Abstract
3058 Background: Paclitaxel is one of the most active single agents in the treatment of breast cancer and is an important component of many commonly used combination regimens. Despite its clinical activity, variability in toxicity and response remain a major problem for patients receiving paclitaxel. Significant variability (4–10 fold) in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. Methods: To determine the contribution of inherited differences in drug metabolism and excretion to the pharmacokinetics and progression-free survival in patients receiving paclitaxel, genomic DNA was isolated from the plasma of 93 patients with high-risk primary (84% stage II with ≥ 10 axillary nodes, stage IIIA or stage IIIB inflammatory carcinoma) or stage IV (16%) breast cancer. Patients received paclitaxel 575–775 mg/m2 infused over 24 hours, doxorubicin 165 mg/m2 as a continuous infusion over 96 hours, and cyclophosphamide 100 mg/kg. Median overall follow-up was 52 months. Ten polymorphisms in 6 genes associated with metabolism (CYP2C8, CYP1B1, CYP3A4 and CYP3A5) and transport (ABCB1 and ABCG2) of paclitaxel were analyzed using Pyrosequencing. Results: In a preliminary analysis of genotype versus phenotype, we found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, the CYP1B1*3 (4326 C>G; L432V) allele was associated with survival. Patients homozygous for the Leucine allele (45% frequency) had a significantly longer progression free survival (median: 56 months) than patients with at least one Valine allele (median: 30 months; p = 0.037). This association was independent of stage or estrogen/progesterone receptor status. Conclusions: The CYP1B1*3 allele was significantly associated with progression free survival in patients receiving paclitaxel. This finding could reflect altered paclitaxel metabolism. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele. Additional loci and phenotypes are currently being investigated to determine the role of pharmacogenetics on outcome in breast cancer. Supported by CA 33572, CA 62505 and U01 GM63340. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Neopharm, Orion Genomics, Sanofi-Synthelabo, Veridex Merck Bristol
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