Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy.
Zhao, Shuang G. MD 1; Chang, S. Laura PhD 1; Erho, Nicholas MS 2; Yu, Menggang PhD 3; Lehrer, Jonathan BA 2; Alshalalfa, Mohammed PhD 2; Speers, Corey MD; PhD 1; Cooperberg, Matthew R. MD 4; Kim, Won MD 5; Ryan, Charles J. MD 5; Den, Robert B. MD 6; Freedland, Stephen J. MD 7; Posadas, Edwin MD 8; Sandler, Howard MD 9; Klein, Eric A. MD 10; Black, Peter MD 11; Seiler, Roland MD 11; Tomlins, Scott A. MD; PhD 12,13; Chinnaiyan, Arul M. MD; PhD 12,13,14,15; Jenkins, Robert B. MD; PhD 16; Davicioni, Elai PhD 2; Ross, Ashley E. MD; PhD 17; Schaeffer, Edward M. MD; PhD 18; Nguyen, Paul L. MD 19; Carroll, Peter R. MD 4; Karnes, R. Jeffrey MD 16; Spratt, Daniel E. MD 1; Feng, Felix Y. MD 1,4,5,13,20
3(12):1663-1672, December 2017.
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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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