Estrogen receptor alpha and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy

Context: Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC). Objective: We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ER alpha) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival in men with CRPC. Materials and Methods: Patients with CRPC (n=115) treated with docetaxel, single-agent thalidomide (n=42), or healthy controls (n=289) were genotyped for the CYP19 R264C (rs700519) and the ER alpha PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms. Results: Patients carrying two copies of ER alpha polymorphisms had shorter progression-free survival on docetaxel than other patients (median survival difference >= 3.1 months; P <= 0.036). When the analysis was limited to nonobese patients, the relationship between the ER alpha Xbal A>G polymorphism and PFS improved (median survival difference = 3.5 months; P = 0.0078). The CYP19 R264C variant was related to the duration of survival after docetaxel in patients who were >70 years old (median survival difference = 10.6 months; P=0.041). Both ER alpha polymorphisms were also associated with increases in CRPC risk [P <= 0.032; double variants vs. wild-type odds ratio >= 2.6], and the association with the ER alpha PvuII T>C also improved in those men who were <70 years old (P = 0.0073; odds ratio = 3.0). Conclusions: This study demonstrates that estrogen-related genetic variation affects docetaxel clinical response and that this relationship is dependent on age and body-type in men with CRPC. Moreover, this study suggests ER alpha polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age.