Background: Single nucleotide polymorphisms (SNPs) of the aromatase enzyme (CYP19A1) and estrogen receptor alpha (ESR1) may be associated with breast cancer susceptibility and endocrine-mediated side effects. The IBCSG Tamoxifen (Tam) and Exemestane (Exe) Trial (TEXT) includes a translational research project to assess whether selected SNPs may influence treatment efficacy and toxicity. We report on early-onset hot flashes and sweating (HF/S) and musculoskeletal symptoms (MS; myalgia, arthralgia, stiffness) with respect to CYP19A1 and ESR1 SNPs under combined endocrine therapy.

Patients and Methods: 2,672 premenopausal women with HR+ early breast cancer were randomized to treatment with the GnRH-agonist triptorelin (Trip)+Tam or Trip+Exe for 5 years. Randomization was stratified according to intended use of chemotherapy (yes/no) and lymph node status (N- vs N+). Estrogen-depletion side effects (HF/S and MS) were recorded at baseline, 3-monthly during the first year and 6-monthly thereafter using the NCI CTCAE v3.0. DNA was centrally extracted from whole blood with Qiagen kits. SNPs of CYP19A1 (rs4646 and rs10046) and ESR1 (rs207764, rs2234693 and rs9340799) were analyzed by a pyrosequencing method (Diatech Pharmacogenetics S.r.l., Jesi, Italy). Control genotypes (wt/wt; wt/v; v/v) for all SNPs were processed in each run. Logistic regression was used to analyze two endpoints: presence or absence of grade (gr) 2-3 HF/S during first 6 months and gr 2-4 MS during first 12 months. Four genetic models were used to explore associations with side effects: genetic (wt/wt; wt/v; v/v), additive, dominant and recessive.

Results: DNA was isolated and genotyped for 1970 (74%) consenting women. Clinical characteristics and outcomes of this cohort were consistent with the overall trial. At baseline median age was 44, median BMI 24 kg/m2 and 86% had regular menses. During follow-up, 43% reported gr 2-3 HF/S and 27% reported gr 2-4 MS. The 5 SNPs did not deviate from Hardy-Weinberg equilibrium (p>0.30) and minor allele frequency ranged from 29%-48%. The CYP19A1 SNP rs10046 (C>T) was associated with gr 2-3 HF/S. Specifically, women with variant homozygote genotype (T/T) had a reduced risk of HF/S (39% T/T vs 45%). The univariate odds ratio (OR) was 0.77 (95%CI: 0.62-0.96; p=0.02) compared with other variant groups. The multivariate model showed consistent results after adjusting for age, BMI, menstrual status, chemo use, treatment allocation (Tam vs Exe) and baseline HF/S. The other 4 SNPs were not associated with the selected side effects.

Conclusions: Our analysis indicates association of HF/S with CYP19A1 rs10046 genetic variants. The lack of association between early-onset of selected estrogen-depletion side effects and the other 4 SNPs may be masked by the concurrent Trip. Ovarian reserve before treatment may also influence the impact of SNP genotypes on early-onset side effects. Further analysis with details of concurrent medications and treatment adherence will contribute to the interpretation of these results.

Funded by Susan G. Komen for the Cure.

Citation Format: Harriet Johansson, Kathryn P Gray, Olivia Pagani, Meredith M Regan, Giuseppe Viale, Valentina Aristarco, Debora Macis, Antonella Puccio, Susanne Roux, Rudolf Maibach, Marco Colleoni, Manuela Rabaglio-Poretti, Alan S Coates, Richard D Gelber, Aron Goldhirsch, Roswitha Kammler, Bernardo Bonanni, Barbara A Walley. CYP19A1 and ESR1 polymorphisms and selected early-onset side effects during combined endocrine therapy in the IBCSG TEXT trial for premenopausal women with hormone receptor-positive (HR+) early breast cancer [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 P1-12-01.