Abstract
BackgroundThe selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen.MethodsCYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test.ResultsPatients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome.ConclusionsCYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment.
Highlights
The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients
Two multicenter phase III randomized clinical trials, TAX 327 and SWOG 9916, showed a survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients treated with taxane-based chemotherapy [4,5]
No data on response were reported, and further studies are needed to clarify the role of cytochrome P450 1B1 (CYP1B1) genotype and docetaxel activity in CRPC patients. For this purpose we retrospectively evaluated the correlation between the 142C>G, 4326C>G and 4390G>A SNPs and clinical outcome in 60 docetaxel-treated CRPC patients
Summary
The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Two multicenter phase III randomized clinical trials, TAX 327 and SWOG 9916, showed a survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients treated with taxane-based chemotherapy [4,5]. In both trials the rates of prostate-specific-antigen (PSA) response and OS were significantly higher in the docetaxel groups compared to mitoxantrone and prednisone. PSA responses were 45% and 50%, while OS was 18.9 and 17.5 months in docetaxel-treated patients, in the TAX 327 and in the SWOG 9916 trial, respectively. On the basis of these findings, taxane-based chemotherapy is considered the standard first-line therapy for CRPC patients
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