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1. Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

Author

Fonseca, Nicolette M., Maurice-Dror, Corinne, Herberts, Cameron, Tu, Wilson, Fan, William, Murtha, Andrew J., Kollmannsberger, Catarina, Kwan, Edmond M., Parekh, Karan, Schönlau, Elena, Bernales, Cecily Q., Donnellan, Gráinne, Ng, Sarah W. S., Sumiyoshi, Takayuki, Vergidis, Joanna, Noonan, Krista, Finch, Daygen L., Zulfiqar, Muhammad, Miller, Stacy, Parimi, Sunil, Lavoie, Jean-Michel, Hardy, Edward, Soleimani, Maryam, Nappi, Lucia, Eigl, Bernhard J., Kollmannsberger, Christian, Taavitsainen, Sinja, Nykter, Matti, Tolmeijer, Sofie H., Boerrigter, Emmy, Mehra, Niven, van Erp, Nielka P., De Laere, Bram, Lindberg, Johan, Grönberg, Henrik, Khalaf, Daniel J., Annala, Matti, Chi, Kim N., and Wyatt, Alexander W.

Published
2024
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2. Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from Phase 3 randomised clinical studies TITAN and SPARTAN

Author

Shen, John, Chowdhury, Simon, Agarwal, Neeraj, Karsh, Lawrence I., Oudard, Stéphane, Gartrell, Benjamin A., Feyerabend, Susan, Saad, Fred, Pieczonka, Christopher M., Chi, Kim N., Brookman-May, Sabine D., Rooney, Brendan, Bhaumik, Amitabha, McCarthy, Sharon A., Bevans, Katherine B., Mundle, Suneel D., Small, Eric J., Smith, Matthew R., and Graff, Julie N.

Published
2024
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3. Post Hoc Analysis of Rapid and Deep Prostate-specific Antigen Decline and Patient-reported Health-related Quality of Life in SPARTAN and TITAN Patients with Advanced Prostate Cancer

Author

Small, Eric J., Chi, Kim N., Chowdhury, Simon, Bevans, Katherine B., Bhaumik, Amitabha, Saad, Fred, Chung, Byung Ha, Karsh, Lawrence I., Oudard, Stéphane, De Porre, Peter, Brookman-May, Sabine D., McCarthy, Sharon A., Mundle, Suneel D., Uemura, Hirotsugu, Smith, Matthew R., and Agarwal, Neeraj

Published
2024
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8. The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors

Author

Chen, Sujun, Petricca, Jessica, Ye, Wenbin, Guan, Jiansheng, Zeng, Yong, Cheng, Nicholas, Gong, Linsey, Shen, Shu Yi, Hua, Junjie T, Crumbaker, Megan, Fraser, Michael, Liu, Stanley, Bratman, Scott V, van der Kwast, Theodorus, Pugh, Trevor, Joshua, Anthony M, De Carvalho, Daniel D, Chi, Kim N, Awadalla, Philip, Ji, Guoli, Feng, Felix, Wyatt, Alexander W, and He, Housheng Hansen

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Urologic Diseases, Human Genome, Prostate Cancer, Genetic Testing, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Male, Humans, Epigenome, Cell-Free Nucleic Acids, Prostatic Neoplasms, Prostate, DNA Methylation
Abstract

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.

Published
2022

9. Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised clinical TITAN study

Author

Merseburger, Axel S., Agarwal, Neeraj, Bhaumik, Amitabha, Lefresne, Florence, Karsh, Laurence I., Pereira de Santana Gomes, Andrea J., Soto, Álvaro Juárez, Given, Robert W., Brookman-May, Sabine D., Mundle, Suneel D., McCarthy, Sharon A., Uemura, Hirotsugu, Chowdhury, Simon, Chi, Kim N., and Bjartell, Anders

Published
2023
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10. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Author

Parnis, Francis, Joshua, Anthony M., Horvath, Lisa G., Steer, Christopher, Marx, Gavin, Sandhu, Shahneen, Gurney, Howard, Ferguson, Thomas, Van Bruwaene, Siska, Luyten, Daisy, Schatteman, Peter, Lumen, Nicolaas, Dirix, Luc, Goeminne, Jean-Charles, Gil, Thierry, Seront, Emmanuel, Vulsteke, Christof, Kussumoto, Celio, Franke, Fabio A., Martinelli de Oliveira, Fabricio Augusto, Pereira de Santana Gomes, Andrea Juliana, Pinczowski, Hélio, Preto, Daniel D'Almeida, Zucca, Luis Eduardo, Borges, Giuliano Santos, Murad, Andre M., Saad, Fred, Chi, Kim N., Fradet, Yves, Fleshner, Neil E., Emmenegger, Urban, Brasso, Klaus, Fizazi, Karim, Culine, Stephane, Thiery-Vuillemin, Antoine, Joly, Florence, Fléchon, Aude, Hilgers, Werner, Eymard, Jean-Christophe, Borchiellini, Delphine, Barthélémy, Philippe, Berger, Raanan, Leibowitz-Amit, Raya, Mermershtain, Wilmosh, Rouvinov, Keren, Peer, Avivit, Kovel, Svetlana, Sella, Avishay, Lolkema, Martijn P., van den Eertwegh, Alfonsus J.M., Voortman, Johannes, Aarts, Maureen J., Gietema, Jourik A., Kim, Choung-Soo, Choi, Young-Deuk, Chung, Byung-Ha, Gafanov, Rustem A., Kopyltsov, Evgeniy, Usynin, Evgeny A., Carles, Joan, Mellado, Begoña, Maroto, José Pablo, García-Donás, Jesús, Rodríguez Moreno, Juan Francisco, Durán, Ignacio, Pérez-Valderrama, Begoña, Castro, Elena, Olmos, David, Méndez-Vidal, María José, Estellés, David Lorente, Sarrió, Regina Gironés, Muñoz-Langa, José, Herranz, Urbano Anido, Puente Vázquez, Javier, Castellanos, Enrique, Hellström, Martin, Widmark, Anders, Lissbrant, Ingela Franck, Jellvert, Åsa, Külich, Cecilia, Blom, René, Ståhl, Olof, Chiang, Po-Hui, Kang, Chih-Hsiung, Ou, Yen-Chuan, Wang, Shian-Shiang, Wu, Hsi-Chin, Lu, Yu-Chuan, Attard, Gerhardt, Khoo, Vincent, Bahl, Amit, Kellati, Prasad, Parikh, Omi, Srinivasan, Rajaguru, Lester, Jason F., Staffurth, John N., Cheng, Heather H., Efstathiou, Eleni, Pilié, Patrick G., George, Daniel J., Karsh, Lawrence I., Kelly, W. Kevin, Danila, Daniel C., Sieber, Paul R., Smith, Matthew R., Heath, Elisabeth I., Vaishampayan, Ulka N., Flaig, Thomas W., Emamekhoo, Hamid, Pinski, Jacek K., Kalebasty, Arash Rezazadeh, Maly, Joseph J., Moon, Helen, Smith, Matthew R, Scher, Howard I, Lara, Primo N, Jr, Yu, Evan Y, George, Daniel J, Chi, Kim N, Danila, Daniel C, Mason, Gary E, Espina, Byron M, Zhao, Xin, Urtishak, Karen A, Francis, Peter, and Lopez-Gitlitz, Angela

