Potential role of MAD1 1673G>A and ERCC1 8092C>A polymorphisms in the resistance to chemotherapy in advanced ovarian cancer: A pilot study.

Abstract

e17045 Background: Ovarian cancer (OC) is the most lethal gynecological cancer and 70% of cases are in advanced stages at diagnosis. The standard treatment for those stages is optimal cytoreduction plus chemotherapy based on carboplatin-paclitaxel. Nevertheless, 60%-70% of patients will progress after diagnosis, becoming resistant in some point of the disease. There are no biomarkers to predict response to chemotherapy in OC. Some polymorphisms, including MAD1 1673G > A and ERCC1 8092C > A have shown potential to predict chemoresistance in other tumors. Thus, we explored the role of these polymorphisms in the resistance to chemotherapy in advanced OC. Methods: We genotypified 89 OC patients samples, and also determined the mRNA expression for both genes by RT-PCR. We compared distributions using chi-squared test and determined differences in overall survival and free-relapse survival using Kaplan-Meier curves and log-rank test. Results: Most of cases were IIIC stage (35.48%), papillary histological subtype (32.26%), highly differentiated (67.74%), and 35.48% tumors with recurrence. Distribution for MAD1 genotype was 35.48% for wild-type (WT), 32.26% for heterozygous (HT), and 32.26% for homozygous polymorphic condition (Poly). For ERCC1, we found a distribution of 25.81% for WT, 51.61% for HT, and 22.58% for Poly. When comparing distributions, we found statistically significant differences between sensitive vs. resistant tumors ( p= 0.02), with lack of the WT condition for ERCC1 in sensitive tumors. When analyzing haplotypes in regard to platinum-sensitivity, we also found statistical differences in the distribution of haplotypes ( p = 0.02). No association between genotypes and expression was observed. Remarkably, we found a lower free-relapse survival in the presence of at least one WT allele for the MAD1 polymorphism (p = 0.021, log-rank test). Conclusions: In this pilot study, we have found that ERCC1 8092C > A polymorphism, as well as haplotypes for these two genes, could be associated with chemoresistance. MAD1 1673G > A polymorphism could play also a role in recurrence in advanced OC.