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ABSTRACT BACKGROUND We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive

utility in a large clinico-genomic database of CRC patients (_n_ = 24,939). METHODS The classifier was trained against the original CMS datasets using an SVM model and validated in an

independent blinded TCGA dataset (88.0% accuracy). Kaplan–Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (_p_ < 0.05 considered

significant). RESULTS CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In _RAS_-wildtype mCRC, left-sided tumors and CMS2 classification were associated

with longer TOT with anti-EGFR antibodies (cetuximab and panitumumab). When restricting to only CMS2, there was no significant difference in TOT between right- versus left-sided tumors. CMS1

tumors were associated with a longer median TOT with pembrolizumab relative to other CMS groups, even when analyzing only microsatellite stable (MSS) tumors. DISCUSSION A WTS-based CMS

classifier allowed investigation of a large multi-institutional clinico-genomic mCRC cohort, suggesting anti-EGFR therapy benefit for right-sided _RAS_-WT CMS2 tumors and immune checkpoint

inhibitor benefit for MSS CMS1. Routine CMS classification of CRC provides important treatment associations that should be further investigated. Access through your institution Buy or

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TARGETED THERAPY GUIDED BY CIRCULATING TUMOR DNA ANALYSIS IN ADVANCED GASTROINTESTINAL TUMORS Article Open access 16 September 2024 COMPREHENSIVE ASSESSMENT OF ACTIONABLE GENOMIC

ALTERATIONS IN PRIMARY COLORECTAL CARCINOMA USING TARGETED NEXT-GENERATION SEQUENCING Article Open access 16 July 2022 WHOLE-EXOME TUMOR-AGNOSTIC CTDNA ANALYSIS ENHANCES MINIMAL RESIDUAL

DISEASE DETECTION AND REVEALS RELAPSE MECHANISMS IN LOCALIZED COLON CANCER Article Open access 29 April 2025 DATA AVAILABILITY The data generated in this study are not publicly available due

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Scholar  Download references FUNDING This work was supported by the National Cancer Institute (K22 CA234406 to JPS, and the Cancer Center Support Grant (P30 CA016672), the Cancer Prevention

& Research Institute of Texas (RR180035 to JPS, JPS is a CPRIT Scholar in Cancer Research), and the Col. Daniel Connelly Memorial Fund. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * The

University of Texas MD Anderson Cancer Center, Houston, TX, USA Saikat Chowdhury, Scott Kopetz & John Paul Shen * Caris Life Sciences, Phoenix, AZ, USA Joanne Xiu, Jennifer R. Ribeiro, 

Theodore Nicolaides, Jian Zhang & Kelsey A. Poorman * University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA W. Michael Korn *

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Heinz-Josef Lenz * Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer

Center, Georgetown University, Washington, DC, USA John L. Marshall * Caris Life Sciences, Irving, TX, USA Matthew J. Oberley, George W. Sledge Jr. & David Spetzler Authors * Saikat

Chowdhury View author publications You can also search for this author inPubMed Google Scholar * Joanne Xiu View author publications You can also search for this author inPubMed Google

Scholar * Jennifer R. Ribeiro View author publications You can also search for this author inPubMed Google Scholar * Theodore Nicolaides View author publications You can also search for this

author inPubMed Google Scholar * Jian Zhang View author publications You can also search for this author inPubMed Google Scholar * W. Michael Korn View author publications You can also

search for this author inPubMed Google Scholar * Kelsey A. Poorman View author publications You can also search for this author inPubMed Google Scholar * Heinz-Josef Lenz View author

publications You can also search for this author inPubMed Google Scholar * John L. Marshall View author publications You can also search for this author inPubMed Google Scholar * Matthew J.

Oberley View author publications You can also search for this author inPubMed Google Scholar * George W. Sledge Jr. View author publications You can also search for this author inPubMed 

Google Scholar * David Spetzler View author publications You can also search for this author inPubMed Google Scholar * Scott Kopetz View author publications You can also search for this

author inPubMed Google Scholar * John Paul Shen View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS SC: Conceptualization, Investigation,

Methodology, Writing-review and editing. JX: Conceptualization, Data curation, Formal analysis, Investigation, Writing-review and editing. JRR: Investigation, Visualization, Writing-original

draft. TN, MJO, GWS, DS: Resources, Investigation. JZ: Formal analysis, Methodology. WMK: Resources, Investigation. KAP: Validation, Methodology. HL, JLM: Investigation. SK,

Conceptualization, Resources, Supervision, Investigation, Methodology. JPS: Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Methodology, Writing-review and

editing. CORRESPONDING AUTHOR Correspondence to John Paul Shen. ETHICS DECLARATIONS COMPETING INTERESTS HL: BMS, Merck, Bayer, Oncocyte, Fulgent, 3T Bioscience, Invitae, Abalos, AffiniT,

Adagene, Replimune. JM: RESEARCH SUPPORT: 2cureX, OnDose, Arcus Biosciences; PAYMENT/HONORARIA: AstraZeneca, Merck, Bayer, Seagen, Pfizer, Takeda, Taiho Pharmaceutical; CONSULTING OR

ADVISORY ROLE: Caris Life Sciences; OTHER: Indivumed (CMO). GWS: MEETING SUPPORT: Caris Life Sciences; STOCK/STOCK OPTIONS: Syndax, Caris Life Sciences, Tessa Pharm. SK: RESEARCH SUPPORT:

Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyol CONSULTNG OR ADVISORY ROLE: Genentech, EMD Serono, Merck,

Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata,

GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics,

Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol-Myers

Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Inc, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina,

Tachyon Therapeutics; STOCK/STOCK OPTIONS: Frontier Medicines; Iylon; Lutris; Navire; Xilis. JPS: RESEARCH SUPPORT: BostonGene, Celsius Therapeutics; CONSULTING OR ADVISORY ROLE: Engine

Biosciences, NaDeNo Nanoscience. JX, JRR, TN, JZ, KAP, MJO, GWS, and DS: employees of Caris Life Sciences. ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was conducted in accordance

with guidelines of the Declaration of Helsinki, Belmont report, and U.S. Common rule. In keeping with 45 CFR 46.101(b) (4), this study was performed utilizing retrospective, deidentified

clinical data. As such, it is considered Institutional Review Board (IRB) exempt and no patient consent was required. Exempt status was determined by Western IRB. ADDITIONAL INFORMATION

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subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors. _Br J Cancer_ 131, 1328–1339 (2024).

https://doi.org/10.1038/s41416-024-02826-0 Download citation * Received: 29 November 2023 * Revised: 08 August 2024 * Accepted: 12 August 2024 * Published: 04 September 2024 * Issue Date: 02

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