Published
2022
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12. Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial

Author

Fizazi, Karim, Herrmann, Ken, Krause, Bernd J, Rahbar, Kambiz, Chi, Kim N, Morris, Michael J, Sartor, Oliver, Tagawa, Scott T, Kendi, Ayse T, Vogelzang, Nicholas, Calais, Jeremie, Nagarajah, James, Wei, Xiao X, Koshkin, Vadim S, Beauregard, Jean-Mathieu, Chang, Brian, Ghouse, Ray, DeSilvio, Michelle, Messmann, Richard A, and de Bono, Johann

Published
2023
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13. Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

Author

Gillessen, Silke, Bossi, Alberto, Davis, Ian D., de Bono, Johann, Fizazi, Karim, James, Nicholas D., Mottet, Nicolas, Shore, Neal, Small, Eric, Smith, Matthew, Sweeney, Christopher J., Tombal, Bertrand, Antonarakis, Emmanuel S., Aparicio, Ana M., Armstrong, Andrew J., Attard, Gerhardt, Beer, Tomasz M., Beltran, Himisha, Bjartell, Anders, Blanchard, Pierre, Briganti, Alberto, Bristow, Rob G., Bulbul, Muhammad, Caffo, Orazio, Castellano, Daniel, Castro, Elena, Cheng, Heather H., Chi, Kim N., Chowdhury, Simon, Clarke, Caroline S., Clarke, Noel, Daugaard, Gedske, De Santis, Maria, Duran, Ignacio, Eeles, Ross, Efstathiou, Eleni, Efstathiou, Jason, Ekeke, Onyeanunam Ngozi, Evans, Christopher P., Fanti, Stefano, Feng, Felix Y., Fonteyne, Valerie, Fossati, Nicola, Frydenberg, Mark, George, Dan, Gleave, Martin, Gravis, Gwenaelle, Halabi, Susan, Heinrich, Daniel, Herrmann, Ken, Higano, Celestia, Hofman, Michael S., Horvath, Lisa G., Hussain, Maha, Jereczek-Fossa, Barbara A., Jones, Rob, Kanesvaran, Ravindran, Kellokumpu-Lehtinen, Pirkko-Liisa, Khauli, Raja B., Klotz, Laurence, Kramer, Gero, Leibowitz, Raja, Logothetis, Christopher, Mahal, Brandon, Maluf, Fernando, Mateo, Joaquin, Matheson, David, Mehra, Niven, Merseburger, Axel, Morgans, Alicia K., Morris, Michael J., Mrabti, Hind, Mukherji, Deborah, Murphy, Declan G., Murthy, Vedang, Nguyen, Paul L., Oh, William K., Ost, Piet, O’Sullivan, Joe M., Padhani, Anwar R., Pezaro, Carmel J., Poon, Darren M.C., Pritchard, Colin C., Rabah, Danny M., Rathkopf, Dana, Reiter, Robert E., Rubin, Mark A., Ryan, Charles J., Saad, Fred, Sade, Juan Pablo, Sartor, Oliver, Scher, Howard I., Sharifi, Nima, Skoneczna, Iwona, Soule, Howard, Spratt, Daniel E., Srinivas, Sandy, Sternberg, Cora N., Steuber, Thomas, Suzuki, Hiroyoshi, Sydes, Matthew R., Taplin, Mary-Ellen, Tilki, Derya, Türkeri, Levent, Turco, Fabio, Uemura, Hiroji, Uemura, Hirotsugu, Ürün, Yüksel, Vale, Claire L., van Oort, Inge, Vapiwala, Neha, Walz, Jochen, Yamoah, Kosj, Ye, Dingwei, Yu, Evan Y., Zapatero, Almudena, Zilli, Thomas, and Omlin, Aurelius

Published
2023
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15. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial

Author

Abdi, Ehtesham, Allan, Suzanne, Bastick, Patricia, Begbie, Stephen, Blum, Robert, Briscoe, Karen, Brungs, Daniel, Bydder, Sean, Chittajallu, Bala Renuka, Cronk, Michelle, Cuff, Katharine, Davis, Ian D, Dowling, Anthony, Frydenberg, Mark, George, Matthew, Horvath, Lisa, Hovey, Elizabeth, Joshua, Anthony, Karanth, Narayan, Kichenadasse, Ganessan, Krieger, Laurence, Marx, Gavin, Mathlum, Maitham, Nott, Louise, Otty, Zulfiquer, Parnis, Francis, Pook, David, Sandhu, Shahneen, Sewak, Sanjeev, Stevanovic, Amanda, Stockler, Martin, Suder, Aneta, Tan, Hsiang, Torres, Javier, Troon, Simon, Underhill, Craig, Weickhardt, Andrew, Zielinski, Robert, Abbas, Tahir, Anan, Ghadeer, Booth, Chris, Campbell, Holly, Chi, Kim, Chin, Joseph, Chouinard, Edmond, Donnelly, Bryan, Drachenberg, Darrel, Faghih, Amir, Finelli, Antonio, Hotte, Sebastien, Noonan, Krista, North, Scott, Rassouli, Mohammad, Reaume, Neil, Rendon, Ricardo, Saad, Fred, Sadikov, Evgeny, Vigneault, Eric, Zalewski, Pawel, McCaffrey, John, McDermott, Ray, Morris, Patrick, O'Connor, Miriam, Donnellan, Paul, O'Donnell, Dearbhaile, Edwards, Jim, Fong, Peter, Tan, Alvin, Chowdhury, Simon, Crabb, Simon, Khan, Omar, Khoo, Vincent, Macdonald, Graham, Payne, Heather, Robinson, Angus, Shamash, Jonathon, Staffurth, John, Thomas, Carys, Thomson, Alastair, Sweeney, Christopher J, Martin, Andrew J, Stockler, Martin R, Cheung, Leanna, Chi, Kim N, Horvath, Lisa G, Joshua, Anthony M, Lawrence, Nicola J, McJannett, Margaret, North, Scott A, Parulekar, Wendy, Pook, David W, Reaume, Martin Neil, Sandhu, Shahneen K, Tan, Thean Hsiang, Vera-Badillo, Francisco, Williams, Scott G, Winter, Diana, Yip, Sonia, Zhang, Alison Y, and Zielinski, Robert R

