Genetic variation of CYP3A5 influences paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients

• Published in: Journal of clinical pharmacology Vol. 56; no. 3; p. 349
• Main Authors: Hu, Lei, Lv, Qiao-Li, Guo, Ying, Cheng, Lin, Wu, Na-Yiyuan, Qin, Chong-Zhen, Zhou, Hong-Hao
• Format: Journal Article
• Language: English
• Published: England 01.03.2016
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Asian Continental Ancestry Group - genetics; Bone Marrow - drug effects; Carboplatin - adverse effects; Carcinoma, Ovarian Epithelial; Cytochrome P-450 CYP3A - genetics; Female; Genotype; Humans; Leukocyte Count; Leukopenia - chemically induced; Middle Aged; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Neutrophils - drug effects; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Paclitaxel - adverse effects; Paresthesia - chemically induced; Pharmacogenomic Variants - drug effects; Pharmacogenomic Variants - genetics; Prospective Studies; toxicity; ovarian cancer; CYP3A5; myelosuppression; Paclitaxel
• ISSN: 1552-4604
• DOI: 10.1002/jcph.587

Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy.