580P - Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers

Background

All international guidelines currently recommend routine testing of all CRC for MSI/dMMR for Lynch Syndrome screening, prognosis information and treatment guidance. In metastatic setting, the analysis for allRAS and BRAF mutational status is recommended to select the most appropriate treatment choice. However, the impact of RAS and BRAF mutations on prognosis and treatment effect in MSI/dMMR patients is not understood in either localized or metastatic setting.

Methods

A retrospective analysis was performed on 463 de-identified records of patients with stage I-IV MSI/dMMR CRC that were profiled by next-generation sequencing (NGS) (Tempus xT DNA-seq of 595-648 genes at 500x coverage and Tempus xR whole-exome capture RNA-seq). MSI status was determined by assessment of 44 or 239 loci by NGS. dMMR was determined by Tempus IHC testing. Tumor mutational burden (TMB), tumor neoantigen burden (TNB), PD-L1 positivity, immune infiltration, and canonical immune pathways (82 gene set signatures) were analyzed.

Results

Among the 463 MSI/dMMR CRCs, 110 tumors harbored a RAS mutation (RASmut) (23.8%) and 123 a BRAF ^V600E mutation (26.6%) Age at diagnosis was significantly lower amongst RASmut patients versus RAS wild-type patients (RASwt) (57 vs. 71 yo, p <.001) and significantly higher amongst BRAF ^V600E mutated patients versus BRAF wild-type (BRAFwt) patients (76 vs. 62 yo, p<.001). RAS ^mut patients exhibited lower TNB (12 vs. 16, p<.001) as well as PD-L1 positivity (15% vs. 31%, p=.058) compared to RASwt patients. Furthermore, the pathway enrichment analyses showed a lower tumor inflammatory profