{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:35:25Z","timestamp":1793658925880,"version":"4.5.1"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)\u00b1binimetinib (Bini) significantly improved overall survival (OS) versus Cetux\u2009+\u2009chemotherapy in previously treated patients with\n                    <jats:italic>BRAF<\/jats:italic>\n                    -V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux\u00b1Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux.\n                    <jats:italic>RAS<\/jats:italic>\n                    ,\n                    <jats:italic>MAP2K1<\/jats:italic>\n                    and\n                    <jats:italic>MET<\/jats:italic>\n                    alterations were most commonly acquired with Enco+Cetux\u00b1Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation was associated with acquired\n                    <jats:italic>MET<\/jats:italic>\n                    amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux\u00b1Bini and mutational signatures (SBS17a\/b). These findings support treatment with Enco+Cetux\u00b1Bini for patients with\n                    <jats:italic>BRAF<\/jats:italic>\n                    -V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT02928224\">NCT02928224<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03235-9","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T06:02:41Z","timestamp":1727071361000},"page":"3261-3271","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase\u20093 BEACON CRC trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-3416","authenticated-orcid":false,"given":"Scott","family":"Kopetz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4661-5540","authenticated-orcid":false,"given":"Fortunato","family":"Ciardiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4246-9344","authenticated-orcid":false,"given":"Jayesh","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Van Cutsem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet Singh","family":"Wasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-4756","authenticated-orcid":false,"given":"Takayuki","family":"Yoshino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedieh","family":"Saffari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phineas","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7658-6587","authenticated-orcid":false,"given":"Tao","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7233-5454","authenticated-orcid":false,"given":"Rona","family":"Yaeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-8139","authenticated-orcid":false,"given":"Josep","family":"Tabernero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"3235_CR1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S1470-2045(10)70130-3","volume":"11","author":"W De Roock","year":"2010","unstructured":"De Roock, W. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753\u2013762 (2010).","journal-title":"Lancet Oncol."},{"key":"3235_CR2","first-page":"1","volume":"42","author":"J Tabernero","year":"2022","unstructured":"Tabernero, J., Ros, J. & \u00c9lez, E. The evolving treatment landscape in BRAF-V600E-mutated metastatic colorectal cancer. Am. Soc. Clin. Oncol. Educ. Book 42, 1\u201310 (2022).","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"3235_CR3","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1056\/NEJMoa1908075","volume":"381","author":"S Kopetz","year":"2019","unstructured":"Kopetz, S. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381, 1632\u20131643 (2019).","journal-title":"N. Engl. J. Med."},{"key":"3235_CR4","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1200\/JCO.20.02088","volume":"39","author":"J Tabernero","year":"2021","unstructured":"Tabernero, J. et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J. Clin. Oncol. 39, 273\u2013284 (2021).","journal-title":"J. Clin. Oncol."},{"key":"3235_CR5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1158\/1078-0432.CCR-16-0140","volume":"23","author":"D Barras","year":"2017","unstructured":"Barras, D. et al. BRAF V600E mutant colorectal cancer subtypes based on gene expression. Clin. Cancer Res. 23, 104\u2013115 (2017).","journal-title":"Clin. Cancer Res."