Published
2023
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16. The DNA methylation landscape of advanced prostate cancer

Author

Zhao, Shuang G, Chen, William S, Li, Haolong, Foye, Adam, Zhang, Meng, Sjöström, Martin, Aggarwal, Rahul, Playdle, Denise, Liao, Arnold, Alumkal, Joshi J, Das, Rajdeep, Chou, Jonathan, Hua, Junjie T, Barnard, Travis J, Bailey, Adina M, Chow, Eric D, Perry, Marc D, Dang, Ha X, Yang, Rendong, Moussavi-Baygi, Ruhollah, Zhang, Li, Alshalalfa, Mohammed, Laura Chang, S, Houlahan, Kathleen E, Shiah, Yu-Jia, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Yvonne Kim, M, Fong, Lawrence, Spratt, Daniel E, Morgan, Todd M, Bose, Rohit, Huang, Franklin W, Li, Hui, Chesner, Lisa, Shenoy, Tanushree, Goodarzi, Hani, Asangani, Irfan A, Sandhu, Shahneen, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Febbo, Phillip, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Zwart, Wilbert, Costello, Joseph F, Luo, Jianhua, Tomlins, Scott A, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Gilbert, Luke A, Boutros, Paul C, Farh, Kyle, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, Quigley, David A, and Feng, Felix Y

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Cancer, Prostate Cancer, Human Genome, Urologic Diseases, Cancer Genomics, Biotechnology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Carcinogenesis, DNA Methylation, Epigenomics, Gene Expression Regulation, Neoplastic, Genome, Humans, Male, Middle Aged, Mutation, Prospective Studies, Prostatic Neoplasms, Sequence Analysis, DNA, Exome Sequencing, Whole Genome Sequencing, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Published
2020

17. Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer

Author

Chen, William S, Feng, Eric L, Aggarwal, Rahul, Foye, Adam, Beer, Tomasz M, Alumkal, Joshi J, Gleave, Martin, Chi, Kim N, Reiter, Robert E, Rettig, Matthew B, Evans, Christopher P, Small, Eric J, Sharifi, Nima, and Zhao, Shuang G

Subjects
Biotechnology, Cancer, Clinical Research, Human Genome, Genetic Testing, Prostate Cancer, Genetics, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Androgen Antagonists, Biomarkers, Tumor, DNA, Neoplasm, Follow-Up Studies, Germ Cells, Humans, Male, Polymorphism, Genetic, Prognosis, Prostatic Neoplasms, Castration-Resistant, Retrospective Studies, Survival Rate, Oncology and Carcinogenesis, Urology & Nephrology
Abstract

IntroductionGermline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.MethodsGermline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.ResultsA comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.ConclusionsThis study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.

Published
2020

18. Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

Author

Gillessen, Silke, Attard, Gerhardt, Beer, Tomasz M, Beltran, Himisha, Bjartell, Anders, Bossi, Alberto, Briganti, Alberto, Bristow, Rob G, Chi, Kim N, Clarke, Noel, Davis, Ian D, de Bono, Johann, Drake, Charles G, Duran, Ignacio, Eeles, Ros, Efstathiou, Eleni, Evans, Christopher P, Fanti, Stefano, Feng, Felix Y, Fizazi, Karim, Frydenberg, Mark, Gleave, Martin, Halabi, Susan, Heidenreich, Axel, Heinrich, Daniel, Higano, Celestia Tia S, Hofman, Michael S, Hussain, Maha, James, Nicolas, Kanesvaran, Ravindran, Kantoff, Philip, Khauli, Raja B, Leibowitz, Raya, Logothetis, Chris, Maluf, Fernando, Millman, Robin, Morgans, Alicia K, Morris, Michael J, Mottet, Nicolas, Mrabti, Hind, Murphy, Declan G, Murthy, Vedang, Oh, William K, Ost, Piet, O'Sullivan, Joe M, Padhani, Anwar R, Parker, Chris, Poon, Darren MC, Pritchard, Colin C, Reiter, Robert E, Roach, Mack, Rubin, Mark, Ryan, Charles J, Saad, Fred, Sade, Juan Pablo, Sartor, Oliver, Scher, Howard I, Shore, Neal, Small, Eric, Smith, Matthew, Soule, Howard, Sternberg, Cora N, Steuber, Thomas, Suzuki, Hiroyoshi, Sweeney, Christopher, Sydes, Matthew R, Taplin, Mary-Ellen, Tombal, Bertrand, Türkeri, Levent, van Oort, Inge, Zapatero, Almudena, and Omlin, Aurelius

Subjects
Cancer, Urologic Diseases, Aging, Prostate Cancer, Good Health and Well Being, Bone Neoplasms, Humans, Male, Neoplasm Metastasis, Neoplasm Recurrence, Local, Neoplasm Staging, Practice Guidelines as Topic, Prostate-Specific Antigen, Prostatic Neoplasms, Advanced prostate cancer, High-risk localised prostate cancer, Hormone-sensitive prostate cancer, Castration-resistant prostate cancer, Oligometastatic prostate cancer, Progression-free survival, Overall survival, Prostate cancer treatment, Imaging, Genetics, Tumour genomic profiling, Castration-naïve prostate cancer, Clinical Sciences, Urology & Nephrology
Abstract

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

Published
2020

19. Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer

Author

Reimers, Melissa A, Yip, Steven M, Zhang, Li, Cieslik, Marcin, Dhawan, Mallika, Montgomery, Bruce, Wyatt, Alexander W, Chi, Kim N, Small, Eric J, Chinnaiyan, Arul M, Alva, Ajjai S, Feng, Felix Y, and Chou, Jonathan

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Urologic Diseases, Clinical Research, Genetics, Cancer, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Aged, Cyclin-Dependent Kinases, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Prostatic Neoplasms, Retrospective Studies, Treatment Outcome, Genomics, Next-generation sequencing, Prostate cancer, Cyclin-dependent kinase 12, Urology & Nephrology, Clinical sciences
Abstract

BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p =  0.004) and development of castration-resistant disease (median = 32.7 mo, p

Published
2020

20. Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

Author

Chen, William S, Aggarwal, Rahul, Zhang, Li, Zhao, Shuang G, Thomas, George V, Beer, Tomasz M, Quigley, David A, Foye, Adam, Playdle, Denise, Huang, Jiaoti, Lloyd, Paul, Lu, Eric, Sun, Duanchen, Guan, Xiangnan, Rettig, Matthew, Gleave, Martin, Evans, Christopher P, Youngren, Jack, True, Lawrence, Lara, Primo, Kothari, Vishal, Xia, Zheng, Chi, Kim N, Reiter, Robert E, Maher, Christopher A, Feng, Felix Y, Small, Eric J, Alumkal, Joshi J, and Team, on behalf of the West Coast Prostate Cancer Dream

Subjects
Biotechnology, Clinical Research, Urologic Diseases, Prostate Cancer, Rare Diseases, Genetics, Cancer, Human Genome, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Good Health and Well Being, Aged, Antineoplastic Agents, Benzamides, Biomarkers, Tumor, Drug Resistance, Neoplasm, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Nitriles, Outcome Assessment, Health Care, Phenylthiohydantoin, Predictive Value of Tests, Prognosis, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant, Whole Genome Sequencing, Advanced prostate cancer, Castration-resistant, Clinical outcomes, Enzalutamide, Genomics, Metastatic prostate cancer, Prognostic factors, West Coast Prostate Cancer Dream Team, Clinical Sciences, Urology & Nephrology
Abstract

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.ObjectiveTo use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.Design, setting, and participantsWe performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.Outcome measurements and statistical analysisOS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.Results and limitationsHarboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).ConclusionsThe presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.Patient summaryWe observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

Published
2019

21. Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022

Author

Gillessen, Silke, Bossi, Alberto, Davis, Ian D., de Bono, Johann, Fizazi, Karim, James, Nicholas D., Mottet, Nicolas, Shore, Neal, Small, Eric, Smith, Matthew, Sweeney, Christopher, Tombal, Bertrand, Antonarakis, Emmanuel S., Aparicio, Ana M., Armstrong, Andrew J., Attard, Gerhardt, Beer, Tomasz M., Beltran, Himisha, Bjartell, Anders, Blanchard, Pierre, Briganti, Alberto, Bristow, Rob G., Bulbul, Muhammad, Caffo, Orazio, Castellano, Daniel, Castro, Elena, Cheng, Heather H., Chi, Kim N., Chowdhury, Simon, Clarke, Caroline S., Clarke, Noel, Daugaard, Gedske, De Santis, Maria, Duran, Ignacio, Eeles, Ros, Efstathiou, Eleni, Efstathiou, Jason, Ngozi Ekeke, Onyeanunam, Evans, Christopher P., Fanti, Stefano, Feng, Felix Y., Fonteyne, Valerie, Fossati, Nicola, Frydenberg, Mark, George, Daniel, Gleave, Martin, Gravis, Gwenaelle, Halabi, Susan, Heinrich, Daniel, Herrmann, Ken, Higano, Celestia, Hofman, Michael S., Horvath, Lisa G., Hussain, Maha, Jereczek-Fossa, Barbara Alicja, Jones, Robert, Kanesvaran, Ravindran, Kellokumpu-Lehtinen, Pirkko-Liisa, Khauli, Raja B., Klotz, Laurence, Kramer, Gero, Leibowitz, Raya, Logothetis, Christopher J., Mahal, Brandon A., Maluf, Fernando, Mateo, Joaquin, Matheson, David, Mehra, Niven, Merseburger, Axel, Morgans, Alicia K., Morris, Michael J., Mrabti, Hind, Mukherji, Deborah, Murphy, Declan G., Murthy, Vedang, Nguyen, Paul L., Oh, William K., Ost, Piet, O'Sullivan, Joe M., Padhani, Anwar R., Pezaro, Carmel, Poon, Darren M.C., Pritchard, Colin C., Rabah, Danny M., Rathkopf, Dana, Reiter, Robert E., Rubin, Mark. A., Ryan, Charles J., Saad, Fred, Pablo Sade, Juan, Sartor, Oliver A., Scher, Howard I., Sharifi, Nima, Skoneczna, Iwona, Soule, Howard, Spratt, Daniel E., Srinivas, Sandy, Sternberg, Cora N., Steuber, Thomas, Suzuki, Hiroyoshi, Sydes, Matthew R., Taplin, Mary-Ellen, Tilki, Derya, Türkeri, Levent, Turco, Fabio, Uemura, Hiroji, Uemura, Hirotsugu, Ürün, Yüksel, Vale, Claire L., van Oort, Inge, Vapiwala, Neha, Walz, Jochen, Yamoah, Kosj, Ye, Dingwei, Yu, Evan Y., Zapatero, Almudena, Zilli, Thomas, and Omlin, Aurelius

Published
2023
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22. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Author

Herberts, Cameron, Annala, Matti, Sipola, Joonatan, Ng, Sarah W. S., Chen, Xinyi E., Nurminen, Anssi, Korhonen, Olga V., Munzur, Aslı D., Beja, Kevin, Schönlau, Elena, Bernales, Cecily Q., Ritch, Elie, Bacon, Jack V. W., Lack, Nathan A., Nykter, Matti, Aggarwal, Rahul, Small, Eric J., Gleave, Martin E., Quigley, David A., Feng, Felix Y., Chi, Kim N., and Wyatt, Alexander W.

Published
2022
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23. Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore.

Author

De Bono, Johann S., primary, Morris, Michael J., additional, Sartor, Oliver, additional, Wei, Xiao X., additional, Fizazi, Karim, additional, Herrmann, Ken, additional, Piulats, Josep M., additional, Mahammedi, Hakim, additional, Logothetis, Christopher, additional, George, Daniel J., additional, Eldjerou, Lamis K., additional, Wong, Connie, additional, Barys, Louise, additional, Rajagopal, Nisha, additional, Rodosthenous, Theodoulos, additional, and Chi, Kim N., additional

Published
2024
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24. Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01).

Author

Chi, Kim N., primary, Agarwal, Neeraj, additional, Armstrong, Andrew J., additional, Hellmis, Eva, additional, Schlürmann, Friederike, additional, Sugimoto, Mikio, additional, Ürün, Yüksel, additional, Xing, Nianzeng, additional, Aregay, Mehreteab, additional, Lima, Julianne, additional, Meulendijks, Didier, additional, and Azad, Arun, additional

Published
2024
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25. Health-related quality of life and pain in a phase 3 study of [177Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore).

