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Ryma Benayed
Memorial Sloan Kettering Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3754-0321
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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 99% 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.
Keywords
Somatic Tumor Alterations, NGS Assay, Analytical Validation, De-novo Mutation, Matched White Blood Cell Sequencing
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Yes there is potential Competing Interest. David B. Solit has served as a consultant for/received honoraria from Loxo Oncology, Lilly Oncology, Pfizer, QED Therapeutics, Vivideon Therapeutics and Illumina.
Maria E. Arcila received speaker’s fees from Raindance Technologies.
Marc Ladanyi 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. Rose Brannon has stock ownership in Johnson & Johnson
Soo-Ryum Yang has received consulting fees from Invitae
Michael F. Berger has received consulting fees from Roche and grant support from Illumina and Grail.
Michael F. Berger, Dana Tsui, Preethi Srinivasan, Juber Patel, Brian Houck-Loomis, Maysun Hasan, and Fanli Meng are co-inventors on a provisional patent application for systems and methods for detecting cancer via cfDNA screening.
Ahmet Zehir received speaking fees from Illumina.
Brian Houck-Loomis receives royalties from BioLegend for development of products related to CITE-seq.
Jaclyn Hechtman has received research funding from Bayer, Eli Lilly, and Boehringer Ingelheim; and honoraria or consulting fees from Axiom Healthcare Stetegies, WebMD, Illumina, and Cor2Ed.
Khedoudja Nafa has received honoraria from Biocartis
Sarat Chandarlapaty has received consulting fees from Sermonix, Paige.ai, Novartis, and Lilly.
James J. Harding 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.
Helena Yu 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.
Wassim Abida 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.
Lillian M. Smyth 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.
Dana Tsui has received research support from ThermoFisher Scientific, EPIC Sciences, speaking honoraria and travel support from Nanodigmbio, Cowen, BoA Merrill Lynch,
Dana Tsui and Luis Diaz 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.
Ryma Benayed has received a grant and travel credit from ArcherDx, honoraria for advisory board participation from Loxo oncology, RocheDx and speaking fees from Illumina.
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigures18.docx
Supplementary Figures 1-8
- SupplementalFigures18.docx
Supplementary Figures 1-8
- SupplementalTables16.xlsx
Supplementary Tables 1-6
- SupplementalTables16.xlsx
Supplementary Tables 1-6
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See the published version of this preprint at Nature Communications.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Article
Ryma Benayed
Memorial Sloan Kettering Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3754-0321
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Nature Communications.
Version 1
Posted 07 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Nature Communications.
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 99% 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.
Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Figure 4
Figure 4
Yes there is potential Competing Interest. David B. Solit has served as a consultant for/received honoraria from Loxo Oncology, Lilly Oncology, Pfizer, QED Therapeutics, Vivideon Therapeutics and Illumina.
Maria E. Arcila received speaker’s fees from Raindance Technologies.
Marc Ladanyi 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. Rose Brannon has stock ownership in Johnson & Johnson
Soo-Ryum Yang has received consulting fees from Invitae
Michael F. Berger has received consulting fees from Roche and grant support from Illumina and Grail.
Michael F. Berger, Dana Tsui, Preethi Srinivasan, Juber Patel, Brian Houck-Loomis, Maysun Hasan, and Fanli Meng are co-inventors on a provisional patent application for systems and methods for detecting cancer via cfDNA screening.
Ahmet Zehir received speaking fees from Illumina.
Brian Houck-Loomis receives royalties from BioLegend for development of products related to CITE-seq.
Jaclyn Hechtman has received research funding from Bayer, Eli Lilly, and Boehringer Ingelheim; and honoraria or consulting fees from Axiom Healthcare Stetegies, WebMD, Illumina, and Cor2Ed.
Khedoudja Nafa has received honoraria from Biocartis
Sarat Chandarlapaty has received consulting fees from Sermonix, Paige.ai, Novartis, and Lilly.
James J. Harding 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.
Helena Yu 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.
Wassim Abida 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.
Lillian M. Smyth 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.
Dana Tsui has received research support from ThermoFisher Scientific, EPIC Sciences, speaking honoraria and travel support from Nanodigmbio, Cowen, BoA Merrill Lynch,
Dana Tsui and Luis Diaz 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.
Ryma Benayed has received a grant and travel credit from ArcherDx, honoraria for advisory board participation from Loxo oncology, RocheDx and speaking fees from Illumina.
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigures18.docx
Supplementary Figures 1-8
- SupplementalFigures18.docx
Supplementary Figures 1-8
- SupplementalTables16.xlsx
Supplementary Tables 1-6
- SupplementalTables16.xlsx
Supplementary Tables 1-6
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