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Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.

ABSTRACT: Chemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22-9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21-16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15-41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06-8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

SUBMITTER: Tsuji D

PROVIDER: S-EPMC5591095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe majority of cancer patients undergoing chemotherapy show neutropenic condition which is a common side effect of myelosuppressive chemotherapy diagnosed as the reduced complete blood cell count. Such cancer patients have a higher risk of febrile neutropenia. The present study aimed to validate whether there was a risk of neutropenia in cancer patients receiving chemotherapy at Bhaktapur Cancer Hospital, Nepal.MethodsCross-sectional study was performed among 203 cancer patients of all age groups who attended Bhaktapur Cancer Hospital from May 2018 to January 2019 and who received a chemotherapy course. Patients receiving at least one cycle of chemotherapy as the first-line treatment were included. Statistical analysis was performed using SPSS 25. Loglinear analysis was used to analyze more than 2×2 categories among the grades and outcome of neutropenia. Multinomial logistic regression was applied to analyze the impact of various predictor variables such as chemotherapy cycles, grades of neutropenia, and gender on the outcome of neutropenia. Variation in the absolute neutrophil count (ANC) level at various days of chemotherapy cycles was assessed with the multivariate analysis of variance (MANOVA). The p-value <0.05 was considered significant at each condition.ResultsThe main cancer type during the study period was breast cancer (41, 20.2%). Out of 163 neutropenic patients, 149 had severe neutropenia and 14 had mild neutropenia. Most patients were continued up to the 6th cycle of chemotherapy. There was significant association between the grade of neutropenia and the outcome of the condition (p-value 0.017). There were significant relations of the grade of neutropenia and smoking habit with the recovering status (p values 0.033 and 0.001, respectively). The absolute neutrophil count (ANC) level increased and decreased inconsistently (statistically non-significantly) in between treatment period of day 1 to 52.ConclusionChemotherapy-induced neutropenia was a common occurrence. Majority (133, 66.5%) grade 4 neutropenic patients were recovering after the chemotherapy cycles. The physicians are warranted that they be ready for any unpredictable situation during chemotherapy treatment.

Project description:Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan ®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III-IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III-IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy.

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Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.

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