Surgery (RMH) - Research Publications

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    Defining Prostatic Vascular Pedicle Recurrence and the Anatomy of Local Recurrence of Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.
    Dundee, P ; Furrer, MA ; Corcoran, NM ; Peters, J ; Pan, H ; Ballok, Z ; Ryan, A ; Guerrieri, M ; Costello, AJ (Elsevier BV, 2022-07)
    Background: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. Objective: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. Design setting and participants: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. Intervention: PSMA PET/CT for BCR following RP. Results and limitations: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. Conclusions: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. Patient summary: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.
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    Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens
    Yuen, KC ; Tran, B ; Anton, A ; Hamidi, H ; Costello, AJ ; Corcoran, NM ; Lawrentschuk, N ; Rainey, N ; Semira, MCG ; Gibbs, P ; Mariathasan, S ; Sandhu, S ; Kadel, EE (WILEY, 2022-04-18)
    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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    The Prostate Cancer Immune Microenvironment, Biomarkers and Therapeutic Intervention
    Zhang, Y ; Campbell, BK ; Stylli, SS ; Corcoran, NM ; Hovens, CM (MDPI AG, 2022-04-10)
    Advanced prostate cancers have a poor survival rate and a lack of effective treatment options. In order to broaden the available treatments, immunotherapies have been investigated. These include cancer vaccines, immune checkpoint inhibitors, chimeric antigen receptor T cells and bispecific antibodies. In addition, combinations of different immunotherapies and with standard therapy have been explored. Despite the success of the Sipuleucel-T vaccine in the metastatic, castrate-resistant prostate cancer setting, other immunotherapies have not shown the same efficacy in this population at large. Some individual patients, however, have shown remarkable responsiveness to these therapies. Therefore, work is underway to identify which populations will respond positively to therapy via the identification of predictive biomarkers. These include biomarkers of the immunologically active tumour microenvironment and biomarkers indicative of high neoantigen expression in the tumour. This review examines the constitution of the prostate tumour immune microenvironment, explores the effectiveness of immunotherapies, and finally investigates how therapy selection can be optimised by the use of biomarkers.
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    Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer
    Pechlivanis, M ; Campbell, BK ; Hovens, CM ; Corcoran, NM (MDPI, 2022-01-01)
    Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature.
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    Genetic factors associated with prostate cancer conversion from active surveillance to treatment
    Jiang, Y ; Meyers, TJ ; Emeka, AA ; Cooley, LF ; Cooper, PR ; Lancki, N ; Helenowski, I ; Kachuri, L ; Lin, DW ; Stanford, JL ; Newcomb, LF ; Kolb, S ; Finelli, A ; Fleshner, NE ; Komisarenko, M ; Eastham, JA ; Ehdaie, B ; Benfante, N ; Logothetis, CJ ; Gregg, JR ; Perez, CA ; Garza, S ; Kim, J ; Marks, LS ; Delfin, M ; Barsa, D ; Vesprini, D ; Klotz, LH ; Loblaw, A ; Mamedov, A ; Goldenberg, SL ; Higano, CS ; Spillane, M ; Wu, E ; Carter, HB ; Pavlovich, CP ; Mamawala, M ; Landis, T ; Carroll, PR ; Chan, JM ; Cooperberg, MR ; Cowan, JE ; Morgan, TM ; Siddiqui, J ; Martin, R ; Klein, EA ; Brittain, K ; Gotwald, P ; Barocas, DA ; Dallmer, JR ; Gordetsky, JB ; Steele, P ; Kundu, SD ; Stockdale, J ; Roobol, MJ ; Venderbos, LDF ; Sanda, MG ; Arnold, R ; Patil, D ; Evans, CP ; Dall'Era, MA ; Vij, A ; Costello, AJ ; Chow, K ; Corcoran, NM ; Rais-Bahrami, S ; Phares, C ; Scherr, DS ; Flynn, T ; Karnes, RJ ; Koch, M ; Dhondt, CR ; Nelson, JB ; McBride, D ; Cookson, MS ; Stratton, KL ; Farriester, S ; Hemken, E ; Stadler, WM ; Pera, T ; Banionyte, D ; Bianco, FJ ; Lopez, IH ; Loeb, S ; Taneja, SS ; Byrne, N ; Amling, CL ; Martinez, A ; Boileau, L ; Gaylis, FD ; Petkewicz, J ; Kirwen, N ; Helfand, BT ; Xu, J ; Scholtens, DM ; Catalona, WJ ; Witte, JS (ELSEVIER, 2022-01-13)
    Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.
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    Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer
    Soekmadji, C ; Corcoran, NM ; Oleinikova, I ; Jovanovic, L ; Ramm, GA ; Nelson, CC ; Jenster, G ; Russell, PJ (WILEY, 2017-10-01)
    The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation.
