Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing
Garrett M. Frampton,Alex Fichtenholtz,Geoff Otto,Kai Wang,Sean R. Downing,Jie He,Michael Schnall-Levin,Jared White,Eric M. Sanford,Peter An,James Sun,Frank Juhn,Kristina W. Brennan,Kiel Iwanik,Ashley Maillet,Jamie Buell,Emily White,Mandy Zhao,Sohail Balasubramanian,Selmira Terzic,Tina Richards,Vera Banning,Lazaro Garcia,Kristen Mahoney,Zac Zwirko,Amy Donahue,Himisha Beltran,Himisha Beltran,Juan Miguel Mosquera,Juan Miguel Mosquera,Mark A. Rubin,Mark A. Rubin,Snjezana Dogan,Cyrus V. Hedvat,Michael F. Berger,Lajos Pusztai,Matthias Lechner,Chris Boshoff,Mirna Jarosz,Christine Vietz,Alexander N. Parker,Vincent A. Miller,Jeffrey S. Ross,Jeffrey S. Ross,John Curran,Maureen T. Cronin,Philip J. Stephens,Doron Lipson,Roman Yelensky +48 more
TLDR
A test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens is described.Abstract:
As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.read more
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Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial
Jonathan E. Rosenberg,Jean H. Hoffman-Censits,Thomas Powles,Michiel S. van der Heijden,Arjun Vasant Balar,Andrea Necchi,Nancy A. Dawson,Peter H. O'Donnell,Ani Balmanoukian,Yohann Loriot,Sandy Srinivas,Margitta Retz,Petros Grivas,Richard W. Joseph,Matthew D. Galsky,Mark D. Fleming,Daniel P. Petrylak,Jose Luis Perez-Gracia,Howard A. Burris,Daniel Castellano,Christina Canil,Joaquim Bellmunt,Dean F. Bajorin,Dorothee Nickles,Richard Bourgon,Garrett M. Frampton,Na Cui,Sanjeev Mariathasan,Oyewale O. Abidoye,Gregg Fine,Robert Dreicer +30 more
TL;DR: Treatment with atezolizumab resulted in a significantly improved RECIST v1.1 response rate, compared with a historical control overall response rate of 10%, and Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolediazepine.
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Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up †
Silvia Novello,Fabrice Barlesi,Raffaele Califano,Raffaele Califano,Tanja Cufer,Simon Ekman,M. Giaj Levra,Keith M. Kerr,Sanjay Popat,Martin Reck,Suresh Senan,G Simo,Johan Vansteenkiste,Sanne Peters +13 more
TL;DR: The ESMO Guidelines Committee concluded that current state-of-the-art oncology practices in France, Belgium, and the Netherlands are suitable for frontline use and recommend further research into these practices.
Journal ArticleDOI
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients
Ahmet Zehir,Ryma Benayed,Ronak Shah,Aijazuddin Syed,Sumit Middha,Hyunjae R. Kim,Preethi Srinivasan,Jianjiong Gao,Debyani Chakravarty,Sean M. Devlin,Matthew D. Hellmann,David Barron,Alison M. Schram,Meera Hameed,Snjezana Dogan,Dara S. Ross,Jaclyn F. Hechtman,Deborah DeLair,Jinjuan Yao,Diana Mandelker,Donavan T. Cheng,Raghu Chandramohan,Abhinita Mohanty,Ryan Ptashkin,Gowtham Jayakumaran,Meera Prasad,Mustafa H Syed,Anoop Balakrishnan Rema,Zhen Y Liu,Khedoudja Nafa,Laetitia Borsu,Justyna Sadowska,Jacklyn Casanova,Ruben Bacares,Iwona Kiecka,Anna Razumova,Julie B Son,Lisa Stewart,Tessara Baldi,Kerry Mullaney,Hikmat Al-Ahmadie,Efsevia Vakiani,Adam Abeshouse,Alexander V Penson,Philip Jonsson,Niedzica Camacho,Matthew T. Chang,Helen Won,Benjamin Gross,Ritika Kundra,Zachary J. Heins,Hsiao-Wei Chen,Sarah Phillips,Hongxin Zhang,Jiaojiao Wang,Angelica Ochoa,Jonathan Wills,Michael H. Eubank,Stacy B. Thomas,Stuart Gardos,Dalicia N. Reales,Jesse Galle,Robert Durany,Roy Cambria,Wassim Abida,Andrea Cercek,Darren R. Feldman,Mrinal M. Gounder,A. Ari Hakimi,James J. Harding,Gopa Iyer,Yelena Y. Janjigian,Emmet Jordan,Ciara Marie Kelly,Maeve A. Lowery,Luc G. T. Morris,Antonio Omuro,Nitya Raj,Pedram Razavi,Alexander N. Shoushtari,Neerav Shukla,Tara Soumerai,Anna M. Varghese,Rona Yaeger,Jonathan A. Coleman,Bernard H. Bochner,Gregory J. Riely,Leonard B. Saltz,Howard I. Scher,Paul Sabbatini,Mark E. Robson,David S. Klimstra,Barry S. Taylor,José Baselga,Nikolaus Schultz,David M. Hyman,Maria E. Arcila,David B. Solit,Marc Ladanyi,Michael F. Berger +99 more
TL;DR: A large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer are compiled and identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types.
Journal ArticleDOI
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
Zachary R. Chalmers,Caitlin F. Connelly,David Fabrizio,Siraj M. Ali,Riley Ennis,Alexa B. Schrock,Brittany Campbell,Adam Shlien,Juliann Chmielecki,Franklin W. Huang,Yuting He,James Sun,Uri Tabori,Mark Kennedy,Daniel S. Lieber,Steven Roels,Jared White,G. Otto,Jeffrey S. Ross,Levi A. Garraway,Levi A. Garraway,Vincent A. Miller,Phillip J. Stephens,Garrett M. Frampton +23 more
TL;DR: Measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly, demonstrating that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy.
Journal ArticleDOI
Comprehensive Characterization of Cancer Driver Genes and Mutations.
Matthew H. Bailey,Collin Tokheim,Eduard Porta-Pardo,Sohini Sengupta,Denis Bertrand,Amila Weerasinghe,Antonio Colaprico,Michael C. Wendl,Jaegil Kim,Brendan Reardon,Patrick Kwok Shing Ng,Kang Jin Jeong,Song Cao,Zixing Wang,Jianjiong Gao,Qingsong Gao,Fang Wang,Eric Minwei Liu,Loris Mularoni,Carlota Rubio-Perez,Niranjan Nagarajan,Isidro Cortes-Ciriano,Daniel Cui Zhou,Wen-Wei Liang,Julian M. Hess,Venkata Yellapantula,David Tamborero,Abel Gonzalez-Perez,Chayaporn Suphavilai,Jia Yu Ko,Ekta Khurana,Peter J. Park,Eliezer M. Van Allen,Eliezer M. Van Allen,Han Liang,Michael S. Lawrence,Adam Godzik,Nuria Lopez-Bigas,Josh Stuart,David A. Wheeler,Gad Getz,Ken Chen,Alexander J. Lazar,Gordon B. Mills,Rachel Karchin,Li Ding +45 more
TL;DR: This study reports a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations, identifying 299 driver genes with implications regarding their anatomical sites and cancer/cell types.
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