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NSAIDs May Up Survival in Certain Head and Neck Cancers

Regular use of common nonsteroidal anti-inflammatory drugs (NSAIDs) may buy time for patients with head and neck cancers with alterations in the PIK3CA gene, according to a retrospective study.

In patients with PIK3CA mutations or amplification, overall survival (OS) was significantly prolonged (HR 0.31, 95% CI 0.14-0.69, P=0.0043) for those who used NSAIDs regularly for at least 6 months after curative treatment, reported Jennifer Grandis, MD, of the University of California, San Francisco, and colleagues.

Disease-specific survival (DSS) was also prolonged (HR 0.23, 95% CI 0.09-0.62, P=0.0032) in these patients compared with non-regular NSAID users, and the effect held regardless of human papillomavirus (HPV) infection, they wrote in the Journal of Experimental Medicine.

The findings came from a biobank-based study of 266 head and neck squamous cell carcinoma (HNSCC) patients at the University of Pittsburgh Medical Center. For patients with PIK3CA-altered HNSCC, the study found a predicted 5-year DSS rate of 72% for NSAID users versus 25% for nonusers, while the predicted 5-year OS rate was 78% for regular NSAID users and 45% for nonregular users.

Using preclinical models, the researchers found that PIK3CA mutation predicted sensitivity to NSAIDs in association with increased systemic prostaglandin E2 (PGE2) production, suggesting a plausible biological rationale for implementing NSAID therapy in PIK3CA-altered HNSCC.

“We conclude that regular NSAID use likely confers a statistically and clinically significant advantage in DSS as well as OS in patients with PIK3CA-altered HNSCC, irrespective of HPV status, through direct interaction between the PI3K and COX [cyclooxygenase] pathways,” Grandis and co-authors wrote.

They noted that regular NSAID use has appeared to be protective against HNSCC incidence in several epidemiological studies, including a 2013 study that used data from the National Cancer Institute’s Prostate, Lung, Colorectal, and Ovarian screening trial. And the protective effect of NSAIDs in colon cancer has long been noted.

“Our experimental evidence is in line with the hypothesis that genomic alteration of PIK3CA upregulates PGE2 secretion, which in turn stimulates cellular proliferation. This autocrine regulatory pathway results in differential susceptibility to COX targeting by NSAIDs,” Grandis and associates said.

Study Details

The study was based on tumor samples and electronic health records drawn from the patients who had undergone curative surgical resection of HNSCC during 2008 to 2013. Most patients had received adjuvant therapy as well. Overall, 73% of the total were male, 25% were HPV-positive, and 84% had a history of smoking. The median age at surgery was 60, and tumor sites included the oral cavity, oropharynx, hypopharynx, and larynx. NSAIDS, primarily baby aspirin, were consumed for other medical reasons such as cardiovascular disease (CVD) protection.

Among the 75 patients with altered PIK3CA, 50 reported no or some NSAID use and 25 reported regular use. Among the 191 with wild-type PIK3CA, 117 reported no or some use, while 74 reported regular use. The majority (67%) of the cohort received adjuvant chemotherapy, radiotherapy, or both, and these therapies did not impact the effect of NSAIDs on PIK3CA outcomes.

Among the 99 regular NSAID users, the most common NSAID used was aspirin (74%), followed by ibuprofen (24.2%), naproxen (7.1%), and celecoxib (3.0%). Less commonly consumed NSAIDs by the participants included rofecoxib, diclofenac, meloxicam, indomethacin, and oxaprozin.

“The finding shows that these cheap and relatively low-risk drugs have potential overlapping benefits for the CVD and [head and neck cancer] age group and a selective benefit in [head and neck cancer] where there is this mutation,” study co-author Robert L. Ferris, MD, of the University of Pittsburgh School of Medicine, said in an interview.

“So should oncologists routinely screen for this mutation? I’d prefer to use these data to design a randomized trial to understand the target of the NSAIDs,” he continued. “The question is, do NSAIDs benefit by reducing PGE2, which drives cancer cell growth and suppresses immunity, or does the PIK3CA mutation have an extrinsic effect on the surrounding immune system, which the NSAIDs block? There’s more than one way to skin the cat,” Ferris said.

Another question possibly worth addressing, he said, is whether an NSAID might work synergistically in patients with a PI3K inhibitor such as buparlisib. For now, Ferris said, oncologists treating HNSCC patients might consider testing for PIK3CA mutation later — say, at the recurrence stage, and if it is present, possibly add an NSAID to treatment.

Grandis told MedPage Today that since no drug is completely safe and head and neck cancers are biologically idiosyncratic, it would be premature to start broadly prescribing baby aspirin on the basis of this retrospective study. But, she said, “if a family member had head and neck cancer, I’d get the tumor sequenced and if it was positive, I’d tell him to take a baby aspirin.”

Based on the current study and preclinical studies using four different NSAIDs, there is no indication that any one NSAID is more protective than another, she noted.

Her group is currently planning two trials in this area. In the first, patients who have had curative therapy will have their primary tumors tested for altered PIK3CA, and if positive, they will be randomized to placebo or baby aspirin for 2 years. “I prophesy that at the end of 2 years we will see a different disease-specific survival in people with the alteration in the baby aspirin arm,” Grandis said.

In a second trial, patients will receive a COX2 inhibitor before curative surgery. Investigators will then examine whether the NSAID has both a favorable impact on the immune system and a direct anti-tumor effect.

Ferris noted that the study’s observations are an interesting example of how electronic records data can drive new clinical investigation.

The investigators were supported by the National Institutes of Health, the American Head and Neck Society, the Foundation for Cancer Research, the American Cancer Society, and the Department of Veterans Affairs.

Grandis and co-authors reported having no competing interests.


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