Abstract 925: Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian cancer

Abstract

Abstract Epithelial Ovarian Carcinomas (EOC) frequently present as late stage malignancies. Because of this lengthy, clinically silent period, a significant number of mutations may accumulate with each emerging clonal population. After surgical removal and chemotherapy, recurrent disease may still occur. Opting for hormonal therapy is a treatment consideration for those patients who have asymptomatic recurrence or, if they are not tolerating treatment well, may require a break from chemotherapy. However, because of the aggressive nature of EOC, hormonal treatment should be administered only if it will provide some efficacious benefit. The active metabolite of Tamoxifen (OH-tamoxifen) can function as a hormonal antagonistic agent to estrogen driven EOCs. However, single nucleotide variations and/or mutations in the ligand binding domain (LBD) of the estrogen receptor alpha (ESR1) gene may negatively affect the ability of OH-tamoxifen to bind and effect its desired action, resulting in wasted time and treatment. Identification of nucleotide variants/ mutations in the ESR1 LBD may be of clinical importance by identifying patients with EOC who may be better suited for treatment with other agents. In this study we identified twelve cases of ESR1(+) EOC in which the treating clinician had requested immunohistochemical confirmation of ESR1 expression. Four separate primer pairs were designed to encompass the amino acids responsible for OH-tamoxifen binding identified from a previous crystallography study. These same regions responsible for binding OH-tamoxifen were also queried in the dbSNP database for nucleotide variations. Representative tissue blocks with >80% tumor content were selected from each case. DNA was extracted from formalin fixed, paraffin embedded tissue sections and subjected to the polymerase chain reaction creating 48 different samples. The resulting amplicons were purified and sequenced, followed by basic local alignment analysis to the most recent NCBI homo sapien gene annotation for the ESR1 gene. No variants were identified in the dbSNP database for the regions of interest. Our results found only one silent nucleotide variation which was located in exon 10. Prior to this study the justification for using tamoxifen in EOC was empiric. Our results indicate that the absence of nucleotide variations in the critical ESR1 LBD for OH-tamoxifen provide scientific evidence and support for its’ continued usage as an optional treatment modality in ESR1(+)EOC. Citation Format: Wilfrido Mojica, Paul Mojica, Don Sykes. Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 925. doi:10.1158/1538-7445.AM2014-925