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Pancreatic Neoplasms: HELP
Articles by Andrew V. Biankin
Based on 79 articles published since 2009
(Why 79 articles?)
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Between 2009 and 2019, A. Biankin wrote the following 79 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Inherited susceptibility to pancreatic cancer in the era of next-generation sequencing. 2015

Humphris, Jeremy / Chang, David K / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia; Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Liverpool, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia; Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Liverpool, Australia. Electronic address: Andrew.Biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #25613311.

ABSTRACT: -- No abstract --

2 Editorial Can we move towards personalised pancreatic cancer therapy? 2014

Jamieson, Nigel Balfour / Chang, David K / Grimmond, Sean M / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. ·Expert Rev Gastroenterol Hepatol · Pubmed #24702631.

ABSTRACT: -- No abstract --

3 Review Molecular subtypes of pancreatic cancer. 2019

Collisson, Eric A / Bailey, Peter / Chang, David K / Biankin, Andrew V. ·University of California, San Francisco, San Francisco, CA, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK. andrew.biankin@glasgow.ac.uk. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk. ·Nat Rev Gastroenterol Hepatol · Pubmed #30718832.

ABSTRACT: Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.

4 Review Chemotherapy and radiotherapy for advanced pancreatic cancer. 2018

Chin, Venessa / Nagrial, Adnan / Sjoquist, Katrin / O'Connor, Chelsie A / Chantrill, Lorraine / Biankin, Andrew V / Scholten, Rob Jpm / Yip, Desmond. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street Darlinghurst, Sydney, NSW, Australia, 2010. ·Cochrane Database Syst Rev · Pubmed #29557103.

ABSTRACT: BACKGROUND: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. OBJECTIVES: To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. SEARCH METHODS: We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. SELECTION CRITERIA: All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. DATA COLLECTION AND ANALYSIS: Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. MAIN RESULTS: We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing.When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.We did not find any survival advantages when comparing 5FU combinations to 5FU alone. AUTHORS' CONCLUSIONS: Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.

5 Review Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development. 2017

Dreyer, Stephan B / Chang, David K / Bailey, Peter / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, United Kingdom. Andrew.Biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia. ·Clin Cancer Res · Pubmed #28373362.

ABSTRACT: Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.

6 Review Pancreatic cancer. 2016

Kleeff, Jorg / Korc, Murray / Apte, Minoti / La Vecchia, Carlo / Johnson, Colin D / Biankin, Andrew V / Neale, Rachel E / Tempero, Margaret / Tuveson, David A / Hruban, Ralph H / Neoptolemos, John P. ·NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Duncan Building, Daulby Street, Liverpool L69 3GA, UK. · Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany. · Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, Indiana, USA. · SWS Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia. · Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · University Surgical Unit, University Hospital Southampton, Southampton, UK. · Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, UK. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · UCSF Pancreas Center, University of California San Francisco - Mission Bay Campus/Mission Hall, San Francisco, California, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, New York, USA. · The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Nat Rev Dis Primers · Pubmed #27158978.

ABSTRACT: Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.

7 Review International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. 2016

Takaori, Kyoichi / Bassi, Claudio / Biankin, Andrew / Brunner, Thomas B / Cataldo, Ivana / Campbell, Fiona / Cunningham, David / Falconi, Massimo / Frampton, Adam E / Furuse, Junji / Giovannini, Marc / Jackson, Richard / Nakamura, Akira / Nealon, William / Neoptolemos, John P / Real, Francisco X / Scarpa, Aldo / Sclafani, Francesco / Windsor, John A / Yamaguchi, Koji / Wolfgang, Christopher / Johnson, Colin D / Anonymous480853. ·Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: takaori@kuhp.kyoto-u.ac.jp. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Academic Unit of Surgery, University of Glasgow, Glasgow, United Kingdom. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. · Pancreatic Surgery Unit, Università Vita e Salute, Milano, Italy. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, United Kingdom. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Endoscopic Unit, Paoli-Calmettes Institute, Marseille, France. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan. · Division of General Surgery, Yale University, New Haven, CT, United States of America. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Surgery, University of Auckland, HBP/Upper GI Unit, Auckland City Hospital, Auckland, New Zealand. · Department of Advanced Treatment of Pancreatic Disease, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Surgery, The Johns Hopkins University, Baltimore, MD, United States of America. · University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom. ·Pancreatology · Pubmed #26699808.