Author

Fizazi, Karim, primary, Morris, Michael J., additional, Shore, Neal D., additional, Chi, Kim N., additional, Crosby, Michael, additional, De Bono, Johann S., additional, Herrmann, Ken, additional, Roubaud, Guilhem, additional, Nagarajah, James, additional, Fleming, Mark T., additional, Lewis, Brian E., additional, Nordquist, Luke, additional, Castellano, Daniel, additional, Carnahan, Natalie, additional, Ghebremariam, Samson, additional, Hertelendi, Marianna, additional, and Sartor, Oliver, additional

Published
2024
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27. Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity

Author

Aggarwal, Rahul R, Quigley, David A, Huang, Jiaoti, Zhang, Li, Beer, Tomasz M, Rettig, Matthew B, Reiter, Rob E, Gleave, Martin E, Thomas, George V, Foye, Adam, Playdle, Denise, Lloyd, Paul, Chi, Kim N, Evans, Christopher P, Lara, Primo N, Feng, Felix Y, Alumkal, Joshi J, and Small, Eric J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Prostate Cancer, Urologic Diseases, Cancer, Rare Diseases, Adenocarcinoma, Biomarkers, Tumor, Biopsy, Genome-Wide Association Study, Humans, Male, Neuroendocrine Tumors, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Transcription, Genetic, Developmental Biology, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.

Published
2019

28. Disparity in public funding of therapies for metastatic castrate-resistant prostate cancer across Canadian provinces

Author

Woon, Dixon TS, Chandrasekar, Thenappan, Aaron, Lorne, Basappa, Naveen S, Chi, Kim N, Conter, Henry J, Gotto, Geoffrey, Hotte, Sebastien J, Malone, Shawn, Saad, Fred, Shayegan, Bobby, Park-Wyllie, Laura, and Hamilton, Robert J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prostate Cancer, Urologic Diseases, Good Health and Well Being, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

INTRODUCTION:Treatment using abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, and radium-223 (Ra-223) improves overall survival (OS) and quality of life for patients with metastatic castrate-resistant prostate cancer (mCRPC). Despite their proven benefits, access to these therapies is not equal across Canada. METHODS:We describe provincial differences in access to approved mCRPC therapies. Data sources include the pan-Canadian Oncology Drug Review database, provincial cancer care resources, and correspondence with pharmaceutical companies. RESULTS:Both androgen receptor-axis-targeted therapies (ARATs), abiraterone acetate plus prednisone and enzalutamide, are funded by provinces in the pre-and post-chemotherapy setting, however, sequential ARAT use is not funded. "Sandwich" therapy, where one ARAT is used pre-chemotherapy and a second is used upon progression on chemotherapy, is funded in six provinces: Ontario (ON), Alberta, New Brunswick, Prince Edward Island (PEI), Nova Scotia (NS), and Newfoundland and Labrador. Ra-223 is funded in five provinces: ON, Quebec (QC), British Columbia (BC), Saskatchewan, and Manitoba to varying degrees; ON allows Ra-223 either pre- or post-chemo (not both); QC allows Ra-223 post-chemo unless chemo is not tolerated; BC allows Ra-223 if other life-prolonging mCRPC therapies have been received or ineligible. Cabazitaxel is funded in all provinces post-docetaxel, except QC and PEI. Cabazitaxel is not funded as fist-line treatment for mCPRC or in combination with other agents. In ON, BC, QC, and PEI, cabazitaxel is not funded after progression on an ARAT in the post-chemotherapy setting. CONCLUSIONS:While all provinces have access to docetaxel and ARATs, sandwiching sequential ARATs with docetaxel is funded only in select provinces. Ra-223 and cabazitaxel access is not ubiquitous across Canada. Such inequalities in access to life-prolonging therapies could lead to disparities in survival and quality of life among patients with mCRPC. Further research should quantify interprovincial variation in outcomes and cost that may result from variable access.

Published
2018

29. Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021

Author

Gillessen, Silke, Armstrong, Andrew, Attard, Gert, Beer, Tomasz M., Beltran, Himisha, Bjartell, Anders, Bossi, Alberto, Briganti, Alberto, Bristow, Robert G., Bulbul, Muhammad, Caffo, Orazio, Chi, Kim N., Clarke, Caroline S., Clarke, Noel, Davis, Ian D., de Bono, Johann S., Duran, Ignacio, Eeles, Ros, Efstathiou, Eleni, Efstathiou, Jason, Ekeke, Onyeanunam Ngozi, Evans, Christopher P., Fanti, Stefano, Feng, Felix Y., Fizazi, Karim, Frydenberg, Mark, George, Dan, Gleave, Martin, Halabi, Susan, Heinrich, Daniel, Higano, Celesta, Hofman, Michael S., Hussain, Maha, James, Nick, Jones, Robert, Kanesvaran, Ravindran, Khauli, Raja B., Klotz, Laurence, Leibowitz, Raya, Logothetis, Chris, Maluf, Fernando, Millman, Robin, Morgans, Alicia K., Morris, Michael J., Mottet, Nicolas, Mrabti, Hind, Murphy, Declan G., Murthy, Vedang, Oh, William K., Ost, Piet, O'Sullivan, Joe M., Padhani, Anwar R., Parker, Chris, Poon, Darren M.C., Pritchard, Colin C., Rabah, Danny M., Rathkopf, Dana, Reiter, Rob E., Rubin, Mark, Ryan, Charles J., Saad, Fred, Sade, Juan P., Sartor, Oliver, Scher, Howard I., Shore, Neal, Skoneczna, Iwona, Small, Eric, Smith, Matthew, Soule, Howard, Spratt, Daniel E., Sternberg, Cora N., Suzuki, Hiroyoshi, Sweeney, Christopher, Sydes, Matthew R., Taplin, Mary-Ellen, Tilki, Derya, Tombal, Bertrand, Türkeri, Levent, Uemura, Hiroji, Uemura, Hirotsugu, van Oort, Inge, Yamoah, Kosj, Ye, Dingwei, Zapatero, Almudena, and Omlin, Aurelius

Published
2022
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30. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study.

