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Pancreatic Neoplasms: HELP
Articles by Daniel J. Renouf
Based on 20 articles published since 2009
(Why 20 articles?)
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Between 2009 and 2019, D. Renouf wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Evolution of systemic therapy for advanced pancreatic cancer. 2010

Renouf, Daniel / Moore, Malcolm. ·Department of Medical Oncology, Princess Margaret Hospital, 5-708, 610 University Avenue, Toronto, ON M5G 2M9, Canada. daniel.renouf@uhn.on.ca ·Expert Rev Anticancer Ther · Pubmed #20397918.

ABSTRACT: The prognosis for advanced pancreatic cancer remains poor and successful drug development in this disease continues to be a major challenge. In the last decade the approach to drug development in pancreatic cancer has included a focus on combinations of cytotoxic agents. While some promising results were seen in Phase II studies, none of the Phase III trials of cytotoxic combinations were able to demonstrate an improvement in overall survival over that seen with the single-agent gemcitabine. Newer studies have assessed the efficacy of 'targeted' agents that inhibit pathways thought to be important in the development, growth, invasion and metastasis of pancreatic cancer. Although some agents had promising activity in preclinical studies, none has made a major impact in the clinic. There has been some success with the addition of the EGF receptor tyrosine kinase inhibitor erlotinib to gemcitabine, which was the first combination to achieve an overall survival benefit compared with gemcitabine alone in a Phase III trial. Future directions for drug development in pancreatic cancer will mainly involve testing new targeted agents, although some cytotoxic combinations are currently in Phase III testing. There is a need to better understand the biology of the disease and incorporate this into trials in an attempt to search for predictive and prognostic markers that will aid in drug development. Control of pancreatic cancer will require combinations of targeted agents, probably individualized based on tumor genetics. We are just beginning to explore the efficacy of combining targeted agents in the clinic.

2 Clinical Trial A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer. 2016

Renouf, D J / Hedley, D / Krzyzanowska, M K / Schmuck, M / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. drenouf@bccancer.bc.ca. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. ·Cancer Chemother Pharmacol · Pubmed #27422303.

ABSTRACT: OBJECTIVES: AUY922 is a novel heat shock protein inhibitor with preclinical activity in pancreatic cancer. This phase II study evaluated the efficacy of AUY922 in patients with advanced pancreatic cancer previously treated with chemotherapy. METHODS: In this single-arm, Simon two-stage phase II trial, patients with metastatic or locally advanced pancreatic ductal adenocarcinoma who had progressed on at least one line of chemotherapy and were of good performances status (ECOG 0 or 1) were treated with AUY922 at a dose of 70 mg/m(2) IV weekly. The primary endpoint was disease control rate (objective response and stable disease ≥16 weeks). RESULTS: Twelve patients were accrued, all of whom received treatment. At least possibly related ≥grade 3 adverse events included fatigue (8 %) and AST elevation (8 %). Ten patients were evaluable for response with 1 (10 %) having stable disease and 9 (90 %) progressive disease. The median progression-free survival was 1.6 months, and the median overall survival was 2.9 months. CONCLUSIONS: AUY922 was not associated with significant efficacy in previously treated patients with advanced pancreatic cancer.

3 Clinical Trial A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. 2014

Renouf, D J / Tang, P A / Hedley, D / Chen, E / Kamel-Reid, S / Tsao, M S / Tran-Thanh, D / Gill, S / Dhani, N / Au, H J / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. Electronic address: drenouf@bccancer.bc.ca. · Tom Baker Cancer Centre, Calgary, AB, Canada. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. · Cross Cancer Institute, Edmonton, AB, Canada. ·Eur J Cancer · Pubmed #24857345.

ABSTRACT: BACKGROUND: Erlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine. METHODS: Erlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks). RESULTS: Fifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200-300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾ grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17-47%)). Disease control was observed in nine patients (24% (95% CI: 10-38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19-47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival. CONCLUSIONS: Erlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.

4 Clinical Trial A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer. 2012

Renouf, Daniel J / Tang, Patricia A / Major, Pierre / Krzyzanowska, Monika K / Dhesy-Thind, Bindi / Goffin, John R / Hedley, David / Wang, Lisa / Doyle, L / Moore, Malcolm J. ·University Health Network-Princess Margaret Hospital, Toronto, ON, Canada. ·Invest New Drugs · Pubmed #21526355.

ABSTRACT: BACKGROUND: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. RESULTS: Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. CONCLUSION: Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.