ABSTRACT: BACKGROUND: Pancreatic cancer is one of the most devastating diseases with an extremely high mortality. Medical organizations and scientific societies have published a number of guidelines to address active treatment of pancreatic cancer. The aim of this consensus review was to identify where there is agreement or disagreement among the existing guidelines and to help define the gaps for future studies. METHODS: A panel of expert pancreatologists gathered at the 46th European Pancreatic Club Meeting combined with the 18th International Association of Pancreatology Meeting and collaborated on critical reviews of eight English language guidelines for the clinical management of pancreatic cancer. Clinical questions (CQs) of interest were proposed by specialists in each of nine areas. The recommendations for the CQs in existing guidelines, as well as the evidence on which these were based, were reviewed and compared. The evidence was graded as sufficient, mediocre or poor/absent. RESULTS: Only 4 of the 36 CQs, had sufficient evidence for agreement. There was also agreement in five additional CQs despite the lack of sufficient evidence. In 22 CQs, there was disagreement regardless of the presence or absence of evidence. There were five CQs that were not addressed adequately by existing guidelines. CONCLUSION: The existing guidelines provide both evidence- and consensus-based recommendations. There is also considerable disagreement about the recommendations in part due to the lack of high level evidence. Improving the clinical management of patients with pancreatic cancer, will require continuing efforts to undertake research that will provide sufficient evidence to allow agreement.

8 Review Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. 2015

Nagrial, Adnan M / Chin, Venessa T / Sjoquist, Katrin M / Pajic, Marina / Horvath, Lisa G / Biankin, Andrew V / Yip, Desmond. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: a.nagrial@garvan.org.au. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. · NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincents's Clinical School, Faculty of Medicine, University of NSW, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia. · The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; The Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, UK. · Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia; ANU Medical School, Australian National University, Acton, ACT, Australia. ·Crit Rev Oncol Hematol · Pubmed #26481952.

ABSTRACT: There remains uncertainty regarding the optimal second-line chemotherapy in advanced pancreatic ductal adenocarcinoma (PDAC). The current recommendation of 5-fluorouracil and oxaliplatin may not be relevant in current practice, as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) has become a more popular first line therapy in fit patients. The majority of studies in this setting are single-arm Phase II trials with significant heterogeneity of patient populations, treatments and outcomes. In this review, we sought to systematically review and synthesise all prospective data available for the second-line treatment of advanced PDAC.

9 Review Cancer Genetics and Implications for Clinical Management. 2015

Jamieson, Nigel B / Chang, David K / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow Royal Infirmary, University of Glasgow, Alexandra Parade, Glasgow G31 2ER, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia. Electronic address: andrew.biankin@glasgow.ac.uk. ·Surg Clin North Am · Pubmed #26315514.

ABSTRACT: There is now compelling evidence that the molecular heterogeneity of cancer is associated with disparate phenotypes with variable outcomes and therapeutic responsiveness to therapy in histologically indistinguishable cancers. This diversity may explain why conventional clinical trial designs have mostly failed to show efficacy when patients are enrolled in an unselected fashion. Knowledge of the molecular phenotype has the potential to improve therapeutic selection and hence the early delivery of the optimal therapeutic regimen. Resolution of the challenges associated with a more stratified approach to health care will ensure more precise diagnostics and enhance therapeutic selection, which will improve overall outcomes.

10 Review Pancreatic cancer genomics: where can the science take us? 2015

Graham, J S / Jamieson, N B / Rulach, R / Grimmond, S M / Chang, D K / Biankin, A V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · Department of Surgery, Bankstown Hospital, Sydney, Australia. · St Vincent's Clinical School, Faculty of Medicine, Sydney, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. ·Clin Genet · Pubmed #25388820.

ABSTRACT: The incidence of pancreatic ductal adenocarcinoma (PDAC) is steadily increasing and the annual death-to-incidence ratio approaches one. This is a figure that has not changed for several decades. Surgery remains the only chance of cure; however, only less than 20% of patients are amenable to operative resection. Despite successful surgical resection, the majority of the patients still succumb to recurrent metastatic disease. Therefore, there is an urgent need to develop novel therapeutic strategies and to better select patients for current therapies. In this review, we will discuss current management by highlighting the landmark clinical trials that have shaped current care. We will then discuss the challenges of therapeutic development using the current randomized-controlled trial paradigm when confronted with the molecular heterogeneity of PDAC. Finally, we will discuss strategies that may help to shape the management of PDAC in the near future.

