Rahul Aggarwal1,2, Nicholas R Rydzewski1, Li Zhang2,3, Adam Foye2,3, Won Kim2,3, Kyle T Helzer1, Hamza Bakhtiar1, S Laura Chang4, Marc D Perry2,4, Martin Gleave5, Robert E Reiter6, Jiaoti Huang7, Christopher P Evans8, Joshi J Alumkal9, Joshua M Lang10, Menggang Yu11, David A Quigley2,12, Martin Sjöström2,4, Eric J Small2,3, Felix Y Feng2,3,4,13, Shuang G Zhao1,14. 1. Department of Human Oncology, University of Wisconsin, Madison. 2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco. 3. Division of Hematology and Oncology, University of California, San Francisco. 4. Department of Radiation Oncology, University of California, San Francisco. 5. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 6. Jonsson Comprehensive Cancer Center, Departments of Medicine and Urology, University of California Los Angeles. 7. Department of Pathology, Duke University, Durham, North Carolina. 8. Comprehensive Cancer Center, Department of Urologic Surgery, University of California Davis, Sacramento. 9. Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor. 10. Department of Medicine, University of Wisconsin, Madison. 11. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison. 12. Department of Epidemiology and Biostatistics, University of California, San Francisco. 13. Department of Urology, University of California, San Francisco. 14. William S. Middleton Memorial Veterans Hospital, Madison.
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.
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.
Authors: Philip Sutera; Matthew P Deek; Kim Van der Eecken; Alexander W Wyatt; Amar U Kishan; Jason K Molitoris; Matthew J Ferris; M Minhaj Siddiqui; Zaker Rana; Mark V Mishra; Young Kwok; Elai Davicioni; Daniel E Spratt; Piet Ost; Felix Y Feng; Phuoc T Tran Journal: Prostate Date: 2022-08 Impact factor: 4.012
Authors: Xintao Qiu; Lisha G Brown; Jennifer L Conner; Holly M Nguyen; Nadia Boufaied; Sarah Abou Alaiwi; Ji-Heui Seo; Talal El Zarif; Connor Bell; Edward O'Connor; Brian Hanratty; Mark Pomerantz; Matthew L Freedman; Myles Brown; Michael C Haffner; Peter S Nelson; Felix Y Feng; David P Labbé; Henry W Long; Eva Corey Journal: JCI Insight Date: 2022-05-23
Authors: Ilsa M Coleman; Navonil DeSarkar; Colm Morrissey; Li Xin; Martine P Roudier; Erolcan Sayar; Dapei Li; Eva Corey; Michael C Haffner; Peter S Nelson Journal: Clin Cancer Res Date: 2022-07-15 Impact factor: 13.801
Authors: Joakin O Mori; Jason White; Isra Elhussin; Babatunde M Duduyemi; Balasubramanyam Karanam; Clayton Yates; Honghe Wang Journal: Front Oncol Date: 2022-08-10 Impact factor: 5.738
Authors: Hamza Bakhtiar; Kyle T Helzer; Yeonhee Park; Yi Chen; Nicholas R Rydzewski; Matthew L Bootsma; Yue Shi; Paul M Harari; Marina Sharifi; Martin Sjöström; Joshua M Lang; Menggang Yu; Shuang G Zhao Journal: NPJ Genom Med Date: 2022-10-17 Impact factor: 6.083