5 Clinical Trial A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. 2012

Renouf, Daniel J / Moore, Malcolm J / Hedley, David / Gill, Sharlene / Jonker, Derek / Chen, Eric / Walde, David / Goel, Rakesh / Southwood, Bernadette / Gauthier, Isabelle / Walsh, Wendy / McIntosh, Lynn / Seymour, Lesley. ·Division of Medical Oncology and Hematology, Rm 5-708, Princess Margaret Hospital, 610 University Avenue, Toronto M5G2M9, Canada. ·Invest New Drugs · Pubmed #21170669.

ABSTRACT: AIM: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. RESULTS: Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. CONCLUSION: Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

6 Article Genomic characterization of a well-differentiated grade 3 pancreatic neuroendocrine tumor. 2019

Williamson, Laura M / Steel, Michael / Grewal, Jasleen K / Thibodeau, My Lihn / Zhao, Eric Y / Loree, Jonathan M / Yang, Kevin C / Gorski, Sharon M / Mungall, Andrew J / Mungall, Karen L / Moore, Richard A / Marra, Marco A / Laskin, Janessa / Renouf, Daniel J / Schaeffer, David F / Jones, Steven J M. ·Canada's Michael Smith Genome Science Centre, BC Cancer, Vancouver, British Columbia V5Z 4S6, Canada. · Department of Pathology & Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia V6T 2B5, Canada. · Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada. · Division of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada. · Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. · Pancreas Centre BC, Vancouver, British Columbia V5Z 1M9, Canada. ·Cold Spring Harb Mol Case Stud · Pubmed #31160355.

ABSTRACT: Pancreatic neuroendocrine neoplasms (PanNENs) represent a minority of pancreatic neoplasms that exhibit variability in prognosis. Ongoing mutational analyses of PanNENs have found recurrent abnormalities in chromatin remodeling genes (e.g.,

7 Article Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. 2019

McDonald, Paul C / Chafe, Shawn C / Brown, Wells S / Saberi, Saeed / Swayampakula, Mridula / Venkateswaran, Geetha / Nemirovsky, Oksana / Gillespie, Jordan A / Karasinska, Joanna M / Kalloger, Steve E / Supuran, Claudiu T / Schaeffer, David F / Bashashati, Ali / Shah, Sohrab P / Topham, James T / Yapp, Donald T / Li, Jinyang / Renouf, Daniel J / Stanger, Ben Z / Dedhar, Shoukat. ·Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada. · NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy. · Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address: sdedhar@bccrc.ca. ·Gastroenterology · Pubmed #31078621.

ABSTRACT: BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (Kras RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In Kras CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.

8 Article None 2019

Jones, Martin R / Williamson, Laura M / Topham, James T / Lee, Michael K C / Goytain, Angela / Ho, Julie / Denroche, Robert E / Jang, GunHo / Pleasance, Erin / Shen, Yaoquing / Karasinska, Joanna M / McGhie, John P / Gill, Sharlene / Lim, Howard J / Moore, Malcolm J / Wong, Hui-Li / Ng, Tony / Yip, Stephen / Zhang, Wei / Sadeghi, Sara / Reisle, Carolyn / Mungall, Andrew J / Mungall, Karen L / Moore, Richard A / Ma, Yussanne / Knox, Jennifer J / Gallinger, Steven / Laskin, Janessa / Marra, Marco A / Schaeffer, David F / Jones, Steven J M / Renouf, Daniel J. ·BC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. · BC Cancer, Division of Medical Oncology, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. drenouf@bccancer.bc.ca. ·Clin Cancer Res · Pubmed #31068372.

ABSTRACT: PURPOSE: Gene fusions involving neuregulin 1 ( EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as CONCLUSIONS: This work adds to a growing body of evidence that

9 Article Outcomes and Characteristics of Patients Receiving Second-line Therapy for Advanced Pancreatic Cancer. 2019

Tsang, Erica S / Wong, Hui-Li / Wang, Ying / Renouf, Daniel J / Cheung, Winson Y / Lim, Howard J / Gill, Sharlene / Loree, Jonathan M / Kennecke, Hagen F. ·Division of Medical Oncology, BC Cancer. · Department of Medicine, University of British Columbia, Vancouver, BC. · Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne, Australia. · Department of Medical Oncology, University of Calgary, Calgary, AB, Canada. · Department of Oncology, Virginia Mason Cancer Institute, Seattle, WA. ·Am J Clin Oncol · Pubmed #30499841.

