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Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients

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Abstract

Background

Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen.

Methods

Patients were monitored for adverse reactions throughout the treatment, then divided into “none or mild” (80 %) or “severe” (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 109/L anytime during the treatment. DNA was extracted from patients’ peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis.

Results

Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 109/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004).

Conclusion

Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene–environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.

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Acknowledgments

This investigation was supported by GlaxoSmithKline Oncology International Ethnic Research Initiative (GSK-ERI) funding (Co-PI: Nelson LS Tang and Winnie Yeo).

Ethical Standards

The study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China

    Nelson L. S. Tang, Chen Di Liao & Xingyan Wang

  2. Laboratory of Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, Sha Tin, Hong Kong SAR, China

    Nelson L. S. Tang

  3. Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China

    Nelson L. S. Tang

  4. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, China

    Nelson L. S. Tang

  5. State Key Lab of Oncology in South China, Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China

    Frankie K. F. Mo, Vicky T. C. Chan, Rita Ng, Elizabeth Pang, Joyce J. S. Suen & Winnie Yeo

  6. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China

    Jean Woo

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  1. Nelson L. S. Tang
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  2. Chen Di Liao
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Correspondence to Nelson L. S. Tang.

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Tang, N.L.S., Liao, C.D., Wang, X. et al. Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients. J Cancer Res Clin Oncol 139, 419–427 (2013). https://doi.org/10.1007/s00432-012-1345-5

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  • DOI: https://doi.org/10.1007/s00432-012-1345-5

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