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Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms

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Abstract

Objective

Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations.

Methods

In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk.

Results

Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10–8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67–7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20–0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16–11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts.

Conclusions

Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

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Data availability

Data and material are available upon reasonable request to the corresponding author.

Code availability

Code is available upon reasonable request to the corresponding author.

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Funding

This research was supported by the Pharmacogenetics Research Network Grant No. U-01 GM61373 and Clinical Pharmacology Training Grant No. 5T32-GM08425 (both awarded to David A. Flockhart) from the National Institute of General Medical Sciences, National Institutes of Health (NIH); from Grants No. M01-RR000042 (University of Michigan), M01-RR00750 (Indiana University), and M01-RR00052 (Johns Hopkins University) from the National Center for Research Resources (NCRR), a component of the NIH; the Breast Cancer Research Foundation (BCRF) (N003173 to JMR); the National Cancer Institute (5T32CA083654, CA251343 to NLH); the National Institute of General Medical Sciences (GM099143 to J.M.R.); and the National Institutes of Health through the University of Michigan’s Cancer Center Support Grant (P30 CA046592) by the use of the following Cancer Center Core: University of Michigan DNA Sequencing Core. In addition, these studies were supported by grants from Pfizer (D.F.H.), Novartis Pharma AG (D.F.H.), and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale (D.F.H.). Drugs were supplied by Novartis and Pfizer. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 08/31/2021.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St., Room 3054, Ann Arbor, MI, 48109-1065, USA

    Daniel L. Hertz

  2. Department of Mathematics and Statistics, Skidmore College, Saratoga Springs, NY, 12866, USA

    Julie A. Douglas & Robert M. Miller

  3. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA

    Julie A. Douglas

  4. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Kelley M. Kidwell

  5. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

    Christina L. Gersch, Daniel F. Hayes, N. Lynn Henry & James M. Rae

  6. Indiana University School of Medicine, Indianapolis, IN, USA

    Zeruesenay Desta, Anna Maria Storniolo & Todd C. Skaar

  7. Johns Hopkins School of Medicine, Baltimore, MD, USA

    Vered Stearns

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  1. Daniel L. Hertz
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Contributions

DLH was involved in designing this analysis and writing the manuscript. JAD and RMM conducted the statistical analysis. KMK cleaned the data for analysis and helped design the analysis. CLG helped generate the genetic data. ZD and TS helped design the initial trial and generate data. AMS, VS, DFH, and NLH designed the initial clinical trial and enrolled participants. JMR helped design this analysis and oversaw the genetic data generation and analysis.

Corresponding author

Correspondence to Daniel L. Hertz.

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Ethics approval

This was a retrospective secondary analysis of a previously reported prospective clinical study. The prospective study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of each of the three participating Universities.

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Informed consent was obtained from all individual participants included in the study.

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The authors affirm that human research participants provided informed consent to participate. No individual data was included in this manuscript.

Conflict of interest

This work was supported in part by Pfizer and Novartis Pharma AG. Dr. Stearns has received research funding from Abbvie, Biocept, Celgene, Merck, Novartis, Medimmune, Pfizer, and Puma Biotechnology. Dr. Stearns is on an advisory board for Novartis (10/25/2021, is a member of the Data Safety Monitoring Board for Immunomedics, Inc, and Chair of the Data Safety Monitoring Board for AstraZeneca, and has received non-financial support from Foundation Medicine Study Assays. Dr. Henry has received research funding to conduct pharmaceutical sponsored clinical trials from Abbvie, Innocrin Pharmaceuticals, Pfizer, and Blue Note Therapeutics. Dr. Hayes reports research funding from Merrimack Pharmaceuticals, Eli Lilly, Menarini Silicon Biosystems, Puma Biotechnology, Pfizer, and Astra Zeneca in the last 24 months. He also reports consulting fees from Cepheid, Freenome, Artiman Ventures, Agendia, Lexent Bio, Epic Sciences, and Salutogenic Innovations. He is the named investigator of a patent held by the University of Michigan which is licensed to Menarini Silicon Biosystems, from whom he receives annual royalties. He holds stock options in Oncimmune LLC and InBiomotion.

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Hertz, D.L., Douglas, J.A., Miller, R.M. et al. Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms. Support Care Cancer 30, 8059–8067 (2022). https://doi.org/10.1007/s00520-022-07243-8

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