11 Review Personalising pancreas cancer treatment: When tissue is the issue. 2014

Sjoquist, Katrin M / Chin, Venessa T / Chantrill, Lorraine A / O'Connor, Chelsie / Hemmings, Chris / Chang, David K / Chou, Angela / Pajic, Marina / Johns, Amber L / Nagrial, Adnan M / Biankin, Andrew V / Yip, Desmond. ·Katrin M Sjoquist, NHMRC Clinical Trials Centre, University of Sydney, Sydney NSW 1450, Australia. ·World J Gastroenterol · Pubmed #24976722.

ABSTRACT: The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

12 Review Pancreatic cancer genomics. 2014

Chang, David K / Grimmond, Sean M / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD, Australia. Electronic address: s.grimmond@imb.uq.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia. Electronic address: sean.grimmond@glasgow.ac.uk. ·Curr Opin Genet Dev · Pubmed #24480245.

ABSTRACT: Pancreatic cancer is one of the most lethal malignancies. The overall median survival even with treatment is only 6-9 months, with almost 90% succumbing to the disease within a year of diagnosis. It is characterised by an intense desmoplastic stroma that may contribute to therapeutic resistance, and poses significant challenges for genomic sequencing studies. It is recalcitrant to almost all therapies and consequently remains the fourth leading cause of cancer death in Western societies. Genomic studies are unveiling a vast heterogeneity of mutated genes, and this diversity may explain why conventional clinical trial designs have mostly failed to demonstrate efficacy in unselected patients. Those that are available offer only marginal benefits overall, but are associated with clinically significant responses in as yet undefined subgroups. This chapter describes our current understanding of the genomics of pancreatic cancer and the potential impact of these findings on our approaches to treatment.

13 Review Understanding pancreatic cancer genomes. 2013

Cowley, Mark J / Chang, David K / Pajic, Marina / Johns, Amber L / Waddell, Nicola / Grimmond, Sean M / Biankin, Andrew V. ·The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia. ·J Hepatobiliary Pancreat Sci · Pubmed #23660961.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of <12 months even with maximal therapy, and a 5-year survival rate of <5 %. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large-scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI) used exomic sequencing and copy number analysis to define genomic aberrations that characterize a large, clinically focused, prospectively accrued cohort of patients with pancreatic cancer. The cohort consisted of early (clinical stages I and II) non-pre-treated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devised approaches to adjust for low epithelial content in primary tumours and to define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We aim to develop stratified, molecular phenotype-guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient-derived xenografts and cell lines from the above deeply characterized cohort. In addition, we return information to treating clinicians that influences patient care and are launching a clinical trial called IMPaCT (Individualized Molecular Pancreatic Cancer Therapy). This umbrella design trial randomizes patients with metastatic disease to either standard first-line therapy with gemcitabine, or a molecular phenotype-guided approach using next-generation sequencing strategies to screen for actionable mutations defined through the ICGC effort.

14 Review Precursor lesions in pancreatic cancer: morphological and molecular pathology. 2011

Scarlett, Christopher J / Salisbury, Elizabeth L / Biankin, Andrew V / Kench, James. ·Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia. ·Pathology · Pubmed #21436628.

ABSTRACT: Pancreatic cancer has a dismal prognosis and is the fourth most common cause of cancer related death in Western societies. In large part this is due to its typically late presentation, usually as locally advanced or metastatic disease. Identification of the non-invasive precursor lesions to pancreatic cancer raises the possibility of surgical treatment or chemoprevention at an early stage in the evolution of this disease, when more amenable to therapeutic interventions. Precursor lesions to pancreatic ductal adenocarcinoma, in particular pancreatic intraepithelial neoplasia (PanIN), have been recognised under a variety of synonyms for over 50 years. Over the past decade our understanding of the morphology, biological significance and molecular aberrations of these lesions has grown rapidly and there is now a widely accepted progression model integrating the accumulated morphological and molecular observations. Further progress is likely to be accelerated by improved mouse models of pancreatic cancer and by insight into the cancer genome gained by the International Cancer Genome Consortium (ICGC), in which an Australian consortium is leading the pancreatic cancer initiative. This review also outlines the morphological and molecular features of the other two precursors of pancreatic ductal adenocarcinoma, i.e., intraductal papillary mucinous neoplasms and mucinous cystic neoplasms.