},{"key":"3235_CR6","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","volume":"21","author":"J Guinney","year":"2015","unstructured":"Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350\u20131356 (2015).","journal-title":"Nat. Med."},{"key":"3235_CR7","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1093\/jnci\/djab106","volume":"114","author":"S Ten Hoorn","year":"2022","unstructured":"Ten Hoorn, S., de Back, T. R., Sommeijer, D. W. & Vermeulen, L. Clinical value of consensus molecular subtypes in colorectal cancer: a systematic review and meta-analysis. J. Natl Cancer Inst. 114, 503\u2013516 (2022).","journal-title":"J. Natl Cancer Inst."},{"key":"3235_CR8","volume":"14","author":"T Xu","year":"2022","unstructured":"Xu, T. et al. Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR\/BRAF inhibitors. Ther. Adv. Med. Oncol. 14, 17588359221105022 (2022).","journal-title":"Ther. Adv. Med. Oncol."},{"key":"3235_CR9","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/2159-8290.CD-14-1518","volume":"5","author":"LG Ahronian","year":"2015","unstructured":"Ahronian, L. G. et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 5, 358\u2013367 (2015).","journal-title":"Cancer Discov."},{"key":"3235_CR10","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1158\/1078-0432.CCR-22-3094","volume":"29","author":"L Tan","year":"2023","unstructured":"Tan, L. et al. A phase Ib\/II trial of combined BRAF and EGFR inhibition in BRAF V600E positive metastatic colorectal cancer and other cancers: the EVICT (Erlotinib and Vemurafenib In Combination Trial) study. Clin. Cancer Res. 29, 1017\u20131030 (2023).","journal-title":"Clin. Cancer Res."},{"key":"3235_CR11","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.4049\/jimmunol.170.5.2349","volume":"170","author":"EM Aandahl","year":"2003","unstructured":"Aandahl, E. M. et al. CD7 is a differentiation marker that identifies multiple CD8 T cell effector subsets. J. Immunol. 170, 2349\u20132355 (2003).","journal-title":"J. Immunol."},{"key":"3235_CR12","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1093616","volume":"303","author":"SS Diebold","year":"2004","unstructured":"Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529\u20131531 (2004).","journal-title":"Science"},{"key":"3235_CR13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","volume":"160","author":"MS Rooney","year":"2015","unstructured":"Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48\u201361 (2015).","journal-title":"Cell"},{"key":"3235_CR14","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0092-8674(00)80702-3","volume":"100","author":"SJ Szabo","year":"2000","unstructured":"Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655\u2013669 (2000).","journal-title":"Cell"},{"key":"3235_CR15","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/s41591-023-02324-5","volume":"29","author":"J Roelands","year":"2023","unstructured":"Roelands, J. et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat. Med. 29, 1273\u20131286 (2023).","journal-title":"Nat. Med."},{"key":"3235_CR16","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-017-1349-1","volume":"18","author":"D Aran","year":"2017","unstructured":"Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017).","journal-title":"Genome Biol."},{"key":"3235_CR17","unstructured":"Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, v.3.3. Wellcome Sanger Institute https:\/\/cancer.sanger.ac.uk\/signatures\/# (2022)."},{"key":"3235_CR18","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","volume":"578","author":"LB Alexandrov","year":"2020","unstructured":"Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94\u2013101 (2020).","journal-title":"Nature"},{"key":"3235_CR19","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/ng.3659","volume":"48","author":"M Secrier","year":"2016","unstructured":"Secrier, M. et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat. Genet. 48, 1131\u20131141 (2016).","journal-title":"Nat. Genet."