Niall M Corcoran

Royal Melbourne Hospital, Melbourne, Victoria, Australia

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Publications (95)331.29 Total impact

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    ABSTRACT: Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targetskey aberrations arising from the mutational landscape of an individual patient's disease rather than employing a cancer-wide cytotoxic therapy approach.In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutation-directed treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.
    Current cancer drug targets 04/2015; · 3.58 Impact Factor
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    ABSTRACT: Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.
    Nature Communications 04/2015; 6. DOI:10.1038/ncomms7605 · 10.74 Impact Factor
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    ABSTRACT: Background:In an era of personalized medicine, individualized risk assessment using easily available tools on the internet and the literature are appealing. However, uninformed use by clinicians and the public raises potential problems. Herein, we assess the performance of published models to predict insignificant prostate cancer (PCa), using a multi-national low-risk population that may be considered for active surveillance (AS) based on contemporary practice.Methods:Data on men suitable for AS but undergoing upfront radical prostatectomy were pooled from three international academic institutions in Cambridge (UK), Toronto (Canada) and Melbourne (Australia). Four predictive models identified from literature review were assessed for their ability to predict the presence of four definitions of insignificant PCa. Evaluation was performed using area under the curve (AUC) of receiver operating characteristic curves and Brier scores for discrimination, calibration curves and decision curve analysis.Results:A cohort of 460 men meeting the inclusion criteria of all four nomograms was identified. The highest AUCs calculated for any of the four models ranged from 0.618 to 0.664, suggesting weak positive discrimination at best. Models had best discriminative ability for a definition of insignificant disease characterized by organ-confined Gleason score ⩽6 with a total volume ⩽0.5 ml or 1.3 ml. Calibration plots showed moderate range of predictive ability for the Kattan model though this model did not perform well at decision curve analysis.Conclusions:External assessment of models predicting insignificant PCa showed moderate performance at best. Uninformed interpretation may cause undue anxiety or false reassurance and they should be used with caution.Prostate Cancer and Prostatic Disease advance online publication, 10 February 2015; doi:10.1038/pcan.2015.1.
    Prostate Cancer and Prostatic Diseases 02/2015; 18(2). DOI:10.1038/pcan.2015.1 · 2.83 Impact Factor
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    ABSTRACT: The aetiology of urinary incontinence following radical prostatectomy (RP) is incompletely understood. In particular, it is unclear whether there is a relationship between neurovascular bundle (NVB) sparing and post-RP urinary continence. To review systematically the association of NVB sparing in RP with postoperative urinary continence outcomes and synthesise the results in a meta-analysis. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. PubMed, Medline, and Cochrane Central Register of Controlled Trials were searched (December 2013), yielding 3413 unique records. A total of 27 longitudinal cohort studies were selected for inclusion. Studies were evaluated using a predefined criteria adapted from the Cochrane Tool to Assess Risk of Bias in Cohort Studies. Data from 13 749 participants in 27 studies were synthesised in a meta-analysis. An assessment of the study methodology revealed a high risk of bias due to differences in baseline characteristics, outcome assessment, and the likely presence of unreported confounding factors such as meticulous apical dissection. Meta-analysis demonstrated that nerve sparing (NS) compared with non-nerve sparing (NNS) resulted in improved early urinary continence rates up to 6 mo postoperatively. Beyond this time, no significant difference was observed. This effect was seen most clearly for bilateral NS compared with NNS. A sensitivity analysis of prospective cohort studies revealed consistent results. This analysis demonstrates an association between NS and improved urinary continence outcomes up to 6 mo postoperatively. NS in men with poor preoperative erectile function should be considered in the context of oncologic risk stratification because it may improve time to continence recovery. The underlying cause of the relationship between NS and continence is unknown. It may represent preservation of the intrapelvic somatic nerves supplying the rhabdosphincter or the influence of other confounding factors. Future research should be directed towards improving understanding of the anatomy of urinary continence and the pathophysiology of post-RP incontinence. We found that avoiding damage to the nerves around the prostate improves urinary continence in the first 6 mo after surgery. After this time, there is no difference in continence between men who had these nerves removed and those who had them saved. This finding could be due to a true effect of saving these nerves or to a number of other factors affecting the research. Copyright © 2014. Published by Elsevier B.V.
    European Urology 10/2014; DOI:10.1016/j.eururo.2014.10.020 · 12.48 Impact Factor
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    ABSTRACT: Objective To provide an up-to-date summary of current literature on the management of adverse effects of androgen deprivation therapy (ADT).SubjectsAll men suffering from prostate cancer who are treated with androgen deprivation therapy.Methods All relevant medical literature from 2005 to 2014 and older relevant papers were reviewed to formulate this article. Recent health advisory statements from the Australian government, societies and advocacy groups have been incorporated to the document.ResultsThere are numerous adverse effects of ADT that require pro-active prevention and treatment. Ranging from cardiovascular disease, diabetes and osteoporosis to depression, cognitive decline and sexual dysfunction, the range of adverse effects is wide. Baseline assessment, monitoring, prevention and consultation from a multidisciplinary team are important in minimizing the harm from ADT.Conclusions This review provides series of practical recommendations to assist with managing adverse effects of ADT.
    BJU International 10/2014; 115. DOI:10.1111/bju.12964 · 3.13 Impact Factor
  • Clinical Cancer Research 09/2014; 20(18):4972-3. DOI:10.1158/1078-0432.CCR-14-1536 · 8.19 Impact Factor
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    ABSTRACT: Oligometastasis is a state of limited metastatic disease that may be amenable to aggressive local therapy to achieve long-term survival. This review aims to explore the role of ablative radiotherapy and surgical management of prostate cancer (CaP) patients with oligometastasis. We performed a systematic review of the literature from November 2003 to November 2013 in the PubMed and EMBASE databases using structured search terms. From our literature search, we identified 13 cases of oligometastatic CaP managed by surgery. The longest disease-free survival documented was 12 years following pulmonary metastasectomy. We also found 12 studies using radiotherapy to treat oligometastatic CaP with median follow-up ranging from 6 to 43 months. Local control rates and overall survival at 3 years range from 66 to 90% and from 54 to 92%, respectively. Most patients did not report any significant toxicity. The limited current literature suggests oligometastatic CaP may be amenable to more aggressive local ablative therapy to achieve prolonged local control and delay to androgen deprivation therapy (ADT). There is a larger body of evidence supporting the use of radiotherapy than surgery in this disease state. However, no direct comparison with ADT is available to suggest an improvement in overall survival. Further studies are required to determine the role of aggressive-targeted local therapy in oligometastatic CaP.
    Asia-Pacific Journal of Clinical Oncology 08/2014; DOI:10.1111/ajco.12256 · 1.06 Impact Factor
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    ABSTRACT: Background. Stereotactic radiotherapy is a non-invasive, ablative technique which may be particularly effective in treating metastatic renal cell carcinoma (RCC). The study objective was to analyse outcomes and toxicity of stereotactic radiotherapy in metastatic RCC. Material and methods. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of Medline was performed in March 2013. Exclusion criteria included mixed histology studies and case series. Local control, overall survival and toxicities were analysed. Results. From 148 publications identified, 16 and 10 publications for cranial and extracranial metastatic RCC met inclusion criteria, respectively. There were 810 intracranial patients and 2433 targets. The weighted local control was 92%. Overall survival ranged from 6.7 to 25.6 months. Significant Grade 3–4 toxicity ranged from 0% to 6%. The weighted rate of treatment-related mortality was 0.6%, all secondary to intratumoral haemorrhage. There were 389 extracranial patients and 730 targets. The weighted local control was 89%. Median overall survival ranged from 11.7 to 22 months. Grade 3–4 toxicity ranged from 0% to 4%. Treatment-related mortality was 0.5%. Conclusion. Stereotactic radiotherapy is associated with excellent local control and low rates of toxicity for intracranial and extracranial metastatic RCC. Future randomised studies are required to confirm the additional benefit of Stereotactic Ablative Body Radiotherapy (SABR) above standard conservative or palliative approaches.
