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.
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.
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.
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.
EBioMedicine. 2016 Apr 07 [Epub]
Jeri Kim, John W Davis, Eric A Klein, Cristina Magi-Galluzzi, Yair Lotan, John F Ward, Louis L Pisters, Joseph W Basler, Curtis A Pettaway, Andrew Stephenson, Elsa M Li Ning Tapia, Eleni Efstathiou, Xuemei Wang, Kim-Anh Do, J Jack Lee, Ivan P Gorlov, Lana A Vornik, Ashraful M Hoque, Ina N Prokhorova, Howard L Parnes, Scott M Lippman, Ian M Thompson, Powel H Brown, Christopher J Logothetis, Patricia Troncoso
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: ., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA., Department of Urology, The University of Texas Southwestern Medical School, Dallas, TX 75390, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA., Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA., Moores Cancer Center, University of California, San Diego, San Diego, CA 92093, USA., Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.