Data availability
Anonymized patient normal, tumor exome, and RNA-seq bam files containing alignments of the original raw sequencing reads used in this study have been deposited in the European Genome-phenome Archive repository under accession code EGAS00001003280. The processed variant calls are available at EGAD00001006569. The datasets are available under restricted access in compliance with patient consent for data sharing, access can be obtained by approval from the University Health Network data access committee. Custom code to reproduce key figures and results reported in the manuscript are available at https:// github.com/pughlab/inspire-genomics.
CONFLICTS OF INTEREST
Alberto Hernando-Calvo
Travel, Accommodations, Expenses - Kyowa Kirin International and Merck Serono.
S Y Cindy Yang
No Relationships to Disclose
Maria Vila-Casadesús
No Relationships to Disclose
Ming Han
No Relationships to Disclose
Hal K. Berman
No Relationships to Disclose
Anna Spreafico
Consultant for (Advisory Board): Merck (compensated), Bristol-Myers Squibb (compensated), Oncorus (compensated), Janssen (compensated), Medison & Immunocore (compensated). Speaker’s Bureau for: None. Grant/Research support from (Clinical Trials): Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Oncorus, Treadwell, Amgen. Stockholder in: None. Employee of: None.
Albiruni Ryan Abdul Razak
Consult or advisory role: Adaptimmune, Bayer, GlaxoSmithKline, Medison, Inhibrx. Expert testimony: Medison. Research Funding: Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Bristol-Myers Squibb, MedImmune, Amgen, GlaxoSmithkline, Blueprint Medicines, Merck, Abbvie, Adaptaimmune, Iterion Therapeutics, Neoleukin Therapeutics, Daiichi Sankyo, Symphogen, Rain Therapeutics, 23 and Me, Frontier Therapeutics and Boehringer Ingelheim.
Stephanie Lheureux
Honoraria - AstraZeneca; Eisai; GlaxoSmithKline; Merck. Consulting or Advisory Role - AstraZeneca; Eisai; GlaxoSmithKline; Merck; Novartis; Roche/Genentech; Novocure; Shattuck Labs. Research Funding - AstraZeneca (Inst); GlaxoSmithKline (Inst); Merck (Inst); Regeneron (Inst); Repare Therapeutics (Inst); Roche/Genentech (Inst); Tesaro (Inst)
Aaron Richard Hansen
Research funding to the institution from GSK, Merck, Pfizer, MedImmune/Genentech, Roche, Janssen, BMS, AstraZeneca, Astellas, Boehringer Ingelheim, and Bayer; consulting role/advisory boards for GSK, Merck, and Eisai.
Deborah Lo Giacco
No Relationships to Disclose
Judit Matito
No Relationships to Disclose
Trevor John Pugh
Consulting or Advisory Role: Chrysallis Biomedical Advisors, Axiom Healthcare Strategies and SAGA Diagnostics. Patents, Roaylties, Other intellectual property: Hybrid-capture sequencing for determining immune cell clonality. Honoraria: Merck, AstraZeneca, Illumina and PACT Pharma. Research Funding: Roche.
Scott Victor Bratman
Employment – Adela. Leadership – Adela. Stock and Other Ownership Interests - Adela. Research Funding – Nektar. Patents, Royalties, Other Intellectual Property - Co-inventor and holder of a patent related to circulating tumor DNA detection technology.; Co-inventor of patents related to cell-free DNA methylation analysis technology. (Inst)
Alexey Aleshin
Employment and ownership of equity at natera.
Roger Berché
No Relationships to Disclose
Omar Saavedra Santa Gadea
No Relationships to Disclose
Elena Garralda
Consulting or advisory role: Roche, Ellipses pharma, Neomed Therapeutics, Janssen, Boehringer Ingelheim. Seattle Genetics. TFS. Alkermes. Thermo Fisher Scientific. Bristol-Myers Squibb. MabDiscovery. Anaveon. F-Star Therapeutics. Speakers Bureau MSD, Roche, Thermo Fisher Scientific and Lilly. Research funding (recipient institution): Novartis. Roche. Thermo Fisher Scientific, AstraZeneca/MEdImmune, Taiho Oncology, BeiGene. Other relationship (recipient institution): Affimed Gmbh, Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, CytomX Therapeutics. F.Hoffmann La Roche Ltd, F-Satar Beta Limited, Genentech Inc, Genmab B.v, Hutchison MEdipharma Limited, Imcheck Therapeutics, Immunoscore Ltd, Janssen-Cilag SA, Medimmune Llc, Merck kgga, Novartis Farmaceutica, S.a, peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc, Symphogen A/S, Taiho Pharma Usa Inc.
Sawako Elston
No Relationships to Disclose
Lillian L. Siu
Consulting/advisory arrangements with Merck, Pfizer, AstraZeneca, Roche, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko, Coherus, Marengo, InteRNA; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks.
Pamela S. Ohashi
Stock and Other Ownership Interests - Providence Therapeutics; Treadwell Therapeutics. Consulting or Advisory Role - Providence Therapeutics; Tessa Therapeutics, EGLE therapeutics. Research Funding - EMD Serono (Inst); Providence Therapeutics (Inst)
Ana Vivancos
Advisory Board, personal: Bayer, Bristol Meyers Squibb, Guardant Health, Incyte, Roche. Stocks or Shares: Reveal Genomics. Research Grant, institutional, financial interest, preclinical research grant: Incyte and Roche.
Philippe L. Bedard
Local PI, Institutional: Amgen, AstraZeneca, Bicara, BMS, Genentech/Roche, Lilly, Merck, Nektar Therapeutics, Novartis, Pfizer, Sanofi, SeaGen and Zymeworks. Research Grant, Institutional: Pfizer. Funding, institutional: Servier.
ACKNOWLEDGEMENTS
The co-authors would like to acknowledge Natera for the ctDNA assay. * Merck Canada Inc., Kirkland, QC, Canada provided pembrolizumab. This research has been funded by the Comprehensive Program of Cancer Immunotherapy & Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021). A. Hernando-Calvo would like to acknowledge fellowship funding from the Spanish Society of Medical Oncology (SEOM), CRIS Cancer Foundation and Hold´em For Life Oncology Fellowship and the Division of Medical Oncology and Hematology Fellowship Award at Princess Margaret Cancer Centre. University Health Network.