},{"key":"3235_CR20","volume":"9","author":"S Cen","year":"2021","unstructured":"Cen, S. et al. BRAF mutation as a potential therapeutic target for checkpoint inhibitors: a comprehensive analysis of immune microenvironment in BRAF mutated colon cancer. Front. Cell Dev. Biol. 9, 705060 (2021).","journal-title":"Front. Cell Dev. Biol."},{"key":"3235_CR21","first-page":"660","volume":"6","author":"CN Clarke","year":"2015","unstructured":"Clarke, C. N. & Kopetz, E. S. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J. Gastrointest. Oncol. 6, 660\u2013667 (2015).","journal-title":"J. Gastrointest. Oncol."},{"key":"3235_CR22","first-page":"1","volume":"42","author":"IH Sahin","year":"2022","unstructured":"Sahin, I. H., Ciombor, K. K., Diaz, L. A., Yu, J. & Kim, R. Immunotherapy for microsatellite stable colorectal cancers: challenges and novel therapeutic avenues. Am. Soc. Clin. Oncol. Educ. Book 42, 1\u201312 (2022).","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"3235_CR23","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1158\/1078-0432.CCR-19-3579","volume":"26","author":"G Middleton","year":"2020","unstructured":"Middleton, G. et al. BRAF-mutant transcriptional subtypes predict outcome of combined BRAF, MEK, and EGFR blockade with dabrafenib, trametinib, and panitumumab in patients with colorectal cancer. Clin. Cancer Res. 26, 2466\u20132476 (2020).","journal-title":"Clin. Cancer Res."},{"key":"3235_CR24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1158\/2326-6066.CIR-13-0160","volume":"2","author":"MK Callahan","year":"2014","unstructured":"Callahan, M. K. et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol. Res 2, 70\u201379 (2014).","journal-title":"Cancer Immunol. Res"},{"key":"3235_CR25","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1158\/1078-0432.CCR-14-2339","volume":"21","author":"L Liu","year":"2015","unstructured":"Liu, L. et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639\u20131651 (2015).","journal-title":"Clin. Cancer Res."},{"key":"3235_CR26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41590-020-00818-9","volume":"22","author":"V Verma","year":"2021","unstructured":"Verma, V. et al. MEK inhibition reprograms CD8(+) T lymphocytes into memory stem cells with potent antitumor effects. Nat. Immunol. 22, 53\u201366 (2021).","journal-title":"Nat. Immunol."},{"key":"3235_CR27","doi-asserted-by":"crossref","first-page":"653","DOI":"10.2217\/fon-2022-1249","volume":"20","author":"E Elez","year":"2024","unstructured":"Elez, E. et al. SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H\/dMMR BRAF V600E-mutant mCRC. Future Oncol. 20, 653\u2013663 (2024).","journal-title":"Future Oncol."},{"key":"3235_CR28","doi-asserted-by":"crossref","first-page":"TPS265","DOI":"10.1200\/JCO.2023.41.4_suppl.TPS265","volume":"41","author":"VK Morris","year":"2023","unstructured":"Morris, V. K. et al. Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and\/or unresectable colorectal cancer: SWOG S2107. J. Clin. Oncol. 41, TPS265\u2013TPS265 (2023).","journal-title":"J. Clin. Oncol."},{"key":"3235_CR29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1200\/JCO.2022.40.4_suppl.012","volume":"40","author":"VK Morris","year":"2022","unstructured":"Morris, V. K. et al. Phase I\/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer. J. Clin. Oncol. 40, 12\u201312 (2022).","journal-title":"J. Clin. Oncol."},{"key":"3235_CR30","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1038\/s41591-022-01976-z","volume":"28","author":"E Elez","year":"2022","unstructured":"Elez, E. et al. RNF43 mutations predict response to anti-BRAF\/EGFR combinatory therapies in BRAF(V600E) metastatic colorectal cancer. Nat. Med. 28, 2162\u20132170 (2022).","journal-title":"Nat. Med."},{"key":"3235_CR31","doi-asserted-by":"crossref","first-page":"6513","DOI":"10.1158\/0008-5472.CAN-17-0768","volume":"77","author":"R Yaeger","year":"2017","unstructured":"Yaeger, R. et al. Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition. Cancer Res. 77, 6513\u20136523 (2017).","journal-title":"Cancer Res."