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. 2021 Nov 1;7(11):1644-1652.
doi: 10.1001/jamaoncol.2021.3987.

Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer

Rahul Aggarwal  1   2 , Nicholas R Rydzewski  1 , Li Zhang  2   3 , Adam Foye  2   3 , Won Kim  2   3 , Kyle T Helzer  1 , Hamza Bakhtiar  1 , S Laura Chang  4 , Marc D Perry  2   4 , Martin Gleave  5 , Robert E Reiter  6 , Jiaoti Huang  7 , Christopher P Evans  8 , Joshi J Alumkal  9 , Joshua M Lang  10 , Menggang Yu  11 , David A Quigley  2   12 , Martin Sjöström  2   4 , Eric J Small  2   3 , Felix Y Feng  2   3   4   13 , Shuang G Zhao  1   14
Affiliations

Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer

Rahul Aggarwal et al. JAMA Oncol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aggarwal has served as a paid consultant for Janssen, Merck, AstraZeneca, Dendreon, Clovis, Pfizer, and Amgen, and has received research funding from Amgen, Merck, Novartis, AstraZeneca, Xynomic, and Zenith Epigenetics. Dr Huang is a paid consultant for or owns shares in the following companies: Kingmed, MoreHealth, OptraScan, Genetron, Omnitura, Vetonco, York Biotechnology, Genecode, VIVA Biotech, and Sisu Pharma, and received grants from Zenith Epigenetics, BioXcel Therapeutics Inc, and Fortis Therapeutics. Dr Small has served as a paid consultant for Janssen, Fortis Therapeutics, Harpoon Therapeutics, and Teon Therapeutics. Dr Lang holds equity in Salus Discovery LLC. Dr Feng has served as a paid consultant for Astellas, Bayer, BlueEarth Diagnostics, Celgene, EMD Serono, Genentech, Janssen, Myovant, Ryovant, BMS, Exact Sciences, and Varian, and serves on the scientific advisory board for Bluestar Genomics and Serimmune. Drs Zhao, Chang, and Feng have pending patent applications with Decipher Biosciences on luminal and basal subtypes in prostate cancer, as well as other molecular signatures in prostate cancer unrelated to this work. Drs Zhao and Feng have a pending patent application for a molecular signature in breast cancer unrelated to this work licensed to Exact Sciences. Dr Chang was at UCSF at the time of the study and is now an employee of Exact Sciences. Dr Kim was at UCSF at the time of the study and is now an employee of Janssen Pharmaceuticals. Dr Alumkal has served as a paid consultant for or held advisory roles at Astellas Pharma, Bayer, Janssen Biotech Inc, Dendreon, and Bristol-Myers Squibb. His prior institution (Oregon Health and Science University) has received research funding from Aragon Pharmaceuticals Inc, Astellas Pharma, Novartis, Zenith Epigenetics Ltd, and Gilead Sciences Inc.

Figures

Figure 1.
Figure 1.. Luminal and Basal Subtypes of Metastatic Castration-Resistant Prostate Cancer (mCRPC)
A, PAM50 expression (rows) for each sample (columns). B, t-distributed stochastic neighbor-embedding (tSNE) plot.
Figure 2.
Figure 2.. Gene Set Enrichment Analysis
A, Gene set enrichment analysis (GSEA) was completed on the Molecular Signatures Database hallmark gene set collection, focusing on hallmark pathways involved in prostate cancer. A volcano plot of the GSEA results depicts log2 geometric mean fold change in gene expression across each gene set between basal vs luminal samples plotted against the − log10 Benjamini-Hochberg (BH)–corrected P values, to control for the false discovery rate with multiple testing. IFN-γ indicates interferon-γ; Il-6, interleukin 6; and TNF-α, tumor necrosis factor-α. The vertical dotted blue line indicates P < .05. B, GSEA enrichment plot of the androgen response hallmark pathway, showing that the androgen response pathway is positively enriched in basal samples (P < .001).
Figure 3.
Figure 3.. DNA Alterations and Subtypes
Proportion of samples with a biallelic loss of function mutation/copy loss of a tumor suppressor gene and gain of function mutations in oncogenes in each individual cohort as well as pooled.
Figure 4.
Figure 4.. Clinical Outcomes and Subtypes
A, Survival compared between luminal and basal subtypes within the East Coast Dream Team, where all patients received postbiopsy androgen-signaling inhibitor (ASI) treatment. Hazard ratio (HR), 0.39; P = .004. B, Survival compared between luminal and basal subtypes within the West Coast Dream Team further stratified by whether a patient received postbiopsy ASI treatment. Basal with vs without ASI: HR, 0.62; P = .07. Luminal with vs without ASI: HR, 0.27; P < .001. Hazard ratios determined using Cox proportional hazards model.
Figure 5.
Figure 5.. Intrapatient Subtype Variability
Biopsy samples from the Fred Hutchinson Cancer Research Center autopsy cohort, depicting intrapatient variability in both the luminal-basal score and subtype class. Only patients with more than 1 biopsy were included. Each patient is plotted along a single line from the y-axis, with each symbol representing a separate biopsy. Biopsies are color coded based on the luminal-basal cluster group and variability of the linear luminal-basal score is plotted along the x-axis.
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