Association of ABCB1 and SLC22A16 Gene Polymorphisms with Incidence of Doxorubicin-Induced Febrile Neutropenia: A Survey of Iranian Breast Cancer Patients.

Abolfazl Faraji,Hamid Reza Dehghan Manshadi,Massoud Houshmand,Maryam Mobaraki,Mahkameh Zare,Aamir Ahmad

doi:10.1371/journal.pone.0168519

Abstract

Breast cancer is the most common cancer in women worldwide. Doxorubicin-based chemotherapy is used to treat breast cancer patients; however, neutropenia is a common hematologic side effect and can be life-threatening. The ABCB1 and SLC22A16 genes encode proteins that are essential for doxorubicin transport. In this study, we explored the effect of 2 common polymorphisms in ABCB1 (rs10276036 C/T) and SLC22A16 (rs12210538 A/G) on the development of grade 3/4 febrile neutropenia in Iranian breast cancer patients. Our results showed no significant association between these polymorphisms and grade 3/4 febrile neutropenia; however, allele C of ABCB1 (rs10276036 C/T) (p = 0.315, OR = 1.500, 95% CI = 0.679–3.312) and allele A of SLC22A16 (rs12210538 A/G) (p = 0.110, OR = 2.984, 95% CI = 0.743–11.988) tended to have a greater association with grade 3/4 febrile neutropenia, whereas allele T of ABCB1 (rs10276036) (p = 0.130, OR = 0.515, 95% CI = 0.217–1.223) and allele G of SLC22A16 (rs12210538) (p = 0.548, OR = 0.786, 95% CI = 0.358–1.726) tended to protect against this condition. In addition to breast cancer, a statistically significant association was also observed between the development of grade 3/4 febrile neutropenia and other clinical manifestations such as stage IIIC cancer (p = 0.037) and other diseases (p = 0.026). Our results indicate that evaluation of the risk of grade 3/4 neutropenia development and consideration of molecular and clinical findings may be of value when screening for high-risk breast cancer patients.

Highlights

Breast cancer is the most incident cancer type among women
Fars (54%) and Turk (24%) ethnicities were the most prevalent in our cohort; based on the Pearson chi-square test, there was no significant association between ethnicity and the incidence of grade 3/4 febrile neutropenia (p = 0.191)
Genetic polymorphisms were shown to affect neutrophil counts in patients who are administered DOX-based chemotherapy [22]; in these studies, the emergence of chemotherapy-induced severe toxicities was more frequent in Asian patients than in Western patients, suggesting that the former are more susceptible to febrile neutropenia

Summary

Introduction

Breast cancer is the most incident cancer type among women. Doxorubicin (DOX)-based treatments are appropriate for many adult and pediatric solid tumors (including breast cancer), leukemias and lymphomas [1]. Polymorphisms and Doxorubicin-Induced Neutropenia in Breast Cancer. DOX is a secondary metabolite produced by Streptomyces peucetius var. DOX functions through dual mechanisms i) intercalation into DNA and disruption of the DNA repair mechanism that is mediated by topoisomerase II, and ii) releasing of free radicals resulting in the damaging of cell membranes, DNA, and proteins [4]. DOX is oxidized to a semiquinone, an unstable metabolite, which is reconverted to DOX through a pathway that releases reactive oxygen species; this can cause lipid peroxidation, membrane damage, DNA damage, oxidative stress, and cell death via induction of apoptotic pathways (Fig 1) [5]

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