},{"key":"3235_CR32","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1158\/1535-7163.MCT-18-0852","volume":"18","author":"H Lu","year":"2019","unstructured":"Lu, H. et al. SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors. Mol. Cancer Ther. 18, 1323\u20131334 (2019).","journal-title":"Mol. Cancer Ther."},{"key":"3235_CR33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.celrep.2018.12.013","volume":"26","author":"TA Ahmed","year":"2019","unstructured":"Ahmed, T. A. et al. SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors. Cell Rep. 26, 65\u201378.e5 (2019).","journal-title":"Cell Rep."},{"key":"3235_CR34","doi-asserted-by":"crossref","first-page":"102137","DOI":"10.1016\/j.ctrv.2020.102137","volume":"92","author":"E Kun","year":"2021","unstructured":"Kun, E., Tsang, Y. T. M., Ng, C. W., Gershenson, D. M. & Wong, K. K. MEK inhibitor resistance mechanisms and recent developments in combination trials. Cancer Treat. Rev. 92, 102137 (2021).","journal-title":"Cancer Treat. Rev."},{"key":"3235_CR35","doi-asserted-by":"crossref","first-page":"3980","DOI":"10.18632\/oncotarget.14012","volume":"8","author":"B Zhao","year":"2017","unstructured":"Zhao, B. et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget 8, 3980\u20134000 (2017).","journal-title":"Oncotarget"},{"key":"3235_CR36","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1126\/science.aav4474","volume":"366","author":"M Russo","year":"2019","unstructured":"Russo, M. et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366, 1473\u20131480 (2019).","journal-title":"Science"},{"key":"3235_CR37","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1200\/JCO.22.01423","volume":"41","author":"CM Parseghian","year":"2023","unstructured":"Parseghian, C. M. et al. Resistance mechanisms to anti-epidermal growth factor receptor therapy in RAS\/RAF wild-type colorectal cancer vary by regimen and line of therapy. J. Clin. Oncol. 41, 460\u2013471 (2023).","journal-title":"J. Clin. Oncol."},{"key":"3235_CR38","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1038\/s41467-019-12594-8","volume":"10","author":"S Christensen","year":"2019","unstructured":"Christensen, S. et al. 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer. Nat. Commun. 10, 4571 (2019).","journal-title":"Nat. Commun."},{"key":"3235_CR39","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/s41559-021-01470-8","volume":"5","author":"A Woolston","year":"2021","unstructured":"Woolston, A. et al. Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer. Nat. Ecol. Evol. 5, 1024\u20131032 (2021).","journal-title":"Nat. Ecol. Evol."},{"key":"3235_CR40","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.cell.2018.04.012","volume":"173","author":"L Wang","year":"2018","unstructured":"Wang, L. et al. An acquired vulnerability of drug-resistant melanoma with therapeutic potential. Cell 173, 1413\u20131425.e14 (2018).","journal-title":"Cell"},{"key":"3235_CR41","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/j.celrep.2019.07.001","volume":"28","author":"LA Donehower","year":"2019","unstructured":"Donehower, L. A. et al. Integrated analysis of TP53 gene and pathway alterations in The Cancer Genome Atlas. Cell Rep. 28, 1370\u20131384.e5 (2019).","journal-title":"Cell Rep."},{"key":"3235_CR42","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1038\/s41591-021-01579-0","volume":"27","author":"T Powles","year":"2021","unstructured":"Powles, T. et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat. Med. 27, 2200\u20132211 (2021).","journal-title":"Nat. Med."},{"key":"3235_CR43","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-015-0197-4","volume":"7","author":"A Patwardhan","year":"2015","unstructured":"Patwardhan, A. et al. Achieving high-sensitivity for clinical applications using augmented exome sequencing. Genome Med. 7, 71 (2015).","journal-title":"Genome Med."},{"key":"3235_CR44","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","volume":"28","author":"JT Leek","year":"2012","unstructured":"Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882\u2013883 (2012).","journal-title":"Bioinformatics"},{"key":"3235_CR45","volume":"7","author":"PW Eide","year":"2017","unstructured":"Eide, P. W., Bruun, J., Lothe, R. A. & Sveen, A. CMScaller: an R package for consensus molecular subtyping of colorectal cancer pre-clinical models. Sci. Rep. 7, 16618 (2017).","journal-title":"Sci. Rep."