CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

Jemal Hussien Ahmed; Eyasu Makonnen; Getnet Yimer; Daniel Seifu; Abebe Bekele; Mathewos Assefa; Abraham Aseffa; Rawleigh Howe; Alan Fotoohi; Moustapha Hassan; Eleni Aklillu

doi:10.3389/fphar.2019.00481

CYP2J2^∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

Front Pharmacol. 2019 May 14:10:481. doi: 10.3389/fphar.2019.00481. eCollection 2019.

Authors

Jemal Hussien Ahmed^{1

2

3}, Eyasu Makonnen^{1

4}, Getnet Yimer¹, Daniel Seifu⁵, Abebe Bekele⁶, Mathewos Assefa⁷, Abraham Aseffa⁸, Rawleigh Howe⁸, Alan Fotoohi⁹, Moustapha Hassan¹⁰, Eleni Aklillu³

Affiliations

¹ Department of Pharmacology, Addis Ababa University, Addis Ababa, Ethiopia.
² Department of Pharmacy, Jimma University, Jimma, Ethiopia.
³ Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden.
⁴ Center for Inovative Drug Development and Therapeutic Trials, Addis Ababa University, Addis Ababa, Ethiopia.
⁵ Department of Biochemistry, Addis Ababa University, Addis Ababa, Ethiopia.
⁶ Department of Surgery, Addis Ababa University, Addis Ababa, Ethiopia.
⁷ Department of Oncology, Addis Ababa University, Addis Ababa, Ethiopia.
⁸ Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
⁹ Clinical Pharmacology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Laboratory Medicine, Experimental Cancer Medicine, Clinical Research Centre, Karolinska Institutet, Stockholm, Sweden.

Abstract

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.

Keywords: CYP2C9; CYP2J2; Ethiopia; breast cancer; chemotherapy; hematologic toxicity; reduced relative dose intensity.