Abstract
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.
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