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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00481

DOI=10.3389/fphar.2019.00481

ISSN=1663-9812

ABSTRACT=<p>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 (<italic>n</italic> = 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. <italic>CYP2B6<sup>∗</sup>6, CYP3A5<sup>∗</sup>3, CYP2C9 (<sup>∗</sup>2,<sup>∗</sup>3</italic>), <italic>CYP2C19 (<sup>∗</sup>2,<sup>∗</sup>3), CYP2J2<sup>∗</sup>7, POR<sup>∗</sup>28</italic>, and <italic>ABCB1 (rs3842)</italic> 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 &lt; 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 <italic>CYP2J2<sup>∗</sup>7</italic> 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 <italic>CYP2C9<sup>∗</sup>2 or <sup>∗</sup>3</italic> carriers (<italic>p</italic> = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3–62.9%). Higher risk of reduced RDI was associated with <italic>CYP2J2<sup>∗</sup>7</italic> allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21–6.46], BMI ≤ 18.4 kg/m<sup>2</sup> (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 <italic>CYP2B6 <sup>∗</sup>6/<sup>∗</sup>6</italic> 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 <italic>CYP2J2<sup>∗</sup>7</italic> 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.</p>