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    Feasibility for active surveillance in biopsy Gleason 3+4 prostate cancer: an Australian radical prostatectomy cohort
    Wong, L-M ; Tang, V ; Peters, J ; Costello, A ; Corcoran, N (WILEY, 2016-04-01)
    OBJECTIVE: To examine the feasibility of active surveillance for low volume Gleason sum (GS) 3 + 4 disease compared to GS 3 + 3 disease. PATIENTS AND METHODS: Retrospective review of 929 patients, with biopsy proven GS 3 + 3 and 3 + 4 PCa, undergoing upfront radical prostatectomy (RP) was performed. Suitability for AS was adapted from protocols by Royal Marsden Hospital, University of Toronto, and PRIAS by allowing Gleason 3 + 4 disease. The outcomes assessed were adverse pathology at RP (upgrading ≥GS 4 + 3 and/or upstaging ≥pT3) and biochemical recurrence (BCR) after RP. RESULTS: Adverse pathology at RP was compared between GS 3 + 3 vs 3 + 4 groups. When selecting patients using Royal Marsden (n = 714) or University of Toronto (n = 699) protocols, there was statistically significantly more adverse pathology at RP in GS 3 + 4 group (21% vs 31%, P = 0.0028 and 19% vs 33%, P=<0.001 respectively). Using the more stringent PRIAS protocol (n = 198), there was no statistical significant difference in groups. There was no difference in BCR survival between biopsy GS 3 + 3 and 3 + 4 groups, regardless of which AS protocol assessed. Pre-operative PSA and clinical staging were the predictors for BCR. CONCLUSION: Presence of Gleason 3 + 4 at biopsy, when compared to 3 + 3, increases the risk of adverse pathology being present at radical prostatectomy for less stringent selection criteria. When considering AS, a stricter protocol such as PRIAS, limiting PSA density and number of positive cores to ≤2, appears to decrease the risk of adverse pathology. No differences in BCR were seen between biopsy 3 + 3 and 3 + 4 disease, regardless of AS selection criteria.
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    Lifetime Health and Economic Outcomes of Active Surveillance, Radical Prostatectomy, and Radiotherapy for Favorable-Risk Localized Prostate Cancer
    Degeling, K ; Corcoran, NM ; Pereira-Salgado, A ; Hamid, AA ; Siva, S ; IJzerman, MJ (ELSEVIER SCIENCE INC, 2021-11-24)
    OBJECTIVES: To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer. METHODS: A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Costs were included from a public payer perspective in Australian dollars. Outcomes were discounted at 5% over a lifetime horizon. Probabilistic and scenario analyses quantified parameter and structural uncertainty. RESULTS: A total of 60% of patients in the AS arm eventually received radical treatment (surgery or radiotherapy) compared with 90% for RP and 91% for RT. Although AS resulted in fewer treatment-related complications, it led to increased clinical progression (AS 40.7%, RP 17.6%, RT 19.9%) and metastatic disease (AS 13.4%, RP 6.1%, RT 7.0%). QALYs were 10.88 for AS, 11.10 for RP, and 11.13 for RT. Total costs were A$17 912 for AS, A$15 609 for RP, and A$15 118 for RT. At a willingness to pay of A$20 000/QALY, RT had a 61.4% chance of being cost-effective compared to 38.5% for RP and 0.1% for AS. CONCLUSIONS: Although AS resulted in fewer and delayed treatment-related complications, it was not found to be a cost-effective strategy for favorable-risk localized prostate cancer over a lifetime horizon because of an increase in the number of patients developing metastatic disease. RT was the dominant strategy yielding higher QALYs at lower cost although differences compared with RP were small.
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    Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression
    Mangiola, S ; McCoy, P ; Modrak, M ; Souza-Fonseca-Guimaraes, F ; Blashki, D ; Stuchbery, R ; Keam, SP ; Kerger, M ; Chow, K ; Nasa, C ; Le Page, M ; Lister, N ; Monard, S ; Peters, J ; Dundee, P ; Williams, SG ; Costello, AJ ; Neeson, PJ ; Pal, B ; Huntington, ND ; Corcoran, NM ; Papenfuss, AT ; Hovens, CM (BMC, 2021-07-22)
    BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
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    Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy
    Cmero, M ; Kurganovs, NJ ; Stuchbery, R ; McCoy, P ; Grima, C ; Ngyuen, A ; Chow, K ; Mangiola, S ; Macintyre, G ; Howard, N ; Kerger, M ; Dundee, P ; Ruljancich, P ; Clarke, D ; Grummet, J ; Peters, JS ; Costello, AJ ; Norden, S ; Ryan, A ; Parente, P ; Hovens, CM ; Corcoran, NM (LIPPINCOTT WILLIAMS & WILKINS, 2021-06-01)
    PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.