Author

Aggarwal, Rahul, Huang, Jiaoti, Alumkal, Joshi J, Zhang, Li, Feng, Felix Y, Thomas, George V, Weinstein, Alana S, Friedl, Verena, Zhang, Can, Witte, Owen N, Lloyd, Paul, Gleave, Martin, Evans, Christopher P, Youngren, Jack, Beer, Tomasz M, Rettig, Matthew, Wong, Christopher K, True, Lawrence, Foye, Adam, Playdle, Denise, Ryan, Charles J, Lara, Primo, Chi, Kim N, Uzunangelov, Vlado, Sokolov, Artem, Newton, Yulia, Beltran, Himisha, Demichelis, Francesca, Rubin, Mark A, Stuart, Joshua M, and Small, Eric J

Subjects
Prostate Cancer, Clinical Research, Human Genome, Genetics, Cancer, Urologic Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine, DNA Repair, Humans, Male, Middle Aged, Prospective Studies, Prostatic Neoplasms, Castration-Resistant, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

Published
2018

31. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

Author

Quigley, David A, Dang, Ha X, Zhao, Shuang G, Lloyd, Paul, Aggarwal, Rahul, Alumkal, Joshi J, Foye, Adam, Kothari, Vishal, Perry, Marc D, Bailey, Adina M, Playdle, Denise, Barnard, Travis J, Zhang, Li, Zhang, Jin, Youngren, Jack F, Cieslik, Marcin P, Parolia, Abhijit, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Lack, Nathan A, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Ryan, Charles J, Fong, Lawrence, Kim, Won, Friedlander, Terence, Chou, Jonathan, Li, Haolong, Das, Rajdeep, Li, Hui, Moussavi-Baygi, Ruhollah, Goodarzi, Hani, Gilbert, Luke A, Lara, Primo N, Evans, Christopher P, Goldstein, Theodore C, Stuart, Joshua M, Tomlins, Scott A, Spratt, Daniel E, Cheetham, R Keira, Cheng, Donavan T, Farh, Kyle, Gehring, Julian S, Hakenberg, Jörg, Liao, Arnold, Febbo, Philip G, Shon, John, Sickler, Brad, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, and Feng, Felix Y

Subjects
Humans, Prostatic Neoplasms, Neoplasm Metastasis, Cyclin-Dependent Kinases, Proto-Oncogene Proteins c-myc, BRCA2 Protein, Receptors, Androgen, Gene Expression Profiling, Genomics, Tandem Repeat Sequences, Mutation, Aged, Aged, 80 and over, Middle Aged, Male, Tumor Suppressor Protein p53, Genomic Structural Variation, DNA Copy Number Variations, Exome, Whole Genome Sequencing, BRCA2, androgen receptor, castration resistant prostate cancer, chromothripsis, gene fusion, genomics, metastases, structural variation, tandem duplication, whole-genome sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Published
2018

32. Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.

Author

Wyatt, Alexander W, Annala, Matti, Aggarwal, Rahul, Beja, Kevin, Feng, Felix, Youngren, Jack, Foye, Adam, Lloyd, Paul, Nykter, Matti, Beer, Tomasz M, Alumkal, Joshi J, Thomas, George V, Reiter, Robert E, Rettig, Matthew B, Evans, Christopher P, Gao, Allen C, Chi, Kim N, Small, Eric J, and Gleave, Martin E

Subjects
Genetics, Cancer, Human Genome, Urologic Diseases, Prostate Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Adenomatous Polyposis Coli Protein, BRCA2 Protein, Biomarkers, Tumor, Circulating Tumor DNA, Class Ia Phosphatidylinositol 3-Kinase, Cyclin-Dependent Kinase Inhibitor p27, DNA Copy Number Variations, Humans, Liquid Biopsy, Male, Mutation, Neoplasm Metastasis, Nuclear Proteins, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Repressor Proteins, Retinoblastoma Binding Proteins, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Wnt Signaling Pathway, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.

Published
2017

33. Clinical validation of circulating GDF15/MIC‐1 as a marker of response to docetaxel and survival in men with metastatic castration‐resistant prostate cancer

Author

Mahon, Kate L., primary, Sutherland, Sarah IM, additional, Lin, Hui Ming, additional, Stockler, Martin R., additional, Gurney, Howard, additional, Mallesara, Girish, additional, Briscoe, Karen, additional, Marx, Gavin, additional, Higano, Celestia S., additional, de Bono, Johann S., additional, Chi, Kim N., additional, Clark, Georgina, additional, Breit, Samuel N., additional, Brown, David A., additional, and Horvath, Lisa G., additional

Published
2024
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34. 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice

Author

Chi, Kim N., primary, Yip, Steven M., additional, Bauman, Glenn, additional, Probst, Stephan, additional, Emmenegger, Urban, additional, Kollmannsberger, Christian K., additional, Martineau, Patrick, additional, Niazi, Tamim, additional, Pouliot, Frédéric, additional, Rendon, Ricardo, additional, Hotte, Sebastien J., additional, Laidley, David T., additional, and Saad, Fred, additional

Published
2024
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35. Data from Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer

Author

Chen, Naiyu, primary, McGrath, Colleen B., primary, Ericsson, Caroline I., primary, Vaselkiv, Jane B., primary, Rencsok, Emily M., primary, Stopsack, Konrad H., primary, Guard, Hannah E., primary, Autio, Karen A., primary, Rathkopf, Dana E., primary, Enting, Deborah, primary, Bitting, Rhonda L., primary, Mateo, Joaquin, primary, Githiaka, Charles W., primary, Chi, Kim N., primary, Cheng, Heather H., primary, Davis, Ian D., primary, Anderson, Simon G., primary, Badal, Simone Ann Marie, primary, Bjartell, Anders, primary, Russnes, Kjell M., primary, Heath, Elisabeth I., primary, Pomerantz, Mark M., primary, Henegan, John C., primary, Hyslop, Terry, primary, Esteban, Emilio, primary, Omlin, Aurelius, primary, McDermott, Ray, primary, Fay, Andre P., primary, Popoola, Ademola Alabi, primary, Ragin, Camille, primary, Nowak, Joel, primary, Gerke, Travis, primary, Kantoff, Philip W., primary, George, Daniel J., primary, Penney, Kathryn L., primary, and Mucci, Lorelei A., primary

Published
2024
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36. Supplementary Table 1. from Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer

