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ABCB1 Genetic Variation Influences the Toxicity and Clinical Outcome of Patients with Androgen-Independent Prostate Cancer Treated with Docetaxel

Authors' Affiliations: ¹ Clinical Pharmacology Program, ² Molecular Pharmacology Section, ³ Biostatistics and Data Management Section, and ⁴ Molecular Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and ⁵ Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia

Requests for reprints: William D. Figg, National Cancer Institute, Building 10/Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-3623; Fax: 301-402-8606; E-mail: wdfigg{at}helix.nih.gov.

Purpose: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel.

Experimental Design: Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel.

Results: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053).

Conclusion: The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.

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