Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer

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. ParnesScott M. Lippman, Ian M. Thompson, Powel H. Brown, Christopher J. Logothetis, Patricia Troncoso

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 5. mg finasteride or placebo daily in a double-blind study during the 4-6. weeks 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. Findings: 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. Interpretation: 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.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Jan 12 2016

Fingerprint

Finasteride
Prostatic Neoplasms
Randomized Controlled Trials
Tissue
Placebos
Androgen Receptors
Tumors
Neoplasms
Prostatectomy
Caspase 3
Apoptosis
Computer Communication Networks
Intranets
Neoplasm Grading
Cell proliferation
Double-Blind Method
Vascular Endothelial Growth Factor A
Logistics

Keywords

  • 5α- reductase inhibitors
  • Biomarkers
  • Cancer prevention
  • Finasteride
  • Prostate cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kim, J., Davis, J. W., Klein, E. A., Magi-Galluzzi, C., Lotan, Y., Ward, J. F., ... Troncoso, P. (Accepted/In press). Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer. EBioMedicine. https://doi.org/10.1016/j.ebiom.2016.03.047

Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer. / Kim, Jeri; Davis, John W.; Klein, Eric A.; Magi-Galluzzi, Cristina; Lotan, Yair; Ward, John F.; Pisters, Louis L.; Basler, Joseph W.; Pettaway, Curtis A.; Stephenson, Andrew; Li Ning Tapia, Elsa M.; Efstathiou, Eleni; Wang, Xuemei; Do, Kim Anh; Lee, J. Jack; Gorlov, Ivan P.; Vornik, Lana A.; Hoque, Ashraful M.; Prokhorova, Ina N.; Parnes, Howard L.; Lippman, Scott M.; Thompson, Ian M.; Brown, Powel H.; Logothetis, Christopher J.; Troncoso, Patricia.

In: EBioMedicine, 12.01.2016.

Research output: Contribution to journalArticle

Kim, J, Davis, JW, Klein, EA, Magi-Galluzzi, C, Lotan, Y, Ward, JF, Pisters, LL, Basler, JW, Pettaway, CA, Stephenson, A, Li Ning Tapia, EM, Efstathiou, E, Wang, X, Do, KA, Lee, JJ, Gorlov, IP, Vornik, LA, Hoque, AM, Prokhorova, IN, Parnes, HL, Lippman, SM, Thompson, IM, Brown, PH, Logothetis, CJ & Troncoso, P 2016, 'Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer', EBioMedicine. https://doi.org/10.1016/j.ebiom.2016.03.047
Kim, Jeri ; Davis, John W. ; Klein, Eric A. ; Magi-Galluzzi, Cristina ; Lotan, Yair ; Ward, John F. ; Pisters, Louis L. ; Basler, Joseph W. ; Pettaway, Curtis A. ; Stephenson, Andrew ; Li Ning Tapia, Elsa M. ; Efstathiou, Eleni ; Wang, Xuemei ; Do, Kim Anh ; Lee, J. Jack ; Gorlov, Ivan P. ; Vornik, Lana A. ; Hoque, Ashraful M. ; Prokhorova, Ina N. ; Parnes, Howard L. ; Lippman, Scott M. ; Thompson, Ian M. ; Brown, Powel H. ; Logothetis, Christopher J. ; Troncoso, Patricia. / Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer. In: EBioMedicine. 2016.
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abstract = "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 5. mg finasteride or placebo daily in a double-blind study during the 4-6. weeks 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. Findings: 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. Interpretation: 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.",
keywords = "5α- reductase inhibitors, Biomarkers, Cancer prevention, Finasteride, Prostate cancer",
author = "Jeri Kim and Davis, {John W.} and Klein, {Eric A.} and Cristina Magi-Galluzzi and Yair Lotan and Ward, {John F.} and Pisters, {Louis L.} and Basler, {Joseph W.} and Pettaway, {Curtis A.} and Andrew Stephenson and {Li Ning Tapia}, {Elsa M.} and Eleni Efstathiou and Xuemei Wang and Do, {Kim Anh} and Lee, {J. Jack} and Gorlov, {Ivan P.} and Vornik, {Lana A.} and Hoque, {Ashraful M.} and Prokhorova, {Ina N.} and Parnes, {Howard L.} and Lippman, {Scott M.} and Thompson, {Ian M.} and Brown, {Powel H.} and Logothetis, {Christopher J.} and Patricia Troncoso",
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T1 - Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer

AU - Kim, Jeri

AU - Davis, John W.

AU - Klein, Eric A.

AU - Magi-Galluzzi, Cristina

AU - Lotan, Yair

AU - Ward, John F.

AU - Pisters, Louis L.

AU - Basler, Joseph W.

AU - Pettaway, Curtis A.

AU - Stephenson, Andrew

AU - Li Ning Tapia, Elsa M.

AU - Efstathiou, Eleni

AU - Wang, Xuemei

AU - Do, Kim Anh

AU - Lee, J. Jack

AU - Gorlov, Ivan P.

AU - Vornik, Lana A.

AU - Hoque, Ashraful M.

AU - Prokhorova, Ina N.

AU - Parnes, Howard L.

AU - Lippman, Scott M.

AU - Thompson, Ian M.

AU - Brown, Powel H.

AU - Logothetis, Christopher J.

AU - Troncoso, Patricia

PY - 2016/1/12

Y1 - 2016/1/12

N2 - 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 5. mg finasteride or placebo daily in a double-blind study during the 4-6. weeks 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. Findings: 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. Interpretation: 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.

AB - 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 5. mg finasteride or placebo daily in a double-blind study during the 4-6. weeks 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. Findings: 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. Interpretation: 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.

KW - 5α- reductase inhibitors

KW - Biomarkers

KW - Cancer prevention

KW - Finasteride

KW - Prostate cancer

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