A multi-gene algorithm as predictor of response to chemo-radiotherapy in head and neck cancer

Abstract

10086 Background: Chemo-radiotherapy results in clinical cure for stage III/IV head and neck cancer in approximately 40% of cases, with significant treatment-associated morbidity and mortality. Molecular genetic factors predictive of treatment outcome would clearly be of value in selection of patients with highest probability of response. We have analysed the structure and epigenetic regulation of specific genes as possible predictors of outcome to chemo-radiotherapy. The genes analyzed were: p53 (single nucleotide polymorphism (SNP) and mutation), MDM2 (SNP), Chfr (methylation), CRABP1 (methylation). Methods: 84 patients with locally advanced head and neck cancer receiving cisplatin-based chemo-radiotherapy were studied. SNP genotypes were determined by direct sequencing of DNA from normal tissue. Acquired mutations in p53 and aberrant methylation in the CpG islands of specific genes were analyzed by direct sequencing and methylation-specific PCR. Results: There were 6 treatment-related deaths in 84 patients, all occurring in cases with germ-line haplotype p53 72 Arg/Arg, MDM2 309T/T. At the time of analysis, 39/84 (46%) patients had progressed or died, with median time to progression or death = 17.3 months. Complete response was more common in patients whose genetic/epigenetic profile was p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to the profile p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (91% vs 46%, log rank p = 0.002). Progression-free survival was significantly longer for patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to those with p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (% surviving progression-free at 2 years = 74% vs 36%, p = 0.001). Overall survival was significantly longer in patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated compared to those with p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (% surviving at 2 years = 88% vs 40%, p = 0.0004). Conclusions: Genetic and epigenetic parameters influence the toxicity and clinical outcome of chemo-radiotherapy in head and neck cancer. No significant financial relationships to disclose.