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Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity

  • Epidemiology
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Abstract

Purpose

Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced ‘specific’ AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients.

Methods

Genomic DNA was isolated from 198 HR+ breast cancer patients by the phenol–chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software.

Results

Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29–4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele ‘T’ at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs.

Conclusions

To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.

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Acknowledgements

We would like to thank all the study participants, physicians, nursing sisters, pharmacists, and staff of Regional Cancer Center, JIPMER for their support. This study has been supported by Grants (Grant Order No 53/17/2003-BMSdt.12.03.2007) from the Indian Council of Medical Research (ICMR), New Delhi in the form of Senior Research Fellowship under Centre for Advanced Research in Pharmacogenomics and in part by JIPMER intramural research (Grant No Edn.7(1)/2010dt21.02.2011). We are grateful to Mr. Rajan Sundaram, Mrs. Tamijarassy Bascarane, Mrs. Ermin Immaculate, Mrs. Anjana Raj, and Mrs. Revathy Mohan for their skillful technical assistance. We are indebted to Dr. Naveen Kumar AN, and Mr. Sampath Rajeswaran R for their contribution to the recruitment and follow-up of patients for this study.

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Authors and Affiliations

  1. Department of Pharmacology, Centre for Advanced Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

    Gurusamy Umamaheswaran, Sekar Kalaivani, Solai Elango Damodaran, Suresh Chandra Pradhan, Steven Aibor Dkhar & Chandrasekaran Adithan

  2. Departments of Surgery and Medical Education, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

    Dharanipragada Kadambari

  3. School of Life Sciences, Centre for Bioinformatics, Pondicherry University, Puducherry, India

    Suresh Kumar Muthuvel

  4. Department of Animal Sciences, University of Connecticut, Storrs, USA

    Jaganathan Devi

  5. Department of Medical Oncology, Regional Cancer Center, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

    Biswajit Dubashi

  6. Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

    Steven Aibor Dkhar

  7. Department of Oncology, Institute of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden

    Gurusamy Umamaheswaran

  8. Central Inter-Disciplinary Research Facility, Mahatma Gandhi Medical College & Research Institute, Puducherry, India

    Chandrasekaran Adithan

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  1. Gurusamy Umamaheswaran
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Correspondence to Gurusamy Umamaheswaran.

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The study was performed in human participants following the Declaration of Helsinki and its amendments. Research protocols were approved by the Institutional Scientific Advisory and Research Ethics Committees of JIPMER.

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Umamaheswaran, G., Kadambari, D., Muthuvel, S.K. et al. Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity. Breast Cancer Res Treat 182, 147–158 (2020). https://doi.org/10.1007/s10549-020-05656-9

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