CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients
Chemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast canc...
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Frontiers Media S.A.
2019-05-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00481/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jemal Hussien Ahmed Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Getnet Yimer Daniel Seifu Abebe Bekele Mathewos Assefa Abraham Aseffa Rawleigh Howe Alan Fotoohi Moustapha Hassan Eleni Aklillu |
spellingShingle |
Jemal Hussien Ahmed Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Getnet Yimer Daniel Seifu Abebe Bekele Mathewos Assefa Abraham Aseffa Rawleigh Howe Alan Fotoohi Moustapha Hassan Eleni Aklillu CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients Frontiers in Pharmacology CYP2J2 CYP2C9 chemotherapy hematologic toxicity reduced relative dose intensity breast cancer |
author_facet |
Jemal Hussien Ahmed Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Getnet Yimer Daniel Seifu Abebe Bekele Mathewos Assefa Abraham Aseffa Rawleigh Howe Alan Fotoohi Moustapha Hassan Eleni Aklillu |
author_sort |
Jemal Hussien Ahmed |
title |
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients |
title_short |
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients |
title_full |
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients |
title_fullStr |
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients |
title_full_unstemmed |
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients |
title_sort |
cyp2j2∗7 genotype predicts risk of chemotherapy-induced hematologic toxicity and reduced relative dose intensity in ethiopian breast cancer patients |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-05-01 |
description |
Chemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast cancer patients, and implication of pharmacogenetics variations. Breast cancer patients (n = 249) were enrolled prospectively to receive cyclophosphamide based chemotherapy. Hematological toxicity (neutropenia, anemia, and thrombocytopenia) were monitored throughout chemotherapy cycle. The primary and secondary outcomes were incidence of grade 3 or 4 toxicity and reduced RDI, respectively. CYP2B6∗6, CYP3A5∗3, CYP2C9 (∗2,∗3), CYP2C19 (∗2,∗3), CYP2J2∗7, POR∗28, and ABCB1 (rs3842) genotyping were done. Cox proportional hazard and logistic regression were used to estimate risk predictors of toxicity and reduced RDI, respectively. Majority (73.5%) of the patients were < 45 years of age. The incidence of grade 3 or 4 hematological toxicity was 51.0% (95% CI = 44.54–57.46%). Multivariate Cox proportional hazard regression indicated CYP2J2∗7 genotype [Hazard ratio (HR) = 1.82; 95% CI = 1.14–2.90], pretreatment grade 1 leukopenia (HR = 2.75; 95% CI = 1.47–5.15) or grade 1 or 2 neutropenia (HR = 2.75; 95% CI = 1.73–4.35) as significant predictors of hematologic toxicities. The odds of having hematologic toxicities was lower in CYP2C9∗2 or ∗3 carriers (p = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3–62.9%). Higher risk of reduced RDI was associated with CYP2J2∗7 allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21–6.46], BMI ≤ 18.4 kg/m2 (AOR = 5.98; 95% CI = 1.36–26.23), baseline grade 1 leukopenia (AOR = 6.09; 95% CI = 1.24–29.98), and baseline neutropenia (AOR = 3.37; 95% CI = 1.41–8.05). The odds of receiving reduced RDI was lower in patients with CYP2B6 ∗6/∗6 genotype (AOR = 0.19; 95% CI = 0.06–0.77). We report high incidence of chemotherapy-induced hematological toxicities causing larger proportion of patients to receive reduced RDI in Ethiopian breast cancer patients. Patients carrying CYP2J2∗7 allele and low baseline blood counts are at a higher risk for chemotherapy-induced hematologic toxicities and receiving reduced RDI, and may require prior support and close follow up during chemotherapy. |
topic |
CYP2J2 CYP2C9 chemotherapy hematologic toxicity reduced relative dose intensity breast cancer |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00481/full |
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doaj-7a3d8da0e2914472accc2e6e772d6b9a2020-11-25T03:27:03ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-05-011010.3389/fphar.2019.00481413313CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer PatientsJemal Hussien Ahmed0Jemal Hussien Ahmed1Jemal Hussien Ahmed2Eyasu Makonnen3Eyasu Makonnen4Getnet Yimer5Daniel Seifu6Abebe Bekele7Mathewos Assefa8Abraham Aseffa9Rawleigh Howe10Alan Fotoohi11Moustapha Hassan12Eleni Aklillu13Department of Pharmacology, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Pharmacy, Jimma University, Jimma, EthiopiaDivision of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet Huddinge, Stockholm, SwedenDepartment of Pharmacology, Addis Ababa University, Addis Ababa, EthiopiaCenter for Inovative Drug Development and Therapeutic Trials, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Pharmacology, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Biochemistry, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Surgery, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Oncology, Addis Ababa University, Addis Ababa, EthiopiaArmauer Hansen Research Institute, Addis Ababa, EthiopiaArmauer Hansen Research Institute, Addis Ababa, EthiopiaClinical Pharmacology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden0Department of Laboratory Medicine, Experimental Cancer Medicine, Clinical Research Centre, Karolinska Institutet, Stockholm, SwedenDivision of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet Huddinge, Stockholm, SwedenChemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast cancer patients, and implication of pharmacogenetics variations. Breast cancer patients (n = 249) were enrolled prospectively to receive cyclophosphamide based chemotherapy. Hematological toxicity (neutropenia, anemia, and thrombocytopenia) were monitored throughout chemotherapy cycle. The primary and secondary outcomes were incidence of grade 3 or 4 toxicity and reduced RDI, respectively. CYP2B6∗6, CYP3A5∗3, CYP2C9 (∗2,∗3), CYP2C19 (∗2,∗3), CYP2J2∗7, POR∗28, and ABCB1 (rs3842) genotyping were done. Cox proportional hazard and logistic regression were used to estimate risk predictors of toxicity and reduced RDI, respectively. Majority (73.5%) of the patients were < 45 years of age. The incidence of grade 3 or 4 hematological toxicity was 51.0% (95% CI = 44.54–57.46%). Multivariate Cox proportional hazard regression indicated CYP2J2∗7 genotype [Hazard ratio (HR) = 1.82; 95% CI = 1.14–2.90], pretreatment grade 1 leukopenia (HR = 2.75; 95% CI = 1.47–5.15) or grade 1 or 2 neutropenia (HR = 2.75; 95% CI = 1.73–4.35) as significant predictors of hematologic toxicities. The odds of having hematologic toxicities was lower in CYP2C9∗2 or ∗3 carriers (p = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3–62.9%). Higher risk of reduced RDI was associated with CYP2J2∗7 allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21–6.46], BMI ≤ 18.4 kg/m2 (AOR = 5.98; 95% CI = 1.36–26.23), baseline grade 1 leukopenia (AOR = 6.09; 95% CI = 1.24–29.98), and baseline neutropenia (AOR = 3.37; 95% CI = 1.41–8.05). The odds of receiving reduced RDI was lower in patients with CYP2B6 ∗6/∗6 genotype (AOR = 0.19; 95% CI = 0.06–0.77). We report high incidence of chemotherapy-induced hematological toxicities causing larger proportion of patients to receive reduced RDI in Ethiopian breast cancer patients. Patients carrying CYP2J2∗7 allele and low baseline blood counts are at a higher risk for chemotherapy-induced hematologic toxicities and receiving reduced RDI, and may require prior support and close follow up during chemotherapy.https://www.frontiersin.org/article/10.3389/fphar.2019.00481/fullCYP2J2CYP2C9chemotherapyhematologic toxicityreduced relative dose intensitybreast cancer |