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Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients

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Abstract

Purpose

Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer.

Methods

One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia.

Results

More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia.

Conclusions

Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

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Abbreviations

ADR:

Adverse drug reactions

AIs:

Aromatase inhibitors

AUSCAN:

Australian/Canadian osteoarthritis hand index

BMI:

Body mass index

ER:

Estrogen receptor

LC–MS/MS:

Liquid chromatography–mass spectrometry

PR:

Progesterone receptor

SNP:

Single-nucleotide polymorphism

WOMAC:

Western Ontario and McMaster osteoarthritis index

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Acknowledgements

We thank all patients for their collaboration in this study. We would like to thank Cameron Ross, Maureen Trinnear, and James Sinfield for their coordinating assistance. We would also like to acknowledge the entire Breast Disease Site Team at the London Regional Cancer Program for their support of this research. Dr. Richard B. Kim holds the Wolfe Medical Research Chair in Pharmacogenomics at Western. This study was funded by the Cancer Care Ontario (CCO) Research Chair Award (Tier-1) in Experimental Therapeutics (Richard B. Kim) and a Catalyst Grant from the London Regional Cancer Program (Richard B. Kim). Adrienne Borrie was supported by grant funding from the Canadian Institutes of Health Research and the Breast Cancer Society of Canada.

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Authors and Affiliations

  1. Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, Canada

    Adrienne E. Borrie, Wendy A. Teft & Richard B. Kim

  2. Department of Physiology and Pharmacology, LHSC—University Hospital, Western University, Room B9-116, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Adrienne E. Borrie, Wendy A. Teft & Richard B. Kim

  3. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada

    Finnley A. Rose & Yun-Hee Choi

  4. Department of Oncology, Western University, London, ON, Canada

    Francisco E. Perera, Nancy Read, Tracy Sexton, Michael Lock, Theodore A. Vandenberg, Karin Hahn, Jawaid Younus, Diane Logan, Kylea Potvin, Brian Yaremko, Edward Yu, John Lenehan & Stephen Welch

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  1. Adrienne E. Borrie
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Correspondence to Richard B. Kim.

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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.

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Borrie, A.E., Rose, F.A., Choi, YH. et al. Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients. Breast Cancer Res Treat 183, 365–372 (2020). https://doi.org/10.1007/s10549-020-05777-1

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  • DOI: https://doi.org/10.1007/s10549-020-05777-1

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