Harriet Johansson et al., Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial. Breast Cancer Research

Harriet Johansson¹, Kathryn P. Gray², Olivia Pagani^3,4,5, Meredith M. Regan⁶, Giuseppe Viale⁷, Valentina Aristarco¹, Debora Macis¹, Antonella Puccio¹, Susanne Roux⁸, Rudolf Maibach⁸, Marco Colleoni¹, Manuela Rabaglio⁹, Karen N. Price^9,10, Alan S. Coates¹¹, Richard D. Gelber¹², Aron Goldhirsch¹³, Roswitha Kammler¹⁴, Bernardo Bonanni^1†, Barbara A. Walley^15,16† and the TEXT principal investigators

¹Division of Cancer Prevention and Genetics, European Institute of Oncology
²International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T. H. Chan School of Public Health
³Institute of Oncology of Southern Switzerland (IOSI)
⁴International Breast Cancer Study Group
⁵Swiss Group for Clinical Cancer Research SAKK
⁶IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School
⁷Department of Pathology and Laboratory Medicine, IBCSG Central Pathology Laboratory, European Institute of Oncology, and University of Milan
⁸International Breast Cancer Study Group (IBCSG) Coordinating Center
⁹IBCSG Statistical Center, Frontier Science and Technology Research Foundation
¹⁰Dana-Farber Cancer Institute, Department of Biostatistics and Computatonal Biology
¹¹International Breast Cancer Study Group and University of Sydney School of Public Health
¹²IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Harvard Medical School, Frontier Science and Technology Research Foundation
¹³Program for Breast Health, European Institute of Oncology
¹⁴Translational Research Coordination and Central Pathology Office, IBCSG Coordinating Center
¹⁵Breast Unit of Southern Switzerland
¹⁶National Cancer Institute of Canada
^†Contributed equally

Abstract:

Background
Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT).

Methods
Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ?2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models.

Results
There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ?2 hot flashes/sweating (univariate odds ratio (OR)?=?0.78; 95 % CI 0.63–0.97; P?=?0.03), more strongly in patients assigned exemestane?+?OFS (TT vs CT/CC: OR?=?0.65, 95 % CI?=?0.48–0.89) than assigned tamoxifen?+?OFS (OR?=?0.94, 95 % CI?=?0.69–1.27, interaction P?=?0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found.

Conclusion
The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane?+?OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up.

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