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Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients. Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy. Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms. Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.

Nat. Med. 23, 703–713 (2017); published online 08 May 2017; corrected after print 14 June 2017 In the version of this article initially published online, the top value in the y axis of the Kaplan–Meier plots in Figure 3c was incorrectly denoted as 0.1. The correct value is 1. The error has been corrected in the HTML and PDF versions of the article.

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance. Competing Interest Statement D.B.S. has served as a consultant for/received honoraria from Loxo Oncology, Lilly Oncology, Pfizer, QED Therapeutics, Vivideon Therapeutics and Illumina. M.E.A. received speaker fees from Raindance Technologies. M.L. has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda, and Bayer, and research support from LOXO Oncology and Helsinn Healthcare. A.R.B has stock ownership in Johnson & Johnson. S.R.Y has received consulting fees from Invitae. M.F.B. has received consulting fees from Roche and grant support from Illumina and Grail. M.F.B., D.T., P.S., J.B., B.H.L., M.H., and F.M. are co-inventors on a provisional patent application for systems and methods for detecting cancer via cfDNA screening. A.Z. received speaking fees from Illumina. B.H.L. receives royalties from BioLegend for development of products related to CITE-seq. J.H. has received research funding from Bayer, Eli Lilly, and Boehringer Ingelheim; and honoraria or consulting fees from Axiom Healthcare Stetegies, WebMD, Illumina, and Cor2Ed. K.N. has received honoraria from Biocartis. S.C. has received consulting fees from Sermonix, Paige.ai, Novartis, and Lilly. J.J.H. has received consulting fees from Bristol Myers Squibb, Exelexis, Eisai, Merck, ImVax, CytomX, and Eli Lilly and research support from Bristol Myers Squibb, the Wien Initiative in Liver Cancer Research, and the Society of MSKCC. H.Y. has consulted for AstraZeneca, Blueprint Medicine, Janssen Oncology and Daiichi. Her institution has received research funding for clinical trials from AstraZeneca, Daiichi, Pfizer, Novartis, Cullinan Oncology, Lilly. W.A. has received research funding from AstraZeneca, Zenith Epigenetics, Clovis Oncology, GlaxoSmithKline; and honoraria or consulting fees from CARET, Clovis Oncology, Janssen, MORE Health, ORIC Pharmaceuticals, Daiichi Sankyo. L.M.S. is an employee of Loxo Oncology at Lilly. LMS has consulted for Novartis, Pfizer, AstraZeneca and Roche Genentech; received research funding from AstraZeneca, Puma Biotechnology and Roche Genentech; travel or accommodations expenses from AstraZeneca, Pfizer, Puma Biotechnology and Roche Genentech; honoraria from Pfizer and AstraZeneca. D.T. has received research support from ThermoFisher Scientific, EPIC Sciences, speaking honoraria and travel support from Nanodigmbio, Cowen, BoA Merrill Lynch, D.T. and L.D. are co-inventors on a provisional patent application for systems and methods for distinguishing pathological mutations from clonal hematopoietic mutations in plasma cell-free DNA by fragment size analysis. R.B. has received a grant and travel credit from ArcherDx, honoraria for advisory board participation from Loxo oncology and speaking fees from Illumina.