Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.
BACKGROUND
In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.


METHODS
From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.


RESULTS
We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.


CONCLUSIONS
We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jekim@mdanderson.org.
Jeri
J
Kim
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
John W
JW
Davis
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Eric A
EA
Klein
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA.
Cristina
C
Magi-Galluzzi
Department of Urology, The University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
Yair
Y
Lotan
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
John F
JF
Ward
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Louis L
LL
Pisters
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Joseph W
JW
Basler
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Curtis A
CA
Pettaway
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Andrew
A
Stephenson
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Elsa M
EM
Li Ning Tapia
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eleni
E
Efstathiou
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xuemei
X
Wang
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Kim-Anh
KA
Do
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
J Jack
JJ
Lee
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ivan P
IP
Gorlov
Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
Lana A
LA
Vornik
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ashraful M
AM
Hoque
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ina N
IN
Prokhorova
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA.
Howard L
HL
Parnes
Moores Cancer Center, University of California, San Diego, San Diego, CA 92093, USA.
Scott M
SM
Lippman
Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Ian M
IM
Thompson
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Powel H
PH
Brown
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Christopher J
CJ
Logothetis
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Patricia
P
Troncoso
D000284:Administration, Oral; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004311:Double-Blind Method; D018120:Finasteride / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D016896:Treatment Outcome
C410798:AR protein, human; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen; D018120:Finasteride
5α-reductase inhibitors; Biomarkers; Cancer prevention; Finasteride; Prostate cancer