Journal Article

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

Woo, Jean, Chan, Vicky T. C., Tang, Nelson L. S., Pang, Elizabeth, Suen, Joyce J. S., Wang, Xingyan, Mo, Frankie K. F., Yeo, Winnie, Ng, Rita, Liao, Chen Di

2013

Overview

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 × 10 9 /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 × 10 9 /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.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Adolescent / Adult / Aged / Alleles / Antineoplastic agents / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Asian People - genetics / Asian People - statistics & numerical data / Biological and medical sciences / Breast cancer / Breast Neoplasms - diagnosis / Breast Neoplasms - drug therapy / Breast Neoplasms - ethnology / Breast Neoplasms - genetics / Cancer Research / Carcinoma - diagnosis / Carcinoma - drug therapy / Carcinoma - ethnology / Carcinoma - genetics / Case-Control Studies / Chemotherapy / Chemotherapy, Adjuvant - adverse effects / Cohort Studies / Cytochrome P-450 CYP3A - genetics / Cytochrome P-450 CYP3A - physiology / Female / Genetic Predisposition to Disease - ethnology / Genetics / Gynecology. Andrology. Obstetrics / Hematologic and hematopoietic diseases / Hematology / Humans / Internal Medicine / Leukocytes (neutrophilic) / Mammary gland diseases / Medical sciences / Medicine / Medicine & Public Health / Middle Aged / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Myelosuppression / Neutropenia / Neutropenia - chemically induced / Neutropenia - epidemiology / Neutropenia - genetics / Oncology / Original Paper / Other diseases. Hematologic involvement in other diseases / Patients / Peripheral blood / Pharmacogenetics / Pharmacology / Pharmacology. Drug treatments / Side effects / Single-nucleotide polymorphism / Toxicity / Tumors / Young Adult