Surgery (RMH) - Research Publications
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ItemMolecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens(WILEY, 2022-06)BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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ItemChanging face of robot-assisted radical prostatectomy in Melbourne over 12 years(WILEY, 2018-03)BACKGROUND: This study aims to characterize the trends in disease presentation for robot-assisted radical prostatectomy (RARP) over a 12-year period in Melbourne, Australia. METHODS: All patients undergoing an RARP between 2004 and October 2016 while under the care of six high-volume surgeons were included in this study. Data were collected prospectively regarding patient demographics and clinical details of their cancer. RESULTS: Over the 12-year time span of the study, 3075 men underwent an RARP with a median age of 63.01 years. Temporal analysis demonstrated that the median age of patients undergoing prostatectomy advanced with time with the median age in 2016 being 65.51 years compared with 61.0 years in 2004 (P < 0.001). There was also a significant trend to increased D'Amico risk groups over time with the percentage procedures for high-risk patients increasing from 12.6% to 28.10% from 2004 to 2016 (P < 0.001). Upgrade rates between biopsy and pathological Gleason grade scoring significantly trended down over the period of the study (P < 0.001). There was also a shift to increased pathological stage over the 12 years with 22.1% of men having T3 disease in 2004 compared with 49.8% in 2016. CONCLUSION: Our analysis demonstrates increasing treatment of older men with higher risk tumours, consistent with international trends. While this largely reflects a shift in case selection, further work is needed to assess whether the stage shift may relate partially to a decline in screening and increased presentation of higher risk disease.
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