ABSTRACT: OBJECTIVES: There is limited randomized data to guide second-line chemotherapy selection in advanced pancreatic cancer (APC). We aimed to characterize predictors and outcomes of second-line chemotherapy in patients with APC. METHODS: We identified all patients with APC [locally advanced (LAPC) or metastatic (MPC)] who received ≥1 cycle of first-line chemotherapy between January 2012 and December 2015 across 6 cancer centers in British Columbia, Canada. Baseline characteristics and survival outcomes were summarized. RESULTS: Of 676 patients with APC (31% LAPC, 69% MPC) who received ≥1 cycle of chemotherapy, 164 (24%) received second-line chemotherapy. These patients were younger, with lower ECOG and higher CA19-9 at presentation, compared with patients who did not receive second-line chemotherapy. There were no differences in rates of second-line chemotherapy between LAPC and MPC (28% vs. 23%; P=0.18). Only first-line FOLFIRINOX was associated with second-line chemotherapy. Median overall survival (OS) from second-line chemotherapy was longer with second-line gemcitabine/nab-paclitaxel than fluoropyrimidine or gemcitabine (7.9 vs. 5.1 vs. 4.3 mo; P=0.008). On multivariable analysis, longer OS from second-line chemotherapy was associated with gemcitabine/nab-paclitaxel, lower ECOG, and LAPC. CONCLUSIONS: In this population-based cohort, first-line FOLFIRINOX was the strongest predictor of second-line chemotherapy. Duration of therapy remains short and novel treatments are urgently needed.

10 Article Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing. 2018

Wong, Hui-Li / Yang, Kevin C / Shen, Yaoqing / Zhao, Eric Y / Loree, Jonathan M / Kennecke, Hagen F / Kalloger, Steve E / Karasinska, Joanna M / Lim, Howard J / Mungall, Andrew J / Feng, Xiaolan / Davies, Janine M / Schrader, Kasmintan / Zhou, Chen / Karsan, Aly / Jones, Steven J M / Laskin, Janessa / Marra, Marco A / Schaeffer, David F / Gorski, Sharon M / Renouf, Daniel J. ·Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada. · Pancreas Centre BC, Vancouver, British Columbia V5Z 4E6, Canada. · Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada. · Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada. · Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia V5Z 1M9, Canada. · Vancouver Island Centre, British Columbia Cancer Agency, Vancouver, British Columbia V8R 6V5, Canada. · Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada. ·Cold Spring Harb Mol Case Stud · Pubmed #29092957.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of

11 Article Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. 2017

Zhao, Eric Y / Shen, Yaoqing / Pleasance, Erin / Kasaian, Katayoon / Leelakumari, Sreeja / Jones, Martin / Bose, Pinaki / Ch'ng, Carolyn / Reisle, Caralyn / Eirew, Peter / Corbett, Richard / Mungall, Karen L / Thiessen, Nina / Ma, Yussanne / Schein, Jacqueline E / Mungall, Andrew J / Zhao, Yongjun / Moore, Richard A / Den Brok, Wendie / Wilson, Sheridan / Villa, Diego / Shenkier, Tamara / Lohrisch, Caroline / Chia, Stephen / Yip, Stephen / Gelmon, Karen / Lim, Howard / Renouf, Daniel / Sun, Sophie / Schrader, Kasmintan A / Young, Sean / Bosdet, Ian / Karsan, Aly / Laskin, Janessa / Marra, Marco A / Jones, Steven J M. ·Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. · Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada. · Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sjones@bcgsc.ca. ·Clin Cancer Res · Pubmed #29246904.

ABSTRACT:

12 Article Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma. 2017

Tessier-Cloutier, Basile / Kalloger, Steve E / Al-Kandari, Mohammad / Milne, Katy / Gao, Dongxia / Nelson, Brad H / Renouf, Daniel J / Sheffield, Brandon S / Schaeffer, David F. ·Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. skalloger@mac.com. · Pancreas Centre BC, Vancouver, British Columbia, Canada. skalloger@mac.com. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. skalloger@mac.com. · Department of Anatomical Pathology, Abbotosford Regional Hospital and Cancer Centre, Abbotsford, British Columbia, Canada. skalloger@mac.com. · Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. · Division of Medical Oncology, University of British Columbia , Vancouver, British Columbia, Canada. · Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. · Pancreas Centre BC, Vancouver, British Columbia, Canada. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Department of Anatomical Pathology, Abbotosford Regional Hospital and Cancer Centre, Abbotsford, British Columbia, Canada. · Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada. ·BMC Cancer · Pubmed #28870260.

