Abstract B94: Pharmacogenetics of retinoid chemoprevention in head and neck cancer patients: Modulation of response by common genetic variation in the mTOR signaling pathway
Authors: Hildebrandt Michelle A.T. , Lippman Scott M. , Kim Edward , Lee J. Jack , Khuri Fadlo , Spitz Margaret R. , Lotan Reuben , Hong Waun Ki , Wu Xifeng 
Published: May 2012

Patients diagnosed with early stage head and neck squamous cell carcinoma (HNSCC) have a high risk of developing second primary tumors (SPT) or recurrence following curative purpose therapy. To prevent these occurrences, several chemoprevention agents have been developed, including 13-cis-retinoid acid (13-cRA). However, results from clinical trials have remained inconclusive and suggest that biomarkers may be needed to select patients who will receive benefit from therapy. The mTOR signaling pathway plays a major role in the regulation of cell growth, cell survival, and apoptosis. We hypothesized that genetic variation in this pathway may serve as prognostic factors for the development of SPT/recurrence and affect response to chemoprevention therapy. We genotyped 137 SNPs from genes within this pathway in 450 HNSCC patients who received 13-cRA or placebo as part of the Retinoid Head and Neck Second Primary Trial. Genotypes were then analyzed for association with risk of SPT/recurrence to identify biomarkers for prognosis and treatment response. Twenty-two genetic loci were significant prognostic factors for SPT/recurrence in the placebo treatment group. Of these, nine were SNPs within the tuberous sclerosis 1 (TSC1) gene and most often resulted in an increased SPT/recurrence risk for the majority of patients carrying the wild-type genotype. Two of these alleles (rs4962225 and rs7035940) were in strong linkage disequilibrium and resulted in a high risk of SPT/recurrence (HR: 1.92, 95% CI: 1.15–3.23) and a significant 18 month survival disadvantage (Log-rank P = 0.026) in those carrying the wild-type genotype. These results indicate that this locus may be a potential target for chemoprevention. Intriguingly, although 13-cRA did not show a reduction in SPT/recurrence risk overall, response to this therapy was significantly different depending on the patient's genetic background for these potential targets. A significant modulation of SPT/recurrence risk in those who received 13-cRA was observed for seven of the prognostic TSC1 SNPs. The majority of the population with the wild-type genotype were conferred the protective effect of 13-cRA, indicating that the high-risk group for SPT/recurrence were being effectively treated by this chemoprevention intervention. Individuals carrying the wild-type genotype for either TSC1 rs4962225 or rs7035940 were at a 43% reduced risk (95% CI: 0.37–0.88). However those who carried at least one variant allele did not receive the benefit of 13-cRA treatment and were at an increased risk (HR: 1.91, 95% CI: 1.10–3.32). These results indicate that genetic variation within the mTOR pathway, particularly TSC1, could potentially be used to better identify patients who are at high-risk of SPT/recurrence and also those who are candidates for chemoprevention therapy based on their favorable genetic background.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B94.