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

• Type of Material: Article
• Authors: Michelle A. T. Hildebrandt, University of Texas MD Anderson Cancer Center; Scott M. Lippman, University of Texas MD Anderson Cancer Center; Carol J. Etzel, University of Texas MD Anderson Cancer Center; Edward Kim, University of Texas MD Anderson Cancer Center; J. Jack Lee, University of Texas MD Anderson Cancer Center; Fadlo Khuri, Emory University; Margaret R. Spitz, Baylor College of Medicine; Reuben Lotan, University of Texas MD Anderson Cancer Center; Waun Ki Hong, University of Texas MD Anderson Cancer Center; Xifeng Wu, University of Texas MD Anderson Cancer Center
• Language: English
• Date: 2012-07-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2012 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-11-3271
• Title of Journal or Parent Work: CLINICAL CANCER RESEARCH
• Volume: 18
• Issue: 13
• Start Page: 3705
• End Page: 3713
• Grant/Funding Information: This work was supported by the National Institutes of Health CA52051 to W.K.H., CA97007 to W.K.H. and S.M.L., and CA86390 to M.R.S.
• Keywords: SQUAMOUS-CELL CARCINOMA; ACTIVATION; Oncology; TARGET; PRIMARY TUMORS; Life Sciences & Biomedicine; DOWN-REGULATION; ISOTRETINOIN; PREVENTION; KINASE PATHWAY; STAGE; Science & Technology; STATISTICS
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

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 the PI3K/PTEN/AKT/mTOR pathway could serve as biomarkers to identify which 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 = 1.54 × 10 -4) dose-response relationship for SPT/recurrence risk, with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87-7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most 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.