15 Review Role of endoscopic ultrasound in pancreatic cancer. 2009

Chang, David K / Nguyen, Nam Q / Merrett, Neil D / Dixson, Hugh / Leong, Rupert W L / Biankin, Andrew V. ·Department of Surgery, Bankstown Hospital, Bankstown, NSW 2200, Australia. ·Expert Rev Gastroenterol Hepatol · Pubmed #19485810.

ABSTRACT: Pancreatic cancer (PC) is the fourth most common cause of cancer deaths in Western societies. It is an aggressive tumor with an overall 5-year survival rate of less than 5%. Surgical resection offers the only possibility of cure and long-term survival for patients suffering from PC; however, unfortunately, fewer than 20% of patients suffering from PC have disease that is amendable to surgical resection. Therefore, it is important to accurately diagnose and stage these patients to enable optimal treatment of their disease. The imaging modalities involved in the diagnosis and staging of PC include multidetector CT scanning, endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreaticography and MRI. The roles and relative importance of these imaging modalities have changed over the last few decades and continue to change owing to the rapid technological advances in medical imaging, but these investigations continue to be complementary. EUS was first introduced in the mid-1980s in Japan and Germany and has quickly gained acceptance. Its widespread use in the last decade has revolutionized the management of pancreatic disease as it simultaneously provides primary diagnostic and staging information, as well as enabling tissue biopsy. This article discusses the potential benefits and drawbacks of EUS in the primary diagnosis, staging and assessment of resectability, and EUS-guided fine-needle aspiration in PC. Difficult diagnostic scenarios and pitfalls are also discussed. A suggested management algorithm for patients with suspected PC is also presented.

16 Clinical Trial Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. 2015

Chantrill, Lorraine A / Nagrial, Adnan M / Watson, Clare / Johns, Amber L / Martyn-Smith, Mona / Simpson, Skye / Mead, Scott / Jones, Marc D / Samra, Jaswinder S / Gill, Anthony J / Watson, Nicole / Chin, Venessa T / Humphris, Jeremy L / Chou, Angela / Brown, Belinda / Morey, Adrienne / Pajic, Marina / Grimmond, Sean M / Chang, David K / Thomas, David / Sebastian, Lucille / Sjoquist, Katrin / Yip, Sonia / Pavlakis, Nick / Asghari, Ray / Harvey, Sandra / Grimison, Peter / Simes, John / Biankin, Andrew V / Anonymous5550827 / Anonymous5560827. ·The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Prince of Wales Hospital, Randwick, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. · University of Sydney, New South Wales, Australia. Macquarie University Hospital, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Northern Sydney Cancer Centre, Royal North Shore Hospital, New South Wales, Australia. · Bankstown Cancer Centre, Bankstown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. ·Clin Cancer Res · Pubmed #25896973.

ABSTRACT: PURPOSE: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. EXPERIMENTAL DESIGN: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). RESULTS: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. CONCLUSIONS: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

17 Article Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling. 2019

Dreyer, Stephan B / Jamieson, Nigel B / Evers, Lisa / Duthie, Fraser / Cooke, Susie / Marshall, John / Beraldi, Dario / Knight, Stephen / Upstill-Goddard, Rosanna / Dickson, Euan J / Carter, C Ross / McKay, Colin J / Biankin, Andrew V / Chang, David K. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. david.chang@glasgow.ac.uk. ·Chin Clin Oncol · Pubmed #31070037.

ABSTRACT: Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC.

