Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.
P. Itagi, Samantha L. Schuster, Sonali Arora et al.· Nature· 0 citations
Multiple phase 3 studies have shown that early use of androgen receptor (AR) pathway inhibitors (ARPIs) results in marked improvement in overall survival for men with metastatic androgen pathway modulation-sensitive (APMS) prostate cancer (formerly castration-sensitive prostate cancer). However, resistance to these agents and progression to androgen pathway modulation-resistant (APMR) prostate cancer (formerly castration-resistant prostate cancer) inevitably occurs. As such, patients previously treated with an ARPI for APMS prostate cancer have inherently more resistant disease. In spite of this, AR still remains a relevant therapeutic target in most patients with APMR prostate cancer and several novel therapies targeting both AR-dependent and -independent mechanisms of resistance are under clinical development. These include hormonal therapies that appear effective in the setting of well-characterized ARPI resistance mutations (e.g. AR ligand binding domain mutations), and include non-ligand binding domain inhibitors, AR degraders and next-generation extra-gonadal androgen biosynthesis inhibitors. This review will also discuss combinatorial approaches utilizing ARPIs and newer agents designed to suppress key resistance mechanisms (e.g. epigenetic therapies) and emerging data on the use of supraphysiological testosterone to both exert an antitumor effect and “re-sensitize” APMR prostate cancer to downstream ARPIs. Herein, we summarize the next wave of AR-directed therapies being developed for advanced prostate cancer, with a focus on agents being evaluated in ongoing clinical trials.
Gabrielle Paras, M. Schweizer· Urologic oncology· 1 citation
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