},{"key":"3235_CR46","unstructured":"Pag\u00e8s, H., Carlson, M., Falcon S. & Li, N. AnnotationDbi: manipulation of SQLite-based annotations in Bioconductor. R package version 1.62.2. Bioconductor https:\/\/bioconductor.org\/packages\/AnnotationDbi (2023)."},{"key":"3235_CR47","doi-asserted-by":"publisher","unstructured":"Korotkevich, G. et al. Fast gene set enrichment analysis. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/060012 (2021).","DOI":"10.1101\/060012"},{"key":"3235_CR48","doi-asserted-by":"crossref","unstructured":"Dolgalev, I. MSigDB Gene sets for multiple organisms in a tidy data format, v.6.2.1. GitHub https:\/\/github.com\/igordot\/msigdbr (2018).","DOI":"10.32614\/CRAN.package.msigdbr"},{"key":"3235_CR49","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.it.2008.03.002","volume":"29","author":"E Wang","year":"2008","unstructured":"Wang, E., Worschech, A. & Marincola, F. M. The immunologic constant of rejection. Trends Immunol. 29, 256\u2013262 (2008).","journal-title":"Trends Immunol."},{"key":"3235_CR50","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40425-017-0215-8","volume":"5","author":"P Danaher","year":"2017","unstructured":"Danaher, P. et al. Gene expression markers of tumor infiltrating leukocytes. J. Immunother. Cancer 5, 18 (2017).","journal-title":"J. Immunother. Cancer"},{"key":"3235_CR51","volume":"17","author":"E Becht","year":"2016","unstructured":"Becht, E. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 17, 218 (2016).","journal-title":"Genome Biol."},{"key":"3235_CR52","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","volume":"12","author":"AM Newman","year":"2015","unstructured":"Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453\u2013457 (2015).","journal-title":"Nat. Methods"},{"key":"3235_CR53","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1158\/1078-0432.CCR-17-3831","volume":"24","author":"JI Odegaard","year":"2018","unstructured":"Odegaard, J. I. et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin. Cancer Res. 24, 3539\u20133549 (2018).","journal-title":"Clin. Cancer Res."},{"key":"3235_CR54","doi-asserted-by":"crossref","first-page":"100179","DOI":"10.1016\/j.xgen.2022.100179","volume":"2","author":"SMA Islam","year":"2022","unstructured":"Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genom. 2, 100179 (2022).","journal-title":"Cell Genom."},{"key":"3235_CR55","unstructured":"Guideline on the Investigation of Subgroups in Confirmatory Clinical Trials (European Medicines Agency, 2019); https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-investigation-subgroups-confirmatory-clinical-trials_en.pdf"},{"key":"3235_CR56","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1158\/2159-8290.CD-17-1452","volume":"8","author":"Y Gao","year":"2018","unstructured":"Gao, Y. et al. Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discov. 8, 648\u2013661 (2018).","journal-title":"Cancer Discov."},{"key":"3235_CR57","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1158\/0008-5472.CAN-20-0865","volume":"80","author":"AJ Hanrahan","year":"2020","unstructured":"Hanrahan, A. J. et al. Leveraging systematic functional analysis to benchmark an in silico framework distinguishes driver from passenger MEK mutants in cancer. Cancer Res. 80, 4233\u20134243 (2020).","journal-title":"Cancer Res."