18 Article ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. 2018

Pinho, Andreia V / Van Bulck, Mathias / Chantrill, Lorraine / Arshi, Mehreen / Sklyarova, Tatyana / Herrmann, David / Vennin, Claire / Gallego-Ortega, David / Mawson, Amanda / Giry-Laterriere, Marc / Magenau, Astrid / Leuckx, Gunther / Baeyens, Luc / Gill, Anthony J / Phillips, Phoebe / Timpson, Paul / Biankin, Andrew V / Wu, Jianmin / Rooman, Ilse. ·Cancer Division, The Garvan Institute of Medical Research, Sydney, Darlinghurst 2010, NSW, Australia. andreia.pinho@mq.edu.au. · Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Macquarie University 2109, NSW, Australia. andreia.pinho@mq.edu.au. · Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia. andreia.pinho@mq.edu.au. · Oncology Research Centre, Vrije Universiteit Brussel, Brussels, 1090, Belgium. · Cancer Division, The Garvan Institute of Medical Research, Sydney, Darlinghurst 2010, NSW, Australia. · Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia. · St. Vincent's Clinical School, UNSW, Sydney, Darlinghurst 2010, NSW, Australia. · Beta cell Neogenesis Lab, Vrije Universiteit Brussel, Brussels, 1090, Belgium. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, St. Leonards 2065, NSW, Australia. · Lowy Cancer Research Centre, University of New South Wales, Sydney, Sydney 2052, NSW, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G5 0SF, Scotland, UK. · South Western Sydney Clinical School, UNSW, Liverpool, Liverpool 2170, NSW, Australia. · Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing, 100142, China. · Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia. irooman@vub.be. · Oncology Research Centre, Vrije Universiteit Brussel, Brussels, 1090, Belgium. irooman@vub.be. ·Nat Commun · Pubmed #30504844.

ABSTRACT: Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1

19 Article CSF1R 2018

Candido, Juliana B / Morton, Jennifer P / Bailey, Peter / Campbell, Andrew D / Karim, Saadia A / Jamieson, Thomas / Lapienyte, Laura / Gopinathan, Aarthi / Clark, William / McGhee, Ewan J / Wang, Jun / Escorcio-Correia, Monica / Zollinger, Raphael / Roshani, Rozita / Drew, Lisa / Rishi, Loveena / Arkell, Rebecca / Evans, T R Jeffry / Nixon, Colin / Jodrell, Duncan I / Wilkinson, Robert W / Biankin, Andrew V / Barry, Simon T / Balkwill, Frances R / Sansom, Owen J. ·Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. · Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Boston, MA, USA. · MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK. · Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Cambridge, UK. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: o.sansom@beatson.gla.ac.uk. ·Cell Rep · Pubmed #29719257.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.

20 Article Defining the molecular pathology of pancreatic body and tail adenocarcinoma. 2018

Dreyer, S B / Jamieson, N B / Upstill-Goddard, R / Bailey, P J / McKay, C J / Anonymous5070973 / Biankin, A V / Chang, D K. ·West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. ·Br J Surg · Pubmed #29341146.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

21 Article Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. 2018

Chou, Angela / Froio, Danielle / Nagrial, Adnan M / Parkin, Ashleigh / Murphy, Kendelle J / Chin, Venessa T / Wohl, Dalia / Steinmann, Angela / Stark, Rhys / Drury, Alison / Walters, Stacey N / Vennin, Claire / Burgess, Andrew / Pinese, Mark / Chantrill, Lorraine A / Cowley, Mark J / Molloy, Timothy J / Anonymous2871515 / Waddell, Nicola / Johns, Amber / Grimmond, Sean M / Chang, David K / Biankin, Andrew V / Sansom, Owen J / Morton, Jennifer P / Grey, Shane T / Cox, Thomas R / Turchini, John / Samra, Jaswinder / Clarke, Stephen J / Timpson, Paul / Gill, Anthony J / Pajic, Marina. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, SYDPATH, Darlinghurst, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. · St. Vincent's Hospital, Darlinghurst, Australia. · St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia. · Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Queensland, Australia. · University of Melbourne, Melbourne, Victoria, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Surgery, Cancer Research UK, Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Gut · Pubmed #29080858.

ABSTRACT: OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS: Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION: This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

22 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

23 Article Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. 2017

Feigin, Michael E / Garvin, Tyler / Bailey, Peter / Waddell, Nicola / Chang, David K / Kelley, David R / Shuai, Shimin / Gallinger, Steven / McPherson, John D / Grimmond, Sean M / Khurana, Ekta / Stein, Lincoln D / Biankin, Andrew V / Schatz, Michael C / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA. · Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia. · Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA. · Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Nat Genet · Pubmed #28481342.

