Genetic variations in chemotherapy drug action pathways modulate therapeutic response in esophageal cancer

Proc Amer Assoc Cancer Res, Volume 46, 2005 6167 Elucidating the role of genetic variants in critical drug action pathways may provide informative blueprints for optimizing individualized chemotherapy. In this study, we genotyped 235 patients with resectable adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction. Patients were treated with concurrent chemoradiotherapy followed by surgery, or induction chemotherapy followed by concurrent chemoradiotherapy and then surgery. We determined frequencies of polymorphisms in more than 40 genes in pathways relevant for the activity or disposition of platinum analogs, 5-FU and taxols, including drug metabolism, multidrug resistance, cell uptake, cell cycle checkpoints and apoptotic pathways. We then correlated these genetic markers with clinical outcomes, including complete pathologic response, recurrence and survival. Using Cox proportional hazards regression models, we found that in patients treated with 5-FU, the 5,10-methylenetetrahydrofolate reductase ( MTHFR) 1298 AC+CC genotypes were associated with significantly improved survival with a hazard ratio (HR) of 0.56 (95% CI: 0.35 - 0.87) as compared to those with the AA genotype. Using Kaplan-Meier survival curves, carriers of the MTHFR 1298 AC+CC genotype exhibited significantly longer survival (median survival of 51.30 months) compared to patients with the AA genotype (median survival of only 25.37 months, p=0.01). When combining the MTHFR (C677T), MTHFR (A1298C), thymidylate synthase(TS) +157, TS +227and 5-methyltetrahydrofolate-homocysteine methyltransferase ( MTR) D919G g enotypes, there was evidence of improved survival as the number of putative protective alleles increased ( P <0.05). For patients treated with platinum analogs, the MDR1 I1144M variant genotype was associated with reduced recurrence rate (HR=0.16, 95% CI: 0.05-0.55) and improved survival (HR=0.32 95% CI: 0.14-0.72), a pattern more evident when we combined the two MDR1 gene polymorphisms ( S892A and I1144M ), (P<0.05). In addition, we found that variant genotypes of the base excision repair gene, XRCC1 (R399Q) , and oxidative damage repair gene, OGG (S326C) , both involved in the radiotherapy response pathway, were associated with reduced complete pathologic response with HRs of 2.54 (1.15-5.64) and 2.21 (1.06-4.60), respectively. Our results support the concept that genetic profiles can be used to predict treatment response and assist in developing tailored chemotherapeutic regimens in esophageal cancer. Supported by NCI grants CA 74880 and CA 91846, and an M.D. Anderson Cancer Center MRP grant for esophageal cancer.