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Genetics and Genomics

Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors

British Journal of Cancer (2024)Cite this article

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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.

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Fig. 1: Development of Caris Consensus Molecular Subtypes (CMS) classifier.
Fig. 2: Molecular and clinical characteristics of study cohort by CMS classifier.
Fig. 3: Overall survival (OS) of CRC cohort.
Fig. 4: CMS is a predictive biomarker for anti-EGFR antibody treatment.
Fig. 5: CMS is a predictive biomarker for pembrolizumab treatment.

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Data availability

The data generated in this study are not publicly available due to data size and patient privacy but summarized data are available upon reasonable request from the corresponding author.

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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

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Saikat Chowdhury, Scott Kopetz & John Paul Shen

  2. Caris Life Sciences, Phoenix, AZ, USA

    Joanne Xiu, Jennifer R. Ribeiro, Theodore Nicolaides, Jian Zhang & Kelsey A. Poorman

  3. University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

    W. Michael Korn

  4. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Heinz-Josef Lenz

  5. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    John L. Marshall

  6. Caris Life Sciences, Irving, TX, USA

    Matthew J. Oberley, George W. Sledge Jr. & David Spetzler

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  1. Saikat Chowdhury
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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.

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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.

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Chowdhury, S., Xiu, J., Ribeiro, J.R. et al. Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02826-0

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