ABSTRACT: The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.

24 Article Lost in translation: returning germline genetic results in genome-scale cancer research. 2017

Johns, Amber L / McKay, Skye H / Humphris, Jeremy L / Pinese, Mark / Chantrill, Lorraine A / Mead, R Scott / Tucker, Katherine / Andrews, Lesley / Goodwin, Annabel / Leonard, Conrad / High, Hilda A / Nones, Katia / Patch, Ann-Marie / Merrett, Neil D / Pavlakis, Nick / Kassahn, Karin S / Samra, Jaswinder S / Miller, David K / Chang, David K / Pajic, Marina / Anonymous7710904 / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Zeps, Nikolajs / Gill, Anthony J / Biankin, Andrew V. ·Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. · St Vincents Hospital, Darlinghurst, Australia. · Western Sydney University Clinical School, Sydney, Australia. · Genetics Department, SEALS Pathology, Prince of Wales Hospital, Randwick, Sydney, Australia. · School of Medicine, University of New South Wales, Sydney, Australia. · Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, Australia. · Cancer Genetics Department, Royal Prince Alfred Hospital and Liverpool Hospital, Sydney, NSW, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Sydney Cancer Genetics, Sydney, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, Australia. · Division of Surgery, School of Medicine, Western Sydney University, Sydney, Australia. · Department of Medical Oncology, Royal North Shore Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia. · Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Adelaide, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, Australia. · Illumina Inc, 5200 Illumina Way, San Diego, CA, 92122, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. · University of Melbourne, Parkville, Australia. · St John of God Subiaco, Perth, Australia. · School of Surgery, The University of Western Australia, Perth, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia and University of Sydney, Sydney, Australia. · Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. andrew.biankin@glasgow.ac.uk. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK. andrew.biankin@glasgow.ac.uk. ·Genome Med · Pubmed #28454591.

ABSTRACT: BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

25 Article Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. 2017

Vennin, Claire / Chin, Venessa T / Warren, Sean C / Lucas, Morghan C / Herrmann, David / Magenau, Astrid / Melenec, Pauline / Walters, Stacey N / Del Monte-Nieto, Gonzalo / Conway, James R W / Nobis, Max / Allam, Amr H / McCloy, Rachael A / Currey, Nicola / Pinese, Mark / Boulghourjian, Alice / Zaratzian, Anaiis / Adam, Arne A S / Heu, Celine / Nagrial, Adnan M / Chou, Angela / Steinmann, Angela / Drury, Alison / Froio, Danielle / Giry-Laterriere, Marc / Harris, Nathanial L E / Phan, Tri / Jain, Rohit / Weninger, Wolfgang / McGhee, Ewan J / Whan, Renee / Johns, Amber L / Samra, Jaswinder S / Chantrill, Lorraine / Gill, Anthony J / Kohonen-Corish, Maija / Harvey, Richard P / Biankin, Andrew V / Anonymous7171303 / Evans, T R Jeffry / Anderson, Kurt I / Grey, Shane T / Ormandy, Christopher J / Gallego-Ortega, David / Wang, Yingxiao / Samuel, Michael S / Sansom, Owen J / Burgess, Andrew / Cox, Thomas R / Morton, Jennifer P / Pajic, Marina / Timpson, Paul. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. · St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia. · Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia. · Biomedical Imaging Facility, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia. · Department of Pathology, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales 2522, Australia. · Immune Imaging Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2006, Australia. · University of Sydney Medical School, Sydney, New South Wales 2006, Australia. · Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · Cancer Research UK Beatson Institute, Glasgow, Scotland G61 BD, U.K. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research and Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Australian Pancreatic Cancer Genome Initiative. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, Sydney, New South Wales 2560, Australia. · School of Medicine, Western Sydney University, Penrith, Sydney, New South Wales 2751, Australia. · School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, New South Wales 2052, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Scotland G61 BD, U.K. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Scotland G61 BD, U.K. · Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, San Diego, CA 92121, USA. · Centre for Cancer Biology, SA Pathology and University of South Australia School of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia. · The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. m.pajic@garvan.org.au p.timpson@garvan.org.au. ·Sci Transl Med · Pubmed #28381539.

ABSTRACT: The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

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