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03235-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03235-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03235-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T13:09:17Z","timestamp":1731589757000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03235-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":57,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["3235"],"URL":"https:\/\/doi.org\/10.1038\/s41591-024-03235-9","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,23]]},"assertion":[{"value":"10 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.K.: Stock and Other Ownership Interests: Iylon, Lutris, MolecularMatch, Navire. Consulting or Advisory Role: AbbVie, Amal Therapeutics, AstraZeneca\/MedImmune, Bayer Health, Bicara Therapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daiichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HalioDx, Holy Stone Healthcare, Inivata, Ipsen, Iylon, Jacobio, Jazz Pharmaceuticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, Redx Pharma, Repare Therapeutics, Servier, Xilis. Research Funding: Amgen (Inst), Array BioPharma (Inst), Biocartis (Inst), Daiichi Sankyo (Inst), EMD Serono (Inst), Genentech\/Roche (Inst), Guardant Health (Inst), Lilly (Inst), MedImmune (Inst), Novartis (Inst), Sanofi (Inst). D.A.M.: Employment: Formerly Pfizer. Stock and Other Ownership Interests: Pfizer. J.P.: Employment: Formerly Pfizer. Stock and Other Ownership Interests: Pfizer. F.C.: Consulting or Advisory Role: Amgen, Bayer, Merck KGaA, Pfizer, Roche\/Genentech. Research Funding: Amgen (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Merck KGaA (Inst), MSD (Inst), Roche\/Genentech (Inst), Servier (Inst), Symphogen (Inst). J.D.: Consulting or Advisory Role: Amgen (Inst), Bayer, BeiGene, Daiichi Sankyo, Eisai, GSK, Merck KGaA, Pierre Fabre. Research Funding: AstraZeneca\/MedImmune (Inst), BeiGene (Inst), Bionomics (Inst), Bristol Myers Squibb (Inst), GSK (Inst), Lilly (Inst), Novartis (Inst), Roche (Inst). E.V.C.: Consulting or Advisory Role: AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm, ElmediX, Eisai, GSK, Hookipa Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seagen, Servier, Simcere, Takeda, Taiho Pharmaceutical, Terumo. H.S.W.: Consulting or Advisory Role: Amgen, Bayer, Bristol Myers Squibb (Celgene), Boehringer Ingelheim (DMC), BTG, EXACT Therapeutics, Erytech Pharma, Incyte, Merck KGaA, Oaktree Life Sciences, OncoSil, Pfizer, Pierre Fabre, Roche\/Genentech, Seagen, Servier, Shire, Sirtex Medical, Takeda (Hutchinson Med), Zymeworks. Research Funding: Merck KGaA (Inst), MSD (Inst), Pfizer (Inst), Sirtex Medical (Inst). T.Y.: Honoraria: Bayer Yakuhin, Chugai Pharma, Merck KGaA, MSD, Ono Pharmaceutical, Sumitomo Corp., Takeda. Research Funding: Amgen (Inst), Boehringer Ingelheim (Inst), Chugai Pharma (Inst), Daiichi Sankyo Co., Ltd. (Inst), Eisai, FALCO Biosystems, Genomedia (Inst), Molecular Health, MSD (Inst), Nippon Boehringer Ingelheim, Ono Pharmaceutical (Inst), Pfizer (Inst), Roche Diagnostics, Sanofi (Inst), Sumitomo Dainippon (Inst), Sysmex (Inst), Taiho Pharmaceutical (Inst). H.S.: Employment: Pfizer. Stock and Other Ownership Interests: Pfizer. X.Z.: Employment: Pfizer. Stock and Other Ownership Interests: Pfizer. Patents, Royalties, Other Intellectual Property: Johns Hopkins University. P.H.: Employment: Pfizer. Stock and Other Ownership Interests: Pfizer. T.X.: Employment: Pfizer. Stock and Other Ownership Interests: Pfizer. R.Y.: Consulting or Advisory Role: Array BioPharma\/Pfizer, Mirati Therapeutics, Zai Lab, Amgen. Research Funding: Array BioPharma (Inst), Boehringer Ingelheim (Inst), Mirati Therapeutics (Inst), Pfizer (Inst), Daiichi Sankyo (Inst). J.T.: Consulting or Advisory Role: Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, F. Hoffmann-La Roche, Genentech, HalioDx, Hutchison MediPharma, Ikena Oncology, Inspirna Inc., IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seagen Inc., Servier, Taiho Pharmaceutical, Tessa Therapeutics, TheraMyc. Other Relationship: Amgen, Array Biopharma, BeiGene, Boehringer Ingelheim, BMS, Cancer Research UK, Celgene, Debiopharm, F. Hoffman-La Roche, Fundaci\u00f3n Cient\u00edfica de la Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer, Genentech, HalioDX, Hutchinson Medipharma, Imedex, Janssen-Cilag, MedImmune, Medscape, Menarini, Merck Health KGaA, MJH Life Sciences, MSD, Merus, Mirati, Novartis, Oniria Therapeutics, PeerView Institute for Medical Education, Pfizer, PharmaMar, Physicans\u2019 Education Resource, Sanofi-Aventis, Servier, Taiho Pharmaceutical.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}