De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.
Nature cancer. 2024 Jan 04 [Epub ahead of print]
Evan W Warner, Kim Van der Eecken, Andrew J Murtha, Edmond M Kwan, Cameron Herberts, Joonatan Sipola, Sarah W S Ng, Xinyi E Chen, Nicolette M Fonseca, Elie Ritch, Elena Schönlau, Cecily Q Bernales, Gráinne Donnellan, Aslı D Munzur, Karan Parekh, Kevin Beja, Amanda Wong, Sofie Verbeke, Nicolaas Lumen, Jo Van Dorpe, Bram De Laere, Matti Annala, Gillian Vandekerkhove, Piet Ost, Alexander W Wyatt
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada., Department of Pathology, Ghent University Hospital, Ghent, Belgium., Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland., Department of Human Structure and Repair, Ghent University, Ghent, Belgium., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada. .