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1. Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work

Author

Max Robinson, Jacqueline James, Gareth Thomas, Nicholas West, Louise Jones, Jessica Lee, Karin Oien, Alex Freeman, Clare Craig, Philip Sloan, Philip Elliot, Maggie Cheang, Manuel Rodriguez‐Justo, Clare Verrill, and on behalf of the UK National Cancer Research Institute (NCRI) Cellular‐Molecular Pathology (CM‐Path) clinical trials working group

Subjects
pathology, clinical trials, quality assurance, immunohistochemistry, biomarkers, Pathology, RB1-214
Abstract

Abstract While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed ‘pathological complete response’, have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology‐derived data builds confidence around trial‐specific findings and is necessarily focused on the reproducibility of pathological data, including ‘estimates of uncertainty of measurement’, emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter‐observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever‐expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence‐base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials.

Published
2019
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2. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Kevin Litchfield, Stacey Stanislaw, Lavinia Spain, Lisa L. Gallegos, Andrew Rowan, Desiree Schnidrig, Heidi Rosenbaum, Alexandre Harle, Lewis Au, Samantha M. Hill, Zayd Tippu, Jennifer Thomas, Lisa Thompson, Hang Xu, Stuart Horswell, Aoune Barhoumi, Carol Jones, Katherine F. Leith, Daniel L. Burgess, Thomas B.K. Watkins, Emilia Lim, Nicolai J. Birkbak, Philippe Lamy, Iver Nordentoft, Lars Dyrskjøt, Lisa Pickering, Stephen Hazell, Mariam Jamal-Hanjani, James Larkin, Charles Swanton, Nelson R. Alexander, Samra Turajlic, Chris Abbosh, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Sergio Quezada, Stephan Beck, Peter Parker, Henning Walczak, Tariq Enver, Rob Hynds, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David Moore, Teresa Marafioti, Elaine Borg, Miriam Mitchison, Reena Khiroya, Giorgia Trevisan, Peter Ellery, Mark Linch, Sebastian Brandner, Crispin Hiley, Selvaraju Veeriah, Maryam Razaq, Heather Shaw, Gert Attard, Mita Afroza Akther, Cristina Naceur-Lombardelli, Lizi Manzano, Maise Al-Bakir, Simranpreet Summan, Nnenna Kanu, Sophie Ward, Uzma Asghar, Faye Gishen, Adrian Tookman, Paddy Stone, Caroline Stirling, Andrew Furness, Kim Edmonds, Nikki Hunter, Sarah Sarker, Sarah Vaughan, Mary Mangwende, Karla Pearce, Scott Shepherd, Haixi Yan, Ben Shum, Eleanor Carlyle, Steve Hazell, Annika Fendler, Fiona Byrne, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Gordon Stamp, Antonia Toncheva, Emma Nye, Aida Murra, Justine Korteweg, Nahid Sheikh, Debra Josephs, Ashish Chandra, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Lara-Rose Iredale, Tina Mackay, Ben Deakin, Debra Enting, Sarah Rudman, Sharmistha Ghosh, Lena Karapagniotou, Elias Pintus, Andrew Tutt, Sarah Howlett, Vasiliki Michalarea, James Brenton, Carlos Caldas, Rebecca Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison Cluroe, Grant Stewart, Colin Watts, Richard Gilbertson, Ultan McDermott, Simon Tavare, Emma Beddowes, Patricia Roxburgh, Andrew Biankin, Anthony Chalmers, Sioban Fraser, Karin Oien, Andrew Kidd, Kevin Blyth, Matt Krebs, Fiona Blackhall, Yvonne Summers, Caroline Dive, Richard Marais, Fabio Gomes, Mat Carter, Jo Dransfield, John Le Quesne, Dean Fennell, Jacqui Shaw, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Ian Tomlinson, Sanjay Jogai, Christian Ottensmeier, David Harrison, Massimo Loda, Adrienne Flanagan, Mairead McKenzie, Allan Hackshaw, Jonathan Ledermann, Abby Sharp, Laura Farrelly, and Hayley Bridger

Subjects
tumor sampling, tumor sequencing, representative sampling, molecular profiling, tumor hetereogeneity, biomarkers, Biology (General), QH301-705.5
Abstract

Summary: Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020
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3. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author

Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla-Maja Bailey, Marc Jones, Kim Moran-Jones, Derek W. Wright, Fraser Duthie, Karin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Amber Johns, Marina Pajic, Fieke E.M. Froeling, Phillip Beer, Elizabeth A. Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V. Biankin, David K. Chang, Sarah Allison, Dario Beraldi, Euan Cameron, Stephan Dreyer, Paul Grimwood, Shane Kelly, John Marshall, Sancha Martin, Brian McDade, Daniel McElroy, Donna Ramsay, Derek Wright, Marc D. Jones, Jane Hair, Paul Westwood, Nicola Williams, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, Victorian Cancer Biobank, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham, and Basic (bio-) Medical Sciences

Subjects
0301 basic medicine, HRD, homologous recombination deficiency, DNA Repair, PDAC, pancreatic ductal adenocarcinoma, Cell Culture Techniques, DMSO, dimethyl sulfoxide, Transcriptome, 0302 clinical medicine, Molecular Targeted Therapy, SV, structural variation, Original Research, Cancer, PDCL, patient-derived cell line, Gastroenterology, Organoids, PC, pancreatic cancer, oncology, PARP inhibitor, RNAseq, RNA sequencing, 030211 gastroenterology & hepatology, DNA Damage Response, ICGC, International Cancer Genome Consortium, DNA Replication, DNA repair, DNA damage, RPPA, reverse-phase protein array, EC50, median effective concentration, MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, Adenocarcinoma, Biology, DDR, DNA damage response, TOM, topological overlap measure, 03 medical and health sciences, Pancreatic Cancer, Cell Line, Tumor, Pancreatic cancer, GO, Gene Ontology, medicine, Humans, PDX, patient-derived xenograft, Hepatology, DNA replication, Personalized Medicine, Replication Stress, medicine.disease, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, body regions, 030104 developmental biology, siRNA, small interfering RNA, Cancer research, Full Report: Basic and Translational—Pancreas, HR, homologous recombination, Homologous recombination, Biomarkers, DNA Damage
Abstract

Background & Aims Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. Conclusions Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy., Graphical abstract

Published
2021
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