Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients

Abstract

Objective Platinum-based chemotherapy exerts its cytotoxic effect by forming DNA adducts and subsequently inhibiting DNA replication. Removing platinum DNA adducts requires the nucleotide excision repair (NER) pathway. The xeroderma pigmentosum (XP) complementation group of genes plays an essential role in the NER pathway. We hypothesized that genetic polymorphisms in XP genes may predict clinical response to platinum chemotherapeutic treatment and survival in women with gynecological cancers. Method We genotyped 146 cases of advanced epithelial ovarian cancer for XP gene polymorphisms using the PCR-RFLP method. Kaplan–Meier plots and the log-rank test were used to assess associations between survival and recurrence-free interval and the XP gene polymorphisms. Hazard ratio of response was estimated from an adjusted multivariate Cox proportional hazard model. Results Women with a heterozygous variant XPA allele had shorter median survival (21.5 months, P = 0.03) and shorter median time to recurrence (11.3 months, P = 0.05) than women with the homozygous wild-type allele (37.9 and 13.9 months, respectively). Women with a homozygous variant XPG allele had significantly shorter median survival (8.3 months, P = 0.006) compared with women with the homozygous XPG wild-type allele (24.6 months). Polymorphisms in XPC, XPD exon10, and XPD exon23 were associated with a decreased risk of recurrence and death, but were not statistically significant. Conclusions This study suggests that NER gene polymorphisms may correlate with recurrence and patient survival. A larger sample size is needed to assess platinum chemotherapy response with these polymorphisms. These findings may help identify subgroups of cancer patients likely to benefit from individualized treatment strategies. Our next study will examine NER gene polymorphisms in cervical cancer patients.