ABSTRACT: BACKGROUND: Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC). METHODS: A tissue microarray (TMA) was constructed from cases of resected PDAC. PD-L1 immunohistochemistry (IHC) was performed using the SP142 primary antibody. Immunohistochemical assessment for deficient mismatch repair status (MMRd), CD3 and CD8 were performed. All biomarkers were assessed independently by two anatomical pathologists and consensus achieved on all cases. Survival analysis was performed using three thresholds (> = 1%, >5% and >10%) for tumor cell membrane staining. RESULTS: Two-hundred fifty-two cases were included in the TMA and evaluable by IHC. Thirty-one (12%), 17 (7%), 12(5%) cases were positive at percentage cut offs of >0, >5, and >10% respectively. Increased PD-L1 expression was associated with inferior prognosis (p = 0.0367). No statistically significant association was identified between PD-L1 status and MMR status or tumor infiltrating lymphocytes. CONCLUSIONS: This data suggests that there is an inverse relationship between PD-L1 expression and disease specific survival times in resected PDAC. Consequently, this association may represent a phenotype where increased PD-L1 expression has an effect on tumor biology and could therefore identify a subgroup where PD1 blockade could have enhanced effectiveness.

13 Article Defining Eligibility of FOLFIRINOX for First-Line Metastatic Pancreatic Adenocarcinoma (MPC) in the Province of British Columbia: A Population-based Retrospective Study. 2017

Ho, Maria Yi / Kennecke, Hagen F / Renouf, Daniel J / Cheung, Winson Y / Lim, Howard J / Gill, Sharlene. ·Divison of Medical Oncology, Cross Cancer Institute, Edmonton, AB. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada. ·Am J Clin Oncol · Pubmed #26165420.

ABSTRACT: BACKGROUND: FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria. METHODS: Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics. RESULTS: A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%). CONCLUSIONS: Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

14 Article Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX. 2017

Peixoto, Renata D / Ho, Maria / Renouf, Daniel J / Lim, Howard J / Gill, Sharlene / Ruan, Jenny Y / Cheung, Winson Y. ·Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. ·Am J Clin Oncol · Pubmed #25844823.

ABSTRACT: OBJECTIVES: The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. MATERIALS AND METHODS: Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. RESULTS: A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P<0.001; 6.7 vs. 4.9 mo, P=0.008, respectively). After accounting for ECOG PS in the multivariate model, however, eligibility for either FOLFIRINOX or NG no longer predicted for better overall survival. CONCLUSIONS: The majority of patients with MPC are not candidates to either NG or FOLFIRINOX due to restrictive eligibility requirements. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

15 Article Immunophenotyping of ampullary carcinomata allows for stratification of treatment specific subgroups. 2016

Leo, Joyce M / Kalloger, Steve E / Peixoto, Renata D / Gale, Nadia S / Webber, Douglas L / Owen, David A / Renouf, Daniel / Schaeffer, David F. ·Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada The University of British Columbia, Vancouver, British Columbia, Canada. · The University of British Columbia, Vancouver, British Columbia, Canada Pancreas Centre BC, Vancouver, British Columbia, Canada. · Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. · Anatomical Pathology, BC Cancer Agency, Vancouver, British Columbia, Canada. · Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada The University of British Columbia, Vancouver, British Columbia, Canada Pancreas Centre BC, Vancouver, British Columbia, Canada. · The University of British Columbia, Vancouver, British Columbia, Canada Pancreas Centre BC, Vancouver, British Columbia, Canada Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. ·J Clin Pathol · Pubmed #26500334.

ABSTRACT: BACKGROUND: Ampullary carcinomata (AC) can be separated into intestinal (IT) or pancreatobiliary (PB) subtypes. Although morphological, immunohistochemical and molecular differentiation of IT and PB have been well documented; the prognostic significance of histological subtype and whether patients with either subtype benefit from differential chemotherapeutic regimens remains unclear. METHODS: As part of a larger cohort study, patients who underwent resection for AC or pancreatic ductal adenocarcinoma (PDAC) were retrospectively identified. Clinicopathological covariates and outcome were obtained and MUC1, MUC2, CDX2 and CK20 were assessed with immunohistochemistry. RESULTS: Of 99 ACs, the resultant immunophenotypes indicated 48% and 22% were IT and PB, respectively. Thirty (30%) cases were quadruple negative (QN). Within the PDAC cohort (N = 257), the most prevalent immunophenotype was QN (53%). Subsequently, all QN ACs were classified as PB immunohistochemically yielding 47.5% and 52.5% classified as IT and PB, respectively. Involved regional lymph nodes and elevated T-stage were significantly associated with PB compared with IT AC (p = 0.0032 and 0.0396, respectively). Progression-free survival revealed inferior survival for PB versus IT AC (p = 0.0156). CONCLUSIONS: AC can be classified into prognostic groups with unique clinicopathological characteristics using immunohistochemistry. Immunophenotypical similarity of PB and PDAC suggests that treatment regimens similar to those used in PDAC should be explored.

