of prostaglandin E2. Implicated in a variety of cancers, prostaglandin E2 can be induced by the PI3K signaling pathway. Therefore, NSAIDs could also improve outcomes in other types of cancer that contain activating mutations in the PIK3CA gene.
"The present study is the first to demonstrate that regular NSAID usage confers a significant clinical advantage in patients with PIK3CA-altered HNSCC," said Grandis. "Inconsistencies in the type, timing, and dosages of NSAIDs taken by patients in this study limit our ability to make specific therapeutic recommendations.
"But the magnitude of the apparent advantage, especially given the marked morbidity and mortality of this disease, warrants further study in a prospective, randomized clinical trial," she added.
Funding for the study was provided in part by the National Institutes of Health and the American Cancer Society. The authors and Bakst have disclosed no relevant financial relationships.
J Exp Med. Published online January 25, 2019. Full text
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