Explore This IssueAugust 2019
What is the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on disease-specific survival (DSS) and overall survival (OS) in patients with PIK3CA-characterized head and neck squamous cell carcinoma (HNSCC), and what mechanism is involved?
Regular NSAID use likely confers a statistically and clinically significant advantage in DSS and OS in patients with PIK3CA-altered HNSCC.
Background: Regular use of aspirin has been found to be protective against HNSCC development, but there have been inconsistent findings regarding the potential survival benefit of NSAIDs. Activating mutations in PIK3CA, the gene encoding p110α, the catalytic subunit of phosphoinositide-(3)-kinase α (PI3Kα), are common in HNSCC, with 35% of tumors harboring PIK3CA mutation or amplification.
Study design: Electronic medical record review of a cohort of 266 PIK3CA-characterized HNSCC patients, followed by in vivo mouse modeling.
Setting: Department of Otolaryngology, University of Pittsburgh School of Medicine, Penn.
Synopsis: Regular NSAID use was identified in 33% of patients with PIK3CA-altered tumors and 39% of those with WT cells, unamplified PIK3CA. DSS among WT, unamplified PIK3CA patients was unaffected by regular NSAID use, but regular NSAID use was strongly associated with improved DSS for MT and/or amplified PIK3CA patients. Among patients with altered PIK3CA, regular NSAID users had an absolute five-year DSS advantage of 47%. Among patients with altered PIK3CA, regular NSAID users had an absolute five-year OS advantage of 33%. Findings were tested using in vivo HNSCC models. Mice harboring six distinct patient-derived xenografts (PDXs) endogenously expressing either MT or WT PIK3CA were treated with saline or the NSAIDs sulindac, celecoxib, or aspirin followed by assessment of tumor growth. Sulindac, celecoxib, or aspirin treatment reduced the growth rates of MT PIK3CA tumors compared with vehicle-treated tumors, but not PIK3CA WT tumors. Sulindac treatment led to significantly greater reduction in prostaglandin E2 (PGE2) secretion in cells overexpressing MT versus WT PIK3CA. Limitations included NSAID use determination defined through prescription refill records and patient self-reporting, cohort size, particularly among subgroups, and inconsistencies in the type, timing, and dosages of NSAID therapy.
Citation: Hedberg ML, Peyser ND, Bauman JE, et al. Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer. J Exp Med. 2019;216:419–427.