Analysis of polymorphisms in sodium channel, voltage-gated, type I, alpha subunit (SCN1A) as predictors of clinical outcome and toxicity in advanced ovarian cancer patients enrolled in a phase III trial treated with patupilone.

Abstract

5051 Background: Patupilone (P) is a potent member of a class of microtubule-stabilizing cytotoxic agents known as epothilones. Recently, a phase III trial fail to show a significant overall survival advantage in platinum refractory recurrent ovarian, primary fallopian tube and primary peritoneal cancer patients (pts) treated with P compared to pegylated liposomal doxorubicin (PLD). Our previously data demonstrated 2 SCN1A polymorphisms [T1067C (rs2298771) and IVS5_91 (rs3812718)] were associated with clinical outcome and toxicity in mCRC pts enrolled in a phase II study treated with Celebrex and P. Here we tested the hypothesis whether these 2 SCN1A polymorphisms may predict clinical outcome and toxicity in advanced ovarian cancer pts enrolled in a phase III trial. Methods: A total of 829 pts enrolled into P clinical trial between Nov 2005 and Feb 2010. 347 pts’ extracted DNA samples were available for current pharmacogenetic study. 181 samples came from P arm, and the other 166 came from PLD arm. The clinical and pathological characteristics of these 347 pts were not statistically significantly different from pts (n=482) enrolled in the trial but no DNA samples available. PCR-based direct sequencing was performed on genomic DNA samples. Results: In univariable analysis, pts with SCN1A 1067 TT genotype (n=86) had trend shorter median OS=10.7 (95% C.I 8.1, 12.8) months compared to pts harboring C allele (TC+CC) (n=94), median OS=15.3 (95% C.I 11.6, 17.9) months (HR: 0.72, 95% C.I 0.51, 1.02; P=0.059, log-rank test). In combined haplotype (T1067C/IVS5_A91G) analysis, pts with C/G haplotype had lowest risk of dying (HR 0.741(95% C.I 0.555, 0.991) compared to T/A and T/G haplotype. (p=0.043, Wald test). Also, pts with T/G haplotype had lowest grade 3-4 diarrhea risk (HR 0.476(95% C.I 0.234, 0.966) compared to T/A and C/G haplotype (p=0.04,Wald test). Conclusions: Our preliminary results suggest germline polymorphisms in SCN1A gene may be associated with overall survival and toxicity in advanced ovarian cancer pts treated with P. Prospective trials based on these correlative studies are warranted.