CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

Brian Leyland-Jones, Kathryn P Gray, Mark Abramovitz, Mark Bouzyk, Brandon Young, Bradley Long, Roswitha Kammler, Patrizia Dell'Orto, Maria Olivia Biasi, Beat Thürlimann, Maria Bibi Lyng, Henrik J Ditzel, Vernon J Harvey, Patrick Neven, Isabelle Treilleux, Birgitte Bruun Rasmussen, Rudolf Maibach, Karen N Price, Alan S Coates, Aron Goldhirsch & 4 others Olivia Pagani, Giuseppe Viale, James M Rae, Meredith M Regan

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.

Original languageEnglish
JournalBreast Cancer Research and Treatment
Volume151
Issue number2
Pages (from-to)373-84
ISSN0167-6806
DOIs
Publication statusPublished - Jun 2015

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letrozole
Hormones
Aromatase Inhibitors
Proportional Hazards Models
Single Nucleotide Polymorphism
Neoplasms
Alleles
Polymerase Chain Reaction
DNA

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Leyland-Jones, Brian ; Gray, Kathryn P ; Abramovitz, Mark ; Bouzyk, Mark ; Young, Brandon ; Long, Bradley ; Kammler, Roswitha ; Dell'Orto, Patrizia ; Biasi, Maria Olivia ; Thürlimann, Beat ; Lyng, Maria Bibi ; Ditzel, Henrik J ; Harvey, Vernon J ; Neven, Patrick ; Treilleux, Isabelle ; Rasmussen, Birgitte Bruun ; Maibach, Rudolf ; Price, Karen N ; Coates, Alan S ; Goldhirsch, Aron ; Pagani, Olivia ; Viale, Giuseppe ; Rae, James M ; Regan, Meredith M. / CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. In: Breast Cancer Research and Treatment. 2015 ; Vol. 151, No. 2. pp. 373-84.
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title = "CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial",
abstract = "To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 {\%} CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 {\%} CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 {\%} CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 {\%} CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 {\%} CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 {\%} CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.",
author = "Brian Leyland-Jones and Gray, {Kathryn P} and Mark Abramovitz and Mark Bouzyk and Brandon Young and Bradley Long and Roswitha Kammler and Patrizia Dell'Orto and Biasi, {Maria Olivia} and Beat Th{\"u}rlimann and Lyng, {Maria Bibi} and Ditzel, {Henrik J} and Harvey, {Vernon J} and Patrick Neven and Isabelle Treilleux and Rasmussen, {Birgitte Bruun} and Rudolf Maibach and Price, {Karen N} and Coates, {Alan S} and Aron Goldhirsch and Olivia Pagani and Giuseppe Viale and Rae, {James M} and Regan, {Meredith M}",
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doi = "10.1007/s10549-015-3378-3",
language = "English",
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pages = "373--84",
journal = "Breast Cancer Research and Treatment",
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Leyland-Jones, B, Gray, KP, Abramovitz, M, Bouzyk, M, Young, B, Long, B, Kammler, R, Dell'Orto, P, Biasi, MO, Thürlimann, B, Lyng, MB, Ditzel, HJ, Harvey, VJ, Neven, P, Treilleux, I, Rasmussen, BB, Maibach, R, Price, KN, Coates, AS, Goldhirsch, A, Pagani, O, Viale, G, Rae, JM & Regan, MM 2015, 'CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial', Breast Cancer Research and Treatment, vol. 151, no. 2, pp. 373-84. https://doi.org/10.1007/s10549-015-3378-3

CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. / Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark; Bouzyk, Mark; Young, Brandon; Long, Bradley; Kammler, Roswitha; Dell'Orto, Patrizia; Biasi, Maria Olivia; Thürlimann, Beat; Lyng, Maria Bibi; Ditzel, Henrik J; Harvey, Vernon J; Neven, Patrick; Treilleux, Isabelle; Rasmussen, Birgitte Bruun; Maibach, Rudolf; Price, Karen N; Coates, Alan S; Goldhirsch, Aron; Pagani, Olivia; Viale, Giuseppe; Rae, James M; Regan, Meredith M.

In: Breast Cancer Research and Treatment, Vol. 151, No. 2, 06.2015, p. 373-84.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

AU - Leyland-Jones, Brian

AU - Gray, Kathryn P

AU - Abramovitz, Mark

AU - Bouzyk, Mark

AU - Young, Brandon

AU - Long, Bradley

AU - Kammler, Roswitha

AU - Dell'Orto, Patrizia

AU - Biasi, Maria Olivia

AU - Thürlimann, Beat

AU - Lyng, Maria Bibi

AU - Ditzel, Henrik J

AU - Harvey, Vernon J

AU - Neven, Patrick

AU - Treilleux, Isabelle

AU - Rasmussen, Birgitte Bruun

AU - Maibach, Rudolf

AU - Price, Karen N

AU - Coates, Alan S

AU - Goldhirsch, Aron

AU - Pagani, Olivia

AU - Viale, Giuseppe

AU - Rae, James M

AU - Regan, Meredith M

PY - 2015/6

Y1 - 2015/6

N2 - To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.

AB - To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.

U2 - 10.1007/s10549-015-3378-3

DO - 10.1007/s10549-015-3378-3

M3 - Journal article

VL - 151

SP - 373

EP - 384

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 2

ER -