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

Abstract

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 ERα) 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 ERα PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms.

Results: Patients carrying two copies of ERα 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 ERα XbaI 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 ERα 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 ERα 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 ERα polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age.

Trial registration: ClinicalTrials.gov NCT00001446 NCT00020046 NCT00039221 NCT00083005.

Fig. 1.

Survival characteristics of patients on the studied trials vs. genetic variants in ERα and CYP19. A, PFS of docetaxel plus thalidomide in patients carrying only ERα A>G variants (5.8 months; n = 11) and those carrying at least a single wild-type allele (8.3 months; n = 37, P = 0.015). B, PFS of combined docetaxel-based trials in patients carrying only ERα T>C variants (5.7 months; n = 26) and those carrying at least a single wild-type allele (8.8 months; n = 81; P = 0.036). C, Patients carrying only ERα A>G variants (4.8 months; n = 20) and those carrying at least a single wild-type allele (8.8 months; n = 88; P = 0.0012). D, Survival after docetaxel treatment of combined docetaxel trials in patients who were >70 years of age carrying CYP19 variant alleles (15.7 months; n = 5) and those carrying only wild-type alleles (26.3 months; n = 42; P = 0.041). E, PFS of docetaxel-based trials in individuals who were not obese (BMI < 30) carrying only ERα A>G variant alleles (3.2 months; n = 9) and those carrying at least one copy of a wild-type allele (6.7 months, n = 40; P = 0.0078). F, PFS of thalidomide monotherapy in patients carrying ERα T>C homozygous and heterozygous genotypes (5.3 and 3.1 months, respectively; n = 9 and n = 23, respectively) and those carrying wild-type alleles (1.8 months; n = 8; P = 0.040).