62PA exon polymorphism rs700519 (R264C) at CYP19 gene locus is associated with the efficacy of adjuvant letrozole in Indian breast carcinoma patients

Background: Aromatase Inhibitors of the third generation, such as anastrozole, exemestane, and letrozole have been the standard adjuvant therapy for the treatment of HR+ breast cancer (BC) in postmenopausal women. These agents are proven to be effective over tamoxifen therapy in the treatment of breast cancer both in adjuvant and metastatic settings in terms of disease-free survival and adverse events. Intriguingly, in spite of these advances as anti-aromatase compounds, a significant proportion of tumor demonstrates resistance with AIs medication. Therefore, we sought to determine the influence of genetic variations in CYP19 gene on adjuvant letrozole efficacy in hormone receptor positive (HR+) postmenopausal BC. Methods: Genomic DNA was isolated by routine standard phenol-chloroform method from peripheral blood. Genotyping of CYP19 gene polymorphisms was carried out by specific TaqMan genotyping assay on RT-PCR system. The patients were followed up until there was evidence of disease recurrence or death. Data was analyzed by SPSS v19.0. Results: The mean age of the study cohort was 56, range 34 to 85. Out of 191 patients analyzed, 16 (8.4%) of them had both loco regional and distant recurrence of BC. There was a significant difference in the frequency of variant allele 'T' of rs700519 polymorphism (15.6% vs. 35.4%) between recurrence and non-recurrence groups (OR 0.33, 95% CI 0.12-0.90, P = 0.03). A similar trend of association was observed under co-dominant 1 (OR 0.23, 95% CI 0.06-0.87, P = 0.02), dominant (OR 0.24, 95% CI 0.07-0.78, P = 0.01) and additive (OR 0.24, 95% CI 0.08-0.7, P = 0.009) genetic models. Additionally, Kaplan-Meier estimates indicate that the patients carrying heterozygous condition (CT) of rs700519 polymorphism had significantly longer recurrence free survival (log rank P < 0.04). Conclusions: Our results given initial evidence that the polymorphisms of CYP19 gene might be an important pharmacogenetic marker in individualizing letrozole treatment in Indian HR+ BC patients. Disclosure: All authors have declared no conflicts of interest.