    Acta Oncologica 08/2014; 54(2). DOI:10.3109/0284186X.2014.939298 · 3.71 Impact Factor
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    ABSTRACT: Background Urgent assessment of haematuria is critical to exclude malignancy. The objective of this study is to report the outcomes of the first 3 years of a dedicated haematuria clinic at the Royal Melbourne Hospital, a Victorian tertiary hospital.Methods All patients assessed in the haematuria clinic from April 2010 to April 2013 were included in the analysis. Outcomes were recorded prospectively and analysed retrospectively.ResultsA total of 643 patients were seen in the haematuria clinic with non-visible (170, 26%) and visible haematuria (463, 72%) during this time period, all within 28 days of referral being triaged. Sixty-five (10%) patients were diagnosed with urothelial carcinoma, 63 with lower tract disease and two with upper tract urothelial carcinoma and another five (1%) patients with other tumours. Thirty out of 63 (48%) of the bladder urothelial carcinomas were invasive or high-grade. Two hundred and sixty-seven (42%) patients were discharged from the clinic after a single point of contact. One hundred and fifty-three (24%) patients were referred for further definitive management of suspected pathology. Two hundred and twenty-three (34%) patients were referred to outpatients clinic for further investigations. Urothelial carcinoma was diagnosed more often in males, older patients and patients with visible haematuria.Conclusion The Royal Melbourne Hospital haematuria clinic has served as an effective tool for rapid, streamlined assessment of patients presenting with haematuria. Follow-up of investigations by nurses and moving towards a ‘one-stop’ approach are helping to further decrease the number of patients requiring a second clinic visit.
    ANZ Journal of Surgery 07/2014; 85(5). DOI:10.1111/ans.12742 · 1.12 Impact Factor
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    ABSTRACT: Molecular biomarkers are used routinely in the clinical management of several tumours such as prostate, colon, ovarian and pancreatic cancer but management decisions in bladder cancer remain dependent on clinical and pathological criteria, which are limited in their ability to predict outcomes. Molecular markers are urgently needed in detection, surveillance and prognostication of bladder cancer as well as to predict treatment response to intravesical and systemic therapies. Advances in cancer genomics and platforms for biomarker profiling have led to a plethora of biomarkers, which must now be rigorously validated in the clinical setting. Pre-clinical and clinical studies exploring the role of emerging targeted therapies to risk stratify and reduce cancer progression are also needed.
    Pathology 05/2014; 46(4). DOI:10.1097/PAT.0000000000000110 · 2.62 Impact Factor
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    ABSTRACT: Purpose It has been recognised for almost a decade that concentrations of signalling androgens sufficient to activate the androgen receptor are present in castration resistant prostate cancer tissue. The source of these androgens is highly controversial, with 3 competing models proposed. We therefore wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) when incubated with various precursors, and examine concomitant changes in enzyme expression. Experimental Design Freshly harvested prostate tissue (benign, hormone-naïve & hormone refractory prostate cancer) was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by GC-MS. Changes in the expression of androgen synthetic and/or degradative enzymes was determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. Results Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signalling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone refractory compared to hormone naïve cancer. Consistent with this, GSEA of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publically available expression dataset. Importantly we found no evidence to support a significant contribution form either the 'backdoor' or '5-α dione' pathway. Conclusions Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signalling androgens in hormone refractory prostate cancer.
    Clinical Cancer Research 04/2014; 20(21). DOI:10.1158/1078-0432.CCR-13-3483 · 8.19 Impact Factor
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    ABSTRACT: The purpose of this study was to determine if microRNA profiling of urine and plasma at radical prostatectomy can distinguish potentially lethal from indolent prostate cancer. A panel of microRNAs was profiled in the plasma of 70 patients and the urine of 33 patients collected prior to radical prostatectomy. Expression of microRNAs was correlated to the clinical endpoints at a follow-up time of 3.9 years to identify microRNAs that may predict clinical response after radical prostatectomy. A machine learning approach was applied to test the predictive ability of all microRNAs profiled in urine, plasma, and a combination of both, and global performance assessed using the area under the receiver operator characteristic curve (AUC). Validation of urinary expression of miRNAs was performed on a further independent cohort of 36 patients. The best predictor in plasma using eight miRs yielded only moderate predictive performance (AUC = 0.62). The best predictor of high-risk disease was achieved using miR-16, miR-21 and miR-222 measured in urine (AUC = 0.75). This combination of three microRNAs in urine was a better predictor of high-risk disease than any individual microRNA. Using a different methodology we found that this set of miRNAs was unable to predict high-volume, high-grade disease. Our initial findings suggested that plasma and urinary profiling of microRNAs at radical prostatectomy may allow prognostication of prostate cancer behaviour. However we found that the microRNA expression signature failed to validate in an independent cohort of patients using a different platform for PCR. This highlights the need for independent validation patient cohorts and suggests that urinary microRNA signatures at radical prostatectomy may not be a robust way to predict the course of clinical disease after definitive treatment for prostate cancer.
    PLoS ONE 04/2014; 9(4):e91729. DOI:10.1371/journal.pone.0091729 · 3.53 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e504. DOI:10.1016/j.juro.2014.02.1108 · 3.75 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e502. DOI:10.1016/j.juro.2014.02.1102 · 3.75 Impact Factor
  • European Urology Supplements 04/2014; 13(1):e626. DOI:10.1016/S1569-9056(14)60616-3 · 3.37 Impact Factor
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    ABSTRACT: The Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues. We comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation. Our method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.
    BMC Genomics 01/2014; 15(1):51. DOI:10.1186/1471-2164-15-51 · 4.04 Impact Factor
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    ABSTRACT: In order to individually tailor prostate cancer (PCa) treatment, clinicians need better tools to predict prognosis and treatment response. Given the relationship between angiogenesis and cancer progression, circulating endothelial cells (CECs) and their progenitors have logically been proposed as potential biomarkers. The utility of their baseline levels and kinetics has been investigated for years. However, owing to a lack of standardization and validation of CEC and circulating endothelial progenitors enumeration protocols, results have been inconsistent in prostate and other cancers. Similarly, platelets play a significant part in cancer progression, yet the role of platelet-related biomarkers in PCa is unclear. While there have been a number of theoretically interesting platelet-related markers proposed, limited research has been conducted in PCa patients. Currently, CECs and platelets do not have a clear role as biomarkers in routine PCa care. Given the theoretical merits of these cells, prospective trials are warranted.
    Biomarkers in Medicine 12/2013; 7(6):879-891. DOI:10.2217/bmm.13.100 · 2.86 Impact Factor
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    ABSTRACT: Noninvasive biomarkers are used routinely in the clinical management of several cancers but bladder cancer detection and surveillance remains dependent on invasive procedures such as cystoscopy. No validated biomarker currently exists in routine clinical practice other than cytology. Gene-based testing has shown great promise for biomarker profiling and this review addresses the current state of biomarker research in bladder cancer. A comprehensive review of all published literature on urinary biomarkers from 1970 - 2012 was conducted in PubMed. Keywords used alone or in combination were bladder cancer, diagnosis, surveillance, urinary biomarker, molecular biomarkers, methylation, gene expression, single nucleotide polymorphism and microRNA. The cited references of the manuscripts included in the review were also screened. We have reviewed various strategies currently used for gene-based biomarker profiling of bladder cancer. We have comprehensively summarized the performance of several biomarkers in the diagnosis and surveillance of bladder cancer. Finally we have identified biomarkers that have shown potential and now deserve the opportunity to be validated in the clinical setting. Several gene-based urinary biomarkers have demonstrated promise in initial studies, which now need to be rigorously validated in the clinical setting for them to be translated into clinically useful tests in diagnosis, surveillance or risk-stratification of bladder cancer.
    Urologic Oncology 10/2013; 32(1). DOI:10.1016/j.urolonc.2013.07.002 · 3.36 Impact Factor
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    ABSTRACT: Personalised oncology through mutational profiling of cancers requires the procurement of fresh frozen tumour samples for genomics applications. While primary cancers are often surgically excised and therefore yield such tissue, metastases in the setting of a known cancer diagnosis are not routinely sampled prior to systemic therapy. Our study aimed to determine the suitability of extracted nucleic acids for genomics applications using distant metastatic prostate cancer samples obtained via percutaneous or surgical biopsy. Patients with metastatic prostate cancer were recruited for image-guided biopsy of metastases. Patients undergoing surgical procedures for the complications of metastases were also recruited. Tissue samples were flash frozen and cryosectioned for histological examination. DNA and RNA were simultaneously extracted and genomic DNA hybridised onto SNP arrays for genome-wide copy number analysis. 37 samples of metastatic tissue from seven patients with prostate cancer were obtained. Five of these underwent image-guided biopsies whilst two had therapeutic surgical procedures performed. 22 biopsy samples were obtained across the image-guided biopsy patients with 80 % of samples being successfully processed for downstream analysis. Nucleic acid yield from these samples were satisfactory for genomics applications. Copy number analysis revealed a median estimated tumour purity of 53 % and all samples showed chromosomal abnormalities suggestive of malignancy. The procurement of osseous metastatic prostate cancer from live patients, including the use of image-guided biopsy, is safe and feasible. Sufficient tissue can be obtained in a manner such that extracted nucleic acids are suitable for genomics research.
    Clinical and Experimental Metastasis 10/2013; 31(2). DOI:10.1007/s10585-013-9617-2 · 3.73 Impact Factor
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    ABSTRACT: This study aimed to externally validate a previously described nomogram that predicts the need for renal exploration in the trauma setting. The predicted probability of nephrectomy was manually calculated using prospectively collected data from consecutive patients with renal trauma who presented to our institution between May 2001 and January 2010. To assess nomogram performance, receiver operating characteristic curves against the observed exploration rate were generated, and areas under the curve were calculated. Calibration curves were generated to assess performance across the range of predicted probabilities. Logistic regression modeling was used to determine clinical factors predicting exploration in a contemporary setting, and a nomogram was derived and internally validated using bootstrapping. The established nomogram was applied to the 320 patients who presented during the 9-year period. The global performance of the established nomogram was very high, with an area under the curve of 0.95. However, the model performance was poor for higher predicted probabilities, thus lacking predictive ability in the population where the model has the greatest potential utility. A clinical tool was generated to better predict trauma nephrectomy in our contemporary population, using platelet transfusion within the first 24 hours, blood urea nitrogen, hemoglobin, and heart rate on admission. The global accuracy for the new model was similar to the previous nomogram, but it was significantly better calibrated for patients with higher probabilities of nephrectomy, with good predictive accuracy even in patients with Grade 5 injuries. Older nomogram fails to accurately predict renal exploration in high-grade injuries in the contemporary setting. A new nomogram that more accurately predicts the need for exploration is presented. Therapeutic study, level IV; prognostic study, level III.
    10/2013; 75(5):819-23. DOI:10.1097/TA.0b013e3182a8fff5

Publication Stats

463 Citations
331.29 Total Impact Points

Institutions

  • 2003–2015
    • Royal Melbourne Hospital
      • Department of Radiology
      Melbourne, Victoria, Australia
  • 2010–2014
    • University of Melbourne
      • Department of Surgery
      Melbourne, Victoria, Australia
  • 2012
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2011
    • Vancouver Prostate Centre
      Vancouver, British Columbia, Canada
  • 2010–2011
    • Alfred Hospital
      • Department of Urology
      Melbourne, Victoria, Australia