Originally published as JCO Early Release 10.1200/JCO.2005.06.075 on August 8 2005

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Associations Between Drug Metabolism Genotype, Chemotherapy Pharmacokinetics, and Overall Survival in Patients With Breast Cancer

From the West Virginia University Health Sciences Center, Morgantown, WV; Duke University Medical Center, Durham, NC; and DNA Sciences Inc, Fremont, CA

Address reprint requests to William P. Petros, PharmD, West Virginia University Health Sciences Center, PO Box 9300, Morgantown, WV 26506; e-mail: wpetros{at}hsc.wvu.edu

PURPOSE: To evaluate associations between patient survival, pharmacokinetics, and drug metabolism–related genetic polymorphisms in patients receiving a combination chemotherapy regimen for breast cancer.

PATIENTS AND METHODS: A genotype association study was conducted on 85 chemotherapy-naïve patients with metastatic or inflammatory breast cancer that were evaluated for an extended period after receiving standard-dose chemotherapy followed by high-dose cyclophosphamide, cisplatin, and carmustine. Blood pharmacokinetics were evaluated, and DNA was genotyped for 29 polymorphisms in 17 drug metabolism genes.

RESULTS: Patients with cyclophosphamide plasma exposures above the median (implying slower metabolic activation) had a shorter survival than those below the median (1.8 v 3.8 years, respectively; P = .042). Patients having a variant genotype of cytochrome P450 3A4 displayed higher blood concentrations of parent (inactive) cyclophosphamide with the second and third doses (P = .024 and .028, respectively) in addition to slower cyclophosphamide activation over the three doses (P = .031). Median survival for these patients was 1.3 years compared with 2.7 years for those without the variant (P = .043). Similar results were observed for patients carrying a genetic variant of P450 3A5. Median survival for patients with deletions of glutathione-S-transferase M1 gene was 3.5 v 1.5 years for patients with one or both copies (P = .041). Patients with a polymorphism in a gene regulating metallothionein had lower platinum concentrations and shorter survival (P = .033).

CONCLUSION: These data suggest that pretreatment evaluation of drug metabolism genes may explain some interindividual differences in both anticancer drug pharmacokinetics and response. The correlations found here may have implications for other commonly used anticancer drugs.

Supported in part by NIH 5-P01-CA47741 and NIH P50-CA68438; Specialized Program in Research Excellence in Breast Cancer, NIH 5-P30-CA14236-26, NIH UO1 CA84955; and the Mylan Chair of Pharmacology.

Presented in part at the American Association for Cancer Research Annual Meetings, New Orleans, LA, 2001 (abstr 1435) and Orlando, FL, 2004 (abstr 2106); however, no other aspects of the data have been published.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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