Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial.
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.



ClinicalTrials.gov NCT00066703, registered August 6, 2003.
Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy. harriet.johansson@ieo.it.
Harriet
H
Johansson
International 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, 450 Brookline Avenue, Boston, MA, 02215, USA.
Kathryn P
KP
Gray
Institute of Oncology of Southern Switzerland (IOSI), Bellinzona, Switzerland.|International Breast Cancer Study Group, Bern, Switzerland.|Swiss Group for Clinical Cancer Research SAKK, Lugano Viganello, Switzerland.
Olivia
O
Pagani
IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
Meredith M
MM
Regan
Department of Pathology and Laboratory Medicine, IBCSG Central Pathology Laboratory, European Institute of Oncology, and University of Milan, Via Ripamonti 435, Milan, 20141, Italy.
Giuseppe
G
Viale
Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Valentina
V
Aristarco
Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Debora
D
Macis
Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Antonella
A
Puccio
International Breast Cancer Study Group (IBCSG) Coordinating Center, Effingerstrasse 40, Bern, CH-3008, Switzerland.
Susanne
S
Roux
International Breast Cancer Study Group (IBCSG) Coordinating Center, Effingerstrasse 40, Bern, CH-3008, Switzerland.
Rudolf
R
Maibach
Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Marco
M
Colleoni
IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA.
Manuela
M
Rabaglio
IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA.|Dana-Farber Cancer Institute, Department of Biostatistics and Computatonal Biology, 450 Brookline Ave, Boston, MA, 02215, USA.
Karen N
KN
Price
International Breast Cancer Study Group and University of Sydney School of Public Health, Sydney, Australia.
Alan S
AS
Coates
IBCSG 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, 450 Brookline Avenue, Boston, MA, 02215, USA.
Richard D
RD
Gelber
Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Aron
A
Goldhirsch
Translational Research Coordination and Central Pathology Office, IBCSG Coordinating Center, Effingerstrasse 40, Bern, CH-3008, Switzerland.
Roswitha
R
Kammler
Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.
Bernardo
B
Bonanni
Breast Unit of Southern Switzerland, Bellinzona, Switzerland.|National Cancer Institute of Canada, Kingston, ON, Canada.
Barbara A
BA
Walley
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D019584:Hot Flashes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D000071184:Pharmacogenomic Variants; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013546:Sweating / Q000235:genetics
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D001141:Aromatase; C561410:CYP19A1 protein, human
Aromatase inhibitors; Breast cancer; CYP19A1; ESR1; Ovarian suppression; Side effects; Tamoxifen