16 Article Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. 2015

Huang, Ling / Holtzinger, Audrey / Jagan, Ishaan / BeGora, Michael / Lohse, Ines / Ngai, Nicholas / Nostro, Cristina / Wang, Rennian / Muthuswamy, Lakshmi B / Crawford, Howard C / Arrowsmith, Cheryl / Kalloger, Steve E / Renouf, Daniel J / Connor, Ashton A / Cleary, Sean / Schaeffer, David F / Roehrl, Michael / Tsao, Ming-Sound / Gallinger, Steven / Keller, Gordon / Muthuswamy, Senthil K. ·Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada. · McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. · Department of Physiology, Western University, London, Ontario, Canada. · Department of Pharmacology, Western University, London, Ontario, Canada. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Structural Genomics Consortium, Toronto, Ontario, Canada. · Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, British Columbia, Canada. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Division of General Surgery, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. ·Nat Med · Pubmed #26501191.

ABSTRACT: There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

17 Article Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. 2015

Riazy, Maziar / Kalloger, Steve E / Sheffield, Brandon S / Peixoto, Renata D / Li-Chang, Hector H / Scudamore, Charles H / Renouf, Daniel J / Schaeffer, David F. ·Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Pancreas Centre BC, Vancouver, British Columbia, Canada. · Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. · Division of General Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada. ·Mod Pathol · Pubmed #26226846.

ABSTRACT: Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted.

18 Article Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. 2015

Peixoto, Renata D'Alpino / Speers, Caroline / McGahan, Colleen E / Renouf, Daniel J / Schaeffer, David F / Kennecke, Hagen F. ·Division of Medical Oncology, University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Pancreas Centre, Vancouver, British Columbia, Canada. · Gastrointestinal Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Cancer Surveillance & Outcomes, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. ·Cancer Med · Pubmed #25891650.

ABSTRACT: Due to differences in natural history and therapy, clinical trials of patients with advanced pancreatic cancer have recently been subdivided into unresectable locally advanced pancreatic cancer (LAPC) and metastatic disease. We aimed to evaluate prognostic factors in LAPC patients who were treated with first-line chemotherapy and describe patterns of disease progression. Patients with LAPC who initiated first-line palliative chemotherapy, 2001-2011 at the BC Cancer Agency were included. A retrospective chart review was conducted to identify clinicopathologic variables, treatment, and subsequent sites of metastasis. Kaplan-Meier and Cox-regression survival analyses were performed. A total of 244 patients were included in this study. For the majority of patients (94.3%), first-line therapy was single-agent gemcitabine. About 144 (59%) patients developed distant metastatic disease and the most frequent metastatic sites included peritoneum/omentum (42.3%), liver (41%), lungs (13.9%), and distant lymph nodes (9%). Median overall survival (OS) for the entire cohort was 11.7 months (95% CI, 10.6-12.8). Development of distant metastases was associated with significantly inferior survival (HR 3.56, 95% CI 2.57-4.93), as was ECOG 2/3 versus 0/1 (HR 1.69, 95% CI 1.28-2.23), CA 19.9 > 1000 versus ≤ 1000 (HR 1.59, 95% CI 1.19-2.14) and female gender, (HR 1.57, 95% CI 1.19-2.08). In this population-based study, 41% of LAPC patients treated with first-line chemotherapy died without evidence of distant metastases. Prognostic factors for LAPC were baseline performance status, elevated CA 19.9, gender, and development of distant metastasis. Results highlight the heterogeneity of LAPC and the importance of locoregional tumor control.

19 Article Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma. 2015

O'Connor, Kate / Li-Chang, Hector H / Kalloger, Steven E / Peixoto, Renata D / Webber, Douglas L / Owen, David A / Driman, David K / Kirsch, Richard / Serra, Stefano / Scudamore, Charles H / Renouf, Daniel J / Schaeffer, David F. ·Divisions of *Anatomic Pathology #General Surgery, Vancouver General Hospital †The University of British Columbia ‡Pancreas Centre BC §Division of Medical Oncology, BC Cancer Agency, Vancouver, BC ∥Department of Pathology, Western University, London ¶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. ·Am J Surg Pathol · Pubmed #25634751.

ABSTRACT: Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

20 Minor Surgical oncology: Is PBD suitable for resectable pancreatic cancer? 2010

Renouf, Daniel J / Moore, Malcolm J. · ·Nat Rev Clin Oncol · Pubmed #20428219.

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