Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients.
BACKGROUND
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. 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.


METHODS
CYP1B1 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.


RESULTS
Patients 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.


CONCLUSIONS
CYP1B1-4326C>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.
Pastina
Ilaria
I
Department of Medical Oncology, Pisa University Hospital, Pisa, Italy.
Giovannetti
Elisa
E
Chioni
Aldo
A
Sissung
Tristan M
TM
Crea
Francesco
F
Orlandini
Cinzia
C
Price
Douglas K
DK
Cianci
Claudia
C
Figg
William D
WD
Ricci
Sergio
S
Danesi
Romano
R
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000502:physiology; D065633:Cytochrome P-450 CYP1B1; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1