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Original Investigation
May 11, 2017

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

Author Affiliations
  • 1Department of Radiation Oncology, University of Michigan, Ann Arbor
  • 2GenomeDx Biosciences Inc, Vancouver, British Columbia, Canada
  • 3Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison
  • 4Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco
  • 5Department of Medicine, Helen Diller Comprehensive Cancer Center, University of California, San Francisco
  • 6Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania
  • 7Department of Urology, Cedars-Sinai Medical Center, Los Angeles, California
  • 8Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
  • 9Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 10Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
  • 11Department of Urology, University of British Columbia, Vancouver, British Columbia, Canada
  • 12Department of Pathology, University of Michigan, Ann Arbor
  • 13Michigan Center for Translational Pathology, University of Michigan, Ann Arbor
  • 14Department of Urology, University of Michigan, Ann Arbor
  • 15Howard Hughes Medical Institute, University of Michigan, Ann Arbor
  • 16Department of Urology, Mayo Clinic, Rochester, Minnesota
  • 17James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland
  • 18Department of Urology, Northwestern University, Chicago, Illinois
  • 19Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, Massachusetts
  • 20Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco
JAMA Oncol. Published online May 11, 2017. doi:10.1001/jamaoncol.2017.0751
Key Points

Question  Is molecular subtyping by luminal and basal status clinically relevant in prostate cancer?

Findings  In this study of 3782 retrospectively and prospectively collected radical prostatectomy samples, molecular subtyping by the PAM50 classifier consistently segregates patients into luminal A, luminal B, and basal-like subtypes, which are associated with different lineage markers. Patients with luminal tumors exhibit increased androgen signaling, and those with luminal B tumors have poorer outcomes but potentially improved response to postoperative androgen deprivation therapy.

Meaning  Molecular subtyping by luminal and basal status in prostate cancer is prognostic for clinical outcomes and may be associated with response to postoperative 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.

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