Author

Chen, Naiyu, primary, McGrath, Colleen B., primary, Ericsson, Caroline I., primary, Vaselkiv, Jane B., primary, Rencsok, Emily M., primary, Stopsack, Konrad H., primary, Guard, Hannah E., primary, Autio, Karen A., primary, Rathkopf, Dana E., primary, Enting, Deborah, primary, Bitting, Rhonda L., primary, Mateo, Joaquin, primary, Githiaka, Charles W., primary, Chi, Kim N., primary, Cheng, Heather H., primary, Davis, Ian D., primary, Anderson, Simon G., primary, Badal, Simone Ann Marie, primary, Bjartell, Anders, primary, Russnes, Kjell M., primary, Heath, Elisabeth I., primary, Pomerantz, Mark M., primary, Henegan, John C., primary, Hyslop, Terry, primary, Esteban, Emilio, primary, Omlin, Aurelius, primary, McDermott, Ray, primary, Fay, Andre P., primary, Popoola, Ademola Alabi, primary, Ragin, Camille, primary, Nowak, Joel, primary, Gerke, Travis, primary, Kantoff, Philip W., primary, George, Daniel J., primary, Penney, Kathryn L., primary, and Mucci, Lorelei A., primary

Published
2024
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37. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial

Author

Mateo, Joaquin, primary, de Bono, Johann S., additional, Fizazi, Karim, additional, Saad, Fred, additional, Shore, Neal, additional, Sandhu, Shahneen, additional, Chi, Kim N., additional, Agarwal, Neeraj, additional, Olmos, David, additional, Thiery-Vuillemin, Antoine, additional, Özgüroğlu, Mustafa, additional, Mehra, Niven, additional, Matsubara, Nobuaki, additional, Young Joung, Jae, additional, Padua, Charles, additional, Korbenfeld, Ernesto, additional, Kang, Jinyu, additional, Marshall, Helen, additional, Lai, Zhongwu, additional, Barnicle, Alan, additional, Poehlein, Christian, additional, Lukashchuk, Natalia, additional, and Hussain, Maha, additional

Published
2024
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38. Marital status, living arrangement, and survival among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer

Author

Chen, Naiyu, primary, McGrath, Colleen B., additional, Ericsson, Caroline I., additional, Vaselkiv, Jane B., additional, Rencsok, Emily M., additional, Stopsack, Konrad H., additional, Guard, Hannah E., additional, Autio, Karen A., additional, Rathkopf, Dana E., additional, Enting, Deborah, additional, Bitting, Rhonda L., additional, Mateo, Joaquin, additional, Githiaka, Charles Waihenya., additional, Chi, Kim N., additional, Cheng, Heather H., additional, Davis, Ian D., additional, Anderson, Simon G., additional, Badal, Simone Ann Marie., additional, Bjartell, Anders, additional, Russnes, Kjell M., additional, Heath, Elisabeth I., additional, Pomerantz, Mark M., additional, Henegan, John C., additional, Hyslop, Terry, additional, Esteban, Emilio, additional, Omlin, Aurelius, additional, McDermott, Ray, additional, Fay, Andre P., additional, Popoola, Ademola Alabi., additional, Ragin, Camille, additional, Nowak, Joel, additional, Gerke, Travis, additional, Kantoff, Philip W., additional, George, Daniel J., additional, Penney, Kathryn L., additional, and Mucci, Lorelei A., additional

Published
2024
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40. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial

Author

Sweeney, Christopher, Bracarda, Sergio, Sternberg, Cora N, Chi, Kim N, Olmos, David, Sandhu, Shahneen, Massard, Christophe, Matsubara, Nobuaki, Alekseev, Boris, Parnis, Francis, Atduev, Vagif, Buchschacher, Gary L, Jr, Gafanov, Rustem, Corrales, Luis, Borre, Michael, Stroyakovskiy, Daniil, Alves, Gustavo Vasconcelos, Bournakis, Evangelos, Puente, Javier, Harle-Yge, Marie-Laurence, Gallo, Jorge, Chen, Geng, Hanover, Justin, Wongchenko, Matthew J, Garcia, Josep, and de Bono, Johann S

Published
2021
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41. Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

Author

Saad, Fred, Chi, Kim N., Shore, Neal D., Graff, Julie N., Posadas, Edwin M., Lattouf, Jean-Baptiste, Espina, Byron M., Zhu, Eugene, Yu, Alex, Hazra, Anasuya, De Meulder, Marc, Mamidi, Rao N. V. S., Bradic, Branislav, Francis, Peter, Hayreh, Vinny, and Rezazadeh Kalebasty, Arash

Published
2021
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44. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Author

Wong, Suet-Lai Shirley, Tan, Thean Hsiang, Hovey, Elizabeth Jane, Clay, Timothy Dudley, Wan Ng, Siobhan Su, Rutten, Annemie, Machiels, Jean-Pascal, Dumez, Herlinde, Cheng, Susanna Yee-Shan, Ferrario, Cristiano, Sengeloev, Lisa, Jensen, Niels Viggo, Thibault, Constance, Laguerre, Brigitte, Joly, Florence, Culine, Stéphane, Becht, Catherine, Niegisch, Günter, Stöckle, Michael, Grimm, Marc-Oliver, Schwentner, Christina A, Schultze-Seemann, Wolfgang, Kalofonos, Haralambos, Mavroudis, Dimitrios, Papandreou, Christos, Karavasilis, Vasilis, Révész, Janos, Rosenbaum, Eli, Leibowitz-Amit, Raya, Kejzman, Daniel, Sarid, David, Scagliotti, Giorgio Vittorio, Bracarda, Sergio, Massari, Francesco, Osawa, Takahiro, Miyajima, Naoto, Shinohara, Nobuo, Fukuta, Fumimasa, Ohyama, Chikara, Obara, Wataru, Yamashita, Shinichi, Tomita, Yoshihiko, Kawai, Koji, Fukasawa, Satoshi, Oyama, Masafumi, Yonese, Junji, Nagata, Masayoshi, Uemura, Motohide, Nishimura, Kazuo, Kawakita, Mutsushi, Tsunemori, Hiroyuki, Hashine, Katsuyoshi, Inokuchi, Junichi, Yokomizo, Akira, Nagamori, Satoshi, Lee, Hyo Jin, Park, Se Hoon, Rha, Sun Young, Kim, Yu Jung, Lee, Yun-Gyoo, Vazquez Cortés, Leticia, Lorena Urzua Flores, Claudia, Blaisse, Reinoud J.B., Erdkamp, Fransiscus L.G., Aarts, Maureen J.B., Wojcik-Tomaszewska, Joanna, Tomczak, Piotr, Sikora-Kupis, Bozena, Schenker, Michael, Herzal, Alina Amalia, Udrea, Anghel Adrian, Karlov, Petr, Fomkin, Roman, Gajate Borau, Pablo, Grande, Enrique, Delgado Mignorance, Juan Ignacio, Su, Yu-Li, Li, Jian-Ri, Lin, Chien-Liang, Lin, Chia-Chi, Yeh, Su-Peng, Erman, Mustafa, Urun, Yuksel, Golovko, Yuriy, Bondarenko, Igor, Sinielnikov, Ivan, Crabb, Simon J., Syndikus, Isabel, Huddart, Robert, Sundar, Santhanam, Chowdhury, Simon, Sarwar, Naveed, Flaig, Thomas W., Pan, Chong Xian, Schwarz, James K., Cultrera, Jennifer Lyn, Acs, Peter Istvan, Hainsworth, John D., Herms, Benjamin T., Lawler, William Eyre, Lowe, Thomas Eugene, Petrylak, Daniel P, de Wit, Ronald, Chi, Kim N, Drakaki, Alexandra, Sternberg, Cora N, Nishiyama, Hiroyuki, Castellano, Daniel, Hussain, Syed A, Fléchon, Aude, Bamias, Aristotelis, Yu, Evan Y, van der Heijden, Michiel S, Matsubara, Nobuaki, Alekseev, Boris, Necchi, Andrea, Géczi, Lajos, Ou, Yen-Chuan, Coskun, Hasan Senol, Su, Wen-Pin, Bedke, Jens, Gakis, Georgios, Percent, Ivor J, Lee, Jae-Lyun, Tucci, Marcello, Semenov, Andrey, Laestadius, Fredrik, Peer, Avivit, Tortora, Giampaolo, Safina, Sufia, Garcia del Muro, Xavier, Rodriguez-Vida, Alejo, Cicin, Irfan, Harputluoglu, Hakan, Tagawa, Scott T, Vaishampayan, Ulka, Aragon-Ching, Jeanny B, Hamid, Oday, Liepa, Astra M, Wijayawardana, Sameera, Russo, Francesca, Walgren, Richard A, Zimmermann, Annamaria H, Hozak, Rebecca R, Bell-McGuinn, Katherine M, and Powles, Thomas

Published
2020
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45. Prostate-specific antigen (PSA) decline with apalutamide therapy is associated with longer survival and improved outcomes in individuals with metastatic prostate cancer: a plain language summary of the TITAN study

Author

Chowdhury, Simon, primary, Bjartell, Anders, additional, Agarwal, Neeraj, additional, Chung, Byung H, additional, Given, Robert W, additional, Pereira de Santana Gomes, Andrea J, additional, Merseburger, Axel S, additional, Özgüroğlu, Mustafa, additional, Soto, Álvaro Juárez, additional, Uemura, Hirotsugu, additional, Ye, Ding-Wei, additional, Brookman-May, Sabine D, additional, Londhe, Anil, additional, Bhaumik, Amitabha, additional, Mundle, Suneel D, additional, Larsen, Julie S, additional, McCarthy, Sharon A, additional, and Chi, Kim N, additional

Published
2023
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46. Addressing controversial areas in the management of advanced prostate cancer in Canada

Author

Saad, Fred, primary, Hotte, Sebastien J., additional, Noonan, Krista, additional, Malone, Shawn, additional, Morash, Christopher, additional, Niazi, Tamim, additional, Rendon, Ricardo A., additional, Shayegan, Bobby, additional, Basappa, Naveen S., additional, Cagiannos, Ilias, additional, Danielson, Brita, additional, Delouya, Guila, additional, Fernandes, Ricardo, additional, Ferrario, Cristiano, additional, Finelli, Antonio, additional, Gotto, Geoffrey T., additional, Hamilton, Robert J., additional, Izard, Jason P., additional, Kapoor, Anil, additional, Lalani, Aly-Khan, additional, Lavallée, Luke T., additional, Ong, Michael, additional, Pouliot, Frédéric, additional, So, Alan I., additional, Yip, Steven, additional, and Chi, Kim N., additional

Published
2023
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47. Post Hoc Analysis of Rapid and Deep Prostate-specific Antigen Decline and Patient-reported Health-related Quality of Life in SPARTAN and TITAN Patients with Advanced Prostate Cancer

Author

Small, Eric J., primary, Chi, Kim N., additional, Chowdhury, Simon, additional, Bevans, Katherine B., additional, Bhaumik, Amitabha, additional, Saad, Fred, additional, Chung, Byung Ha, additional, Karsh, Lawrence I., additional, Oudard, Stéphane, additional, De Porre, Peter, additional, Brookman-May, Sabine D., additional, McCarthy, Sharon A., additional, Mundle, Suneel D., additional, Uemura, Hirotsugu, additional, Smith, Matthew R., additional, and Agarwal, Neeraj, additional

Published
2023
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48. Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from Phase 3 randomised clinical studies TITAN and SPARTAN

Author

Shen, John, primary, Chowdhury, Simon, additional, Agarwal, Neeraj, additional, Karsh, Lawrence I., additional, Oudard, Stéphane, additional, Gartrell, Benjamin A., additional, Feyerabend, Susan, additional, Saad, Fred, additional, Pieczonka, Christopher M., additional, Chi, Kim N., additional, Brookman-May, Sabine D., additional, Rooney, Brendan, additional, Bhaumik, Amitabha, additional, McCarthy, Sharon A., additional, Bevans, Katherine B., additional, Mundle, Suneel D., additional, Small, Eric J., additional, Smith, Matthew R., additional, and Graff, Julie N., additional

Published
2023
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49. 2023 Canadian Urological Association guideline: Genetic testing in prostate cancer

Author

Rendon, Ricardo A., primary, Selvarajah, Shamini, additional, Wyatt, Alexander W., additional, Kolinsky, Michael, additional, Schrader, Kasmintan A., additional, Fleshner, Neil E., additional, Kinnaird, Adam, additional, Merrimen, Jennifer, additional, Niazi, Tamim, additional, Saad, Fred, additional, Shayegan, Bobby, additional, Wood, Lori, additional, and Chi, Kim N., additional

Published
2023
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50. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Author

Vandekerkhove, Gillian, Lavoie, Jean-Michel, Annala, Matti, Murtha, Andrew J., Sundahl, Nora, Walz, Simon, Sano, Takeshi, Taavitsainen, Sinja, Ritch, Elie, Fazli, Ladan, Hurtado-Coll, Antonio, Wang, Gang, Nykter, Matti, Black, Peter C., Todenhöfer, Tilman, Ost, Piet, Gibb, Ewan A., Chi, Kim N., Eigl, Bernhard J., and Wyatt, Alexander W.

Published
2021
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