The standard treatment for ovarian cancer in advanced stages is surgery followed by taxane-platin therapy. Despite an initial high response rate most patients eventually relapse. The dose limiting toxicities of paclitaxel are neutropenia and neuropathy but the inter-individual variability is large. The purpose of this study was to prospectively investigate the impact of genetic variants in key drug metabolizing/transporter genes on paclitaxel toxicity. CYP2C8*3 and three ABCB1 variants were picked for primary analysis and a host of other candidate genes were assessed in 92 prospectively recruited Scandinavian Caucasian patients with primary ovarian cancer who were treated with paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) after cytoreductive surgery. Clinical toxicity using Common Toxicity Criteria for Adverse Events was assessed by a single investigator for 97 % of the patients and hematologic toxicity was registered. Patients carrying one or two variant alleles of ABCB1 C3435T had progressively more pronounced neutrophil decrease at nadir (P-value 0.03). The same association was found for ABCB1 C1236T and G2677T/A with P-values of 0.06 and 0.02. No statistically significant correlations were found for paclitaxel compliance and sensoric neuropathy. In conclusion: variants in the drug transporter ABCB1 gene impact on the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. To our knowledge this has never been shown before directly in a prospective study; but a similar result was reported in 18 patients by Sissung et al.(Eur J Cancer 2006;42:2893-6). This novelty has implications for the understanding of myelosuppression in particular and for tailored chemotherapy in general.
|Publication status||Published - 2010|