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 Pagani3,4,5, Meredith M. Regan6, Giuseppe Viale7, Valentina Aristarco1, Debora Macis1, Antonella Puccio1, Susanne Roux8, Rudolf Maibach8, Marco Colleoni1, Manuela Rabaglio9, Karen N. Price9,10, Alan S. Coates11, Richard D. Gelber12, Aron Goldhirsch13, Roswitha Kammler14, Bernardo Bonanni1†, Barbara A. Walley15,16† 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


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).

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.

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.

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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