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

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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.

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Acknowledgments

The BIG 1–98 trial is registered at ClinicalTrials.gov (Identifier NCT00004205). We are indebted to the women, physicians, nurses, and data managers who participated in this clinical trial; to the many pathologists who submitted tumor blocks; to the BIG 1–98 Steering Committee; to Novartis for funding of the clinical trial and of the collection of tumor blocks; to the IBCSG for the design of the trial, coordination, data management, medical review, and statistical support; to the IBCSG Central Pathology Office for collection and processing of tumor blocks; to the BIG-198 Collaborative Group (members who submitted tumor blocks are listed in Supplementary Appendix, available online); to Susan G. Komen for the Cure Promise Grant. The translational research, including DNA extraction and genotyping, was funded by Susan G. Komen for the Cure Promise Grant (KG080081 to GV, OP, MMR) and by The Breast Cancer Research Foundation (BCRF) (N003173 to JMR), the National Institutes of Health (1RO1GM099143 to JMR). The Breast International Group (BIG) 1–98 trial was funded by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Other support for the IBCSG: United States National Cancer Institute (CA75362 to MMR).

Compliance with ethical standards

Experiments comply with the current laws of the country in which they were performed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The BIG 1–98 trial was funded by Novartis, who contracted with the IBCSG for provision of services related to the conduct and management of the trial, and provided partial support for collection and review of tumor blocks. Drs. Goldhirsch and Coates are responsible for the scientific management of the IBCSG. Dr. Viale is responsible for management of the IBCSG Central Pathology Office. Dr. Thürlimann owns stock in Novartis. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The remaining authors have no conflicts to declare.

Author information

Authors and Affiliations

  1. Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA

    Brian Leyland-Jones & Brandon Young

  2. International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA

    Kathryn P. Gray, Karen N. Price & Meredith M. Regan

  3. Harvard School of Public Health, Boston, MA, USA

    Kathryn P. Gray

  4. VM Institute of Research, Montreal, QC, Canada

    Mark Abramovitz

  5. AKESOgen, Inc., Norcross, GA, USA

    Mark Bouzyk

  6. Genomic Molecular Pathology, Department of Pathology, University of Chicago, Chicago, IL, USA

    Bradley Long

  7. IBCSG Coordinating Center and Central Pathology Office, Bern, Switzerland

    Roswitha Kammler

  8. IBCSG Central Pathology Office, Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy

    Patrizia Dell’Orto & Giuseppe Viale

  9. Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy

    Maria Olivia Biasi

  10. Breast Center, Kantonsspital, St. Gallen, Switzerland

    Beat Thürlimann

  11. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland

    Beat Thürlimann

  12. Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Maria B. Lyng & Henrik J. Ditzel

  13. Department of Oncology, Odense University Hospital, Odense, Denmark

    Henrik J. Ditzel

  14. Auckland City Hospital, Auckland, New Zealand

    Vernon J. Harvey

  15. Department of Oncology, KU Leuven (University of Leuven), Leuven, Belgium

    Patrick Neven

  16. Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium

    Patrick Neven

  17. Centre Léon Bérard, Lyon, France

    Isabelle Treilleux

  18. Herlev Hospital, Herlev, Denmark

    Birgitte Bruun Rasmussen

  19. IBCSG Coordinating Center, Bern, Switzerland

    Rudolf Maibach

  20. IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA

    Karen N. Price

  21. International Breast Cancer Study Group and University of Sydney, Sydney, Australia

    Alan S. Coates

  22. European Institute of Oncology, Milan, Italy

    Aron Goldhirsch

  23. Institute of Oncology of Southern Switzerland (IOSI), Swiss Group for Clinical Cancer Research (SAKK) and IBCSG Ospedale Italiano, Viganello, Switzerland

    Olivia Pagani

  24. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    James M. Rae

  25. Harvard Medical School, Boston, MA, USA

    Meredith M. Regan

Authors
  1. Brian Leyland-Jones
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  2. Kathryn P. Gray
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  3. Mark Abramovitz
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  4. Mark Bouzyk
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  5. Brandon Young
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  6. Bradley Long
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  7. Roswitha Kammler
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  8. Patrizia Dell’Orto
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  9. Maria Olivia Biasi
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  10. Beat Thürlimann
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  11. Maria B. Lyng
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  12. Henrik J. Ditzel
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  13. Vernon J. Harvey
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  14. Patrick Neven
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  15. Isabelle Treilleux
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  16. Birgitte Bruun Rasmussen
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  18. Karen N. Price
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  19. Alan S. Coates
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  20. Aron Goldhirsch
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  21. Olivia Pagani
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  22. Giuseppe Viale
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  24. Meredith M. Regan
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Corresponding author

Correspondence to Brian Leyland-Jones.

Additional information

On behalf of the BIG 1–98 Collaborative Group.

Members of the BIG 1–98 Collaborative Group who submitted tumor blocks are listed in Supplementary Appendix.

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Leyland-Jones, B., Gray, K.P., Abramovitz, M. et al. CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial. Breast Cancer Res Treat 151, 373–384 (2015). https://doi.org/10.1007/s10549-015-3378-3

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