Predictive Biomarkers and Personalized Medicine Genetic Variants in the PI3K/PTEN/AKT/mTOR Pathway Predict Head and Neck Cancer Patient Second Primary Tumor/Recurrence Risk and Response to Retinoid Chemoprevention

Purpose: The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC) patients. The 13-cis-Retinoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in thePI3K/PTEN/AKT/mTORpathway could serve as biomarkers to identifywhich patients are at high risk of an SPT/recurrence, while also predicting response to 13-cRA chemoprevention. Experimental Design: A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data. Results: Twenty-two genetic loci were associated with increased SPT/recurrence risk, with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/ high-benefit loci identified a significant (P 1⁄4 1.54 10 ) dose–response relationship for SPT/recurrence risk,withpatients carrying four tofivehigh-risk genotypes having a3.76-fold [95%Confidence Interval (CI), 1.87–7.57] increase in risk in the placebo group (n 1⁄4 215). Patients carrying four to five high-risk loci showed themost benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95%CI, 0.13–0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables. Conclusions: These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients. Clin Cancer Res; 1–9. 2012 AACR.