Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

Shuang G. Zhao, S. Laura Chang, Nicholas Erho, Menggang Yu, Jonathan Lehrer, Mohammed Alshalalfa, Corey Speers, Matthew R. Cooperberg, Won Kim, Charles J. Ryan, Robert B. Den, Stephen J. Freedland, Edwin Posadas, Howard Sandler, Eric A. Klein, Peter Black, Roland Seiler, Scott A. Tomlins, Arul M. Chinnaiyan, Robert Brian Jenkins & 8 others Elai Davicioni, Ashley E. Ross, Edward M. Schaeffer, Paul L. Nguyen, Peter R. Carroll, Robert Jeffrey Karnes, Daniel E. Spratt, Felix Y. Feng

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Importance: There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives: To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants: The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures: Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results: Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). Conclusions and Relevance: Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

Original languageEnglish (US)
Pages (from-to)1663-1672
Number of pages10
JournalJAMA Oncology
Volume3
Issue number12
DOIs
StatePublished - Dec 1 2017

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Androgens
Prostatic Neoplasms
Survival
Neoplasm Metastasis
Therapeutics
Recurrence
Neoplasms
Androgen Receptors
Phenobarbital
Prostate
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhao, S. G., Chang, S. L., Erho, N., Yu, M., Lehrer, J., Alshalalfa, M., ... Feng, F. Y. (2017). Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy. JAMA Oncology, 3(12), 1663-1672. https://doi.org/10.1001/jamaoncol.2017.0751

Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy. / Zhao, Shuang G.; Chang, S. Laura; Erho, Nicholas; Yu, Menggang; Lehrer, Jonathan; Alshalalfa, Mohammed; Speers, Corey; Cooperberg, Matthew R.; Kim, Won; Ryan, Charles J.; Den, Robert B.; Freedland, Stephen J.; Posadas, Edwin; Sandler, Howard; Klein, Eric A.; Black, Peter; Seiler, Roland; Tomlins, Scott A.; Chinnaiyan, Arul M.; Jenkins, Robert Brian; Davicioni, Elai; Ross, Ashley E.; Schaeffer, Edward M.; Nguyen, Paul L.; Carroll, Peter R.; Karnes, Robert Jeffrey; Spratt, Daniel E.; Feng, Felix Y.

In: JAMA Oncology, Vol. 3, No. 12, 01.12.2017, p. 1663-1672.

Research output: Contribution to journalArticle

Zhao, SG, Chang, SL, Erho, N, Yu, M, Lehrer, J, Alshalalfa, M, Speers, C, Cooperberg, MR, Kim, W, Ryan, CJ, Den, RB, Freedland, SJ, Posadas, E, Sandler, H, Klein, EA, Black, P, Seiler, R, Tomlins, SA, Chinnaiyan, AM, Jenkins, RB, Davicioni, E, Ross, AE, Schaeffer, EM, Nguyen, PL, Carroll, PR, Karnes, RJ, Spratt, DE & Feng, FY 2017, 'Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy', JAMA Oncology, vol. 3, no. 12, pp. 1663-1672. https://doi.org/10.1001/jamaoncol.2017.0751
Zhao, Shuang G. ; Chang, S. Laura ; Erho, Nicholas ; Yu, Menggang ; Lehrer, Jonathan ; Alshalalfa, Mohammed ; Speers, Corey ; Cooperberg, Matthew R. ; Kim, Won ; Ryan, Charles J. ; Den, Robert B. ; Freedland, Stephen J. ; Posadas, Edwin ; Sandler, Howard ; Klein, Eric A. ; Black, Peter ; Seiler, Roland ; Tomlins, Scott A. ; Chinnaiyan, Arul M. ; Jenkins, Robert Brian ; Davicioni, Elai ; Ross, Ashley E. ; Schaeffer, Edward M. ; Nguyen, Paul L. ; Carroll, Peter R. ; Karnes, Robert Jeffrey ; Spratt, Daniel E. ; Feng, Felix Y. / Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy. In: JAMA Oncology. 2017 ; Vol. 3, No. 12. pp. 1663-1672.
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title = "Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy",
abstract = "Importance: There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives: To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants: The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures: Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results: Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3{\%}]; prospective, 737 [33.3{\%}]), luminal B (retrospective, 447 [28.5{\%}]; prospective, 723 [32.6{\%}]), and basal (retrospective, 582 [37.1{\%}]; prospective, 755 [34.1{\%}]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29{\%}; distant metastasis-free survival [DMFS], 53{\%}; prostate cancer-specific survival [PCSS], 78{\%}; overall survival [OS], 69{\%}), followed by basal prostate cancers (10-year bRFS, 39{\%}; DMFS, 73{\%}; PCSS, 86{\%}; OS, 80{\%}) and luminal A prostate cancers (10-year bRFS, 41{\%}; DMFS, 73{\%}; PCSS, 89{\%}; OS, 82{\%}). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33{\%} vs untreated, 55{\%}; nonluminal B 10-year metastasis: treated, 37{\%} vs untreated, 21{\%}; P = .006 for interaction). Conclusions and Relevance: Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.",
author = "Zhao, {Shuang G.} and Chang, {S. Laura} and Nicholas Erho and Menggang Yu and Jonathan Lehrer and Mohammed Alshalalfa and Corey Speers and Cooperberg, {Matthew R.} and Won Kim and Ryan, {Charles J.} and Den, {Robert B.} and Freedland, {Stephen J.} and Edwin Posadas and Howard Sandler and Klein, {Eric A.} and Peter Black and Roland Seiler and Tomlins, {Scott A.} and Chinnaiyan, {Arul M.} and Jenkins, {Robert Brian} and Elai Davicioni and Ross, {Ashley E.} and Schaeffer, {Edward M.} and Nguyen, {Paul L.} and Carroll, {Peter R.} and Karnes, {Robert Jeffrey} and Spratt, {Daniel E.} and Feng, {Felix Y.}",
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TY - JOUR

T1 - Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

AU - Zhao, Shuang G.

AU - Chang, S. Laura

AU - Erho, Nicholas

AU - Yu, Menggang

AU - Lehrer, Jonathan

AU - Alshalalfa, Mohammed

AU - Speers, Corey

AU - Cooperberg, Matthew R.

AU - Kim, Won

AU - Ryan, Charles J.

AU - Den, Robert B.

AU - Freedland, Stephen J.

AU - Posadas, Edwin

AU - Sandler, Howard

AU - Klein, Eric A.

AU - Black, Peter

AU - Seiler, Roland

AU - Tomlins, Scott A.

AU - Chinnaiyan, Arul M.

AU - Jenkins, Robert Brian

AU - Davicioni, Elai

AU - Ross, Ashley E.

AU - Schaeffer, Edward M.

AU - Nguyen, Paul L.

AU - Carroll, Peter R.

AU - Karnes, Robert Jeffrey

AU - Spratt, Daniel E.

AU - Feng, Felix Y.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Importance: There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives: To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants: The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures: Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results: Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). Conclusions and Relevance: Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

AB - Importance: There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives: To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants: The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures: Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results: Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18, were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). Conclusions and Relevance: Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

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