Role Of Pharmacogenetics In Metastatic Breast Cancer (Mbc) Patients Treated With Exemestane As First-Line Hormonal Therapy. An Italian Multicentre Study

Background: In a subset of MBC patients exemestane is not effective. Single Nucleotide Polymorphisms (SNPs) of genes involved in estrogen availability, in pharmacokinetics (PK) and pharmacodynamics (PD) of exemestane could be responsible for responsiveness. CYP19A1_Ex11+410A/C – rs4646 was found to correlate with improved overall survival in patients treated with letrozole(1) and anastrozole (2). Methods: This multicentre study enrolled 423 patients with diagnosis of MBC or locally advanced-ER-positive breast cancer treated with exemestane as first-line hormonal therapy (prior adjuvant therapy and chemotherapy for metastatic setting were admitted). Objective of the study was to prospectively assess the predictive role of polymorphisms in aromatase gene, in particular CYP19A1_Ex11+410A/C – rs4646, and in genes involved in the PK and PD of exemestane on drug’s activity (Response Rate - RR, time to progression - TTP). The correlation between SNPs and RR was assessed by the Fisher9s exact test two-way. The CYP19A1_Ex11+410A/C – rs4646, CYP1B1*3_4326G/C (rs1056836) and other not pre-planned polymorphisms were analyzed. Moreover, in a subset of patients, PK and PD analysis were also performed. Results: At present time we report the preliminary results on 196 patients. Among these patients, CYP19A1_Ex11+410A/C – rs4646 SNP shows no significant association with RR, whereas in patients carrying at least one variant allele of CYP1B1*3_4326G/C (rs1056836) polymorphism, a statistically significant association with a better response to exemestane was found (dominant model: OR =.436, 95% CI =.21 to .89, p = .029; Clinical benefit, dominant model: OR =.362, 95% CI =.17-0.75, p = .007, Fisher9s Exact Test in accordance with the two-way). The same SNP seems, in the pharmacodynamic analysis, to be associated with the level of estrogen suppression (p =.0508 according to the Kruskal-Wallis ANOVA) and associated to better RR (p =.0287; Clinical B benefit: p =.0209 according to the Wilcoxon-Mann-Whitney test), providing a basis for phenotypic association. The overall results on the entire cohort of patients enrolled are under evaluation as well as the data concerning TTP, toxicity and the correlation with PR, HER2 and Ki67 tumor tissue expression. Conclusions: A predictive role of the CYP1B1*3_4326G/C (rs1056836) polymorphism for RR to exemestane as first- line therapy has been found. Our study suggests that a simple genetic evaluation from peripheral blood, performed prior to therapy, may allow the identification of the patients who are more likely to be responsive to exemestane. Citation Format: Sara Gagno, Mauro Mansutti, Daniele Rossini, Diana Crivellari, Chiara Zanusso, Silvana Saracchini, Donata Sartori, Giampietro Gasparini. Role of pharmacogenetics in metastatic breast cancer (MBC) patients treated with exemestane as first-line hormonal therapy. An Italian multicentre study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-05.