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

the TEXT principal investigators

Research output: Contribution to journalArticle

5 Citations (Scopus)

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. Trial registration: ClinicalTrials.gov NCT00066703, registered August 6, 2003.

Original languageEnglish (US)
Article number110
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Nov 8 2016

Fingerprint

exemestane
Estrogen Receptor alpha
Tamoxifen
Cytochrome P-450 Enzyme System
Hot Flashes
Sweating
Single Nucleotide Polymorphism
Breast Neoplasms
Odds Ratio
Therapeutics
Logistic Models
Genotype
Incidence

Keywords

  • Aromatase inhibitors
  • Breast cancer
  • CYP19A1
  • ESR1
  • Ovarian suppression
  • Side effects
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Breast Cancer Research, Vol. 18, No. 1, 110, 08.11.2016.

Research output: Contribution to journalArticle

@article{6983ac22078c4220b1167baa3cbf54b9,
title = "Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial",
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. Trial registration: ClinicalTrials.gov NCT00066703, registered August 6, 2003.",
keywords = "Aromatase inhibitors, Breast cancer, CYP19A1, ESR1, Ovarian suppression, Side effects, Tamoxifen",
author = "{the TEXT principal investigators} and Harriet Johansson and Gray, {Kathryn P.} and Olivia Pagani and Regan, {Meredith M.} and Giuseppe Viale and Valentina Aristarco and Debora Macis and Antonella Puccio and Susanne Roux and Rudolf Maibach and Marco Colleoni and Manuela Rabaglio and Price, {Karen N.} and Coates, {Alan S.} and Gelber, {Richard D.} and Aron Goldhirsch and Roswitha Kammler and Bernardo Bonanni and Walley, {Barbara A.} and J. Stewart and J. Chirgwin and {van der Westhuizen}, A. and K. Briscoe and B. Koczwara and S. Gauden and E. Moylan and Francis, {P. A.} and M. Nottage and D. Boadle and E. Bayliss and R. Snyder and F. Sardelic and E. Abdi and M. Chipman and A. Gombos and A. Barbeaux and G. Jerusalem and P. Neven and I. L{\'a}ng and F. Plugisi and D. Crivellari and L. Pavesi and L. Gianni and G. Pinotti and C. Tondini and {Di Leo}, A. and C. Graiff and H. Gomez and E. Skof and D. Vorobiof",
year = "2016",
month = "11",
day = "8",
doi = "10.1186/s13058-016-0771-8",
language = "English (US)",
volume = "18",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial

AU - the TEXT principal investigators

AU - Johansson, Harriet

AU - Gray, Kathryn P.

AU - Pagani, Olivia

AU - Regan, Meredith M.

AU - Viale, Giuseppe

AU - Aristarco, Valentina

AU - Macis, Debora

AU - Puccio, Antonella

AU - Roux, Susanne

AU - Maibach, Rudolf

AU - Colleoni, Marco

AU - Rabaglio, Manuela

AU - Price, Karen N.

AU - Coates, Alan S.

AU - Gelber, Richard D.

AU - Goldhirsch, Aron

AU - Kammler, Roswitha

AU - Bonanni, Bernardo

AU - Walley, Barbara A.

AU - Stewart, J.

AU - Chirgwin, J.

AU - van der Westhuizen, A.

AU - Briscoe, K.

AU - Koczwara, B.

AU - Gauden, S.

AU - Moylan, E.

AU - Francis, P. A.

AU - Nottage, M.

AU - Boadle, D.

AU - Bayliss, E.

AU - Snyder, R.

AU - Sardelic, F.

AU - Abdi, E.

AU - Chipman, M.

AU - Gombos, A.

AU - Barbeaux, A.

AU - Jerusalem, G.

AU - Neven, P.

AU - Láng, I.

AU - Plugisi, F.

AU - Crivellari, D.

AU - Pavesi, L.

AU - Gianni, L.

AU - Pinotti, G.

AU - Tondini, C.

AU - Di Leo, A.

AU - Graiff, C.

AU - Gomez, H.

AU - Skof, E.

AU - Vorobiof, D.

PY - 2016/11/8

Y1 - 2016/11/8

N2 - 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. Trial registration: ClinicalTrials.gov NCT00066703, registered August 6, 2003.

AB - 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. Trial registration: ClinicalTrials.gov NCT00066703, registered August 6, 2003.

KW - Aromatase inhibitors

KW - Breast cancer

KW - CYP19A1

KW - ESR1

KW - Ovarian suppression

KW - Side effects

KW - Tamoxifen

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U2 - 10.1186/s13058-016-0771-8

DO - 10.1186/s13058-016-0771-8

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C2 - 27825388

AN - SCOPUS:85005976027

VL - 18

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

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