Abstract 5483: CYP19A1 genetic variation is a potential predictor of outcome in ER-positive postmenopausal early breast cancer patients treated with tamoxifen

Abstract

Abstract Tamoxifen is a selective estrogen receptor modulator which blocks estrogen from binding to the estrogen receptor (ER). Although estrogens are natural hormones vital for development, they are also critical growth factors responsible for cell proliferation and DNA synthesis, thus enhancing the growth of estrogen-responsive breast tumors. With breast cancer being the most frequent cancer in women, the carcinogenic effects of estrogen are mediated by ER which is expressed in approximately 75% of all tumors. Hence tamoxifen is commonly used to treat patients with ER-positive breast cancer. Our group has a long standing interest in the investigation of potential tamoxifen outcome predictors as up to 33% of treated patients relapse or dies at 15 years of follow up. Therefore it is crucial to determine which patient will benefit from tamoxifen or not. In a pilot study of 915 patients, we previously identified a single nucleotide polymorphism (SNP) at the aromatase gene (CYP19A1) which could potentially predict the outcome of postmenopausal patients treated with tamoxifen. Aromatase is a key enzyme in the estrogen biosynthesis pathway and in postmenopausal women, estrogen levels are low with the aromatase being responsible for estrogen synthesis from adipose tissue following the cessation of ovarian function. Therefore any alterations in aromatase function may affect the inhibitory capacity of tamoxifen for estrogen at the ER, resulting in variation of outcome in patients treated with tamoxifen. We hypothesized that genetic variation in CYP19A1 may influence aromatase expression and function, thus affecting the outcome of ER-positive postmenopausal early breast cancer patients treated with tamoxifen. Genotyping was conducted on 55,540 breast cancer patients from 50 studies with the custom Illumina Infinium array (iCOGS) by the Breast Cancer Association Consortium. More than 200,000 SNPs were genotyped of which 89 SNPs are located in the CYP19A1 genomic region. We included patients that are female with European ancestry, available follow up and vital status, invasive breast tumor, ascertained for their first tumor, stage I-III disease, postmenopausal, ER-positive, right truncation at 15 years of follow up, left censoring for study entry and those treated with tamoxifen. Furthermore, studies with less than 10 events for relapse or death were excluded leaving a total of 1313 patients for outcome analyses with distant metastasis-free survival as the endpoint. We identified rs7172156 being associated with poor outcome of which carriers of the minor A allele had a higher risk of distant metastasis or death (P = 0.007). Multivariate Cox regression stratified by study and adjusted for age, node status, tumor size and grade confirmed this observation (HR = 1.30, 95% CI 1.00-1.68, P = 0.049). Our data suggest that rs7172156 could be clinically relevant as a tamoxifen outcome predictor in early breast cancer. Citation Format: Wing-Yee Lo, Werner Schroth, Reiner Hoppe, Marjanka Schmidt, Montserrat Garcia-Closas, Paul Pharaoh, Per Hall, Douglas Easton, Peter Fasching, Hiltrud Brauch, in collaboration with the Breast Cancer Association Consortium. CYP19A1 genetic variation is a potential predictor of outcome in ER-positive postmenopausal early breast cancer patients treated with tamoxifen. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2015-5483