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Original Investigation
September 23, 2021

Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer

Author Affiliations
  • 1Department of Human Oncology, University of Wisconsin, Madison
  • 2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
  • 3Division of Hematology and Oncology, University of California, San Francisco
  • 4Department of Radiation Oncology, University of California, San Francisco
  • 5Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  • 6Jonsson Comprehensive Cancer Center, Departments of Medicine and Urology, University of California Los Angeles
  • 7Department of Pathology, Duke University, Durham, North Carolina
  • 8Comprehensive Cancer Center, Department of Urologic Surgery, University of California Davis, Sacramento
  • 9Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor
  • 10Department of Medicine, University of Wisconsin, Madison
  • 11Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison
  • 12Department of Epidemiology and Biostatistics, University of California, San Francisco
  • 13Department of Urology, University of California, San Francisco
  • 14William S. Middleton Memorial Veterans Hospital, Madison
JAMA Oncol. 2021;7(11):1644-1652. doi:10.1001/jamaoncol.2021.3987
Key Points

Question  What are the prognostic implications of luminal and basal subtypes in metastatic castration-resistant prostate cancer?

Findings  In this cohort study including tissue samples from 634 patients with metastatic prostate cancer, distinct molecular patterns associated with luminal and basal subtypes were identified; in addition, enrichment of small cell/neuroendocrine prostate cancer samples were noted in the basal tumors. The subtypes were prognostic, and the patients with luminal subtypes preferentially benefited from androgen-signaling inhibitors.

Meaning  These findings suggest that patients with luminal tumors should be considered for androgen-signaling inhibitor therapy, and those with basal tumors could be considered for chemotherapeutic approaches given the similarity to small cell/neuroendocrine prostate cancer and the diminished benefit of androgen-signaling inhibitors; further investigation is warranted in prospective clinical trials.

Abstract

Importance  Luminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct and clinically important in predicting response to therapy. These subtypes have not been described in metastatic prostate cancer.

Objectives  To identify clinical and molecular correlates of luminal and basal subtypes in metastatic castration-resistant prostate cancer (mCRPC) and investigate differences in survival, particularly after treatment with androgen-signaling inhibitors (ASIs).

Design, Setting, and Participants  In this cohort study, a retrospective analysis was conducted of 4 cohorts with mCRPC (N = 634) across multiple academic centers. Treatment was at the physicians’ discretion. Details of the study cohorts have been published elsewhere between 2016 and 2019. Data were analyzed from March 2018 to February 2021.

Main Outcomes and Measures  The primary clinical end point was overall survival from the date of tissue biopsy/molecular profiling. Luminal and basal subtypes were also stratified by postbiopsy ASI treatment. The primary molecular analyses included associations with small cell/neuroendocrine prostate cancer (SCNC), molecular pathways, and DNA alterations.

Results  In the 634 patients, 288 (45%) had tumors classified as luminal, and 346 (55%) had tumors classified as basal. However, 53 of 59 (90%) SCNC tumors were basal (P < .001). Similar to primary prostate cancer, luminal tumors exhibited overexpression of AR pathway genes. In basal tumors, a significantly higher rate of RB1 loss (23% basal vs 4% luminal; P < .001), FOXA1 alterations (36% basal vs 27% luminal; P = .03) and MYC alterations (73% basal vs 56% luminal; P < .001) were identified. Patients with basal tumors had worse overall survival compared with those with luminal tumors only in patients treated with an ASI postbiopsy (East Coast Dream Team: hazard ratio [HR], 0.39; 95% CI, 0.20-0.74; P = .004; West Coast Dream Team: HR, 0.57; 95% CI, 0.33-0.97; P = .04). Among patients with luminal tumors, those treated with an ASI had significantly better survival (HR, 0.27; 95% CI, 0.14-0.53; P < .001), whereas patients with basal tumors did not (HR, 0.62; 95% CI, 0.36-1.04, P = .07). The interaction term between subtype and ASI treatment was statistically significant (HR, 0.42; 95% CI, 0.20-0.89; P = .02).

Conclusions and Relevance  These findings represent the largest integrated clinical, transcriptomic, and genomic analysis of mCRPC samples to date, and suggest that mCRPC can be classified as luminal and basal tumors. Analogous to primary prostate cancer, these data suggest that the benefit of ASI treatment is more pronounced in luminal tumors and support the use of ASIs in this population. In the basal tumors, a chemotherapeutic approach could be considered in some patients given the similarity to SCNC and the diminished benefit of ASI therapy. Further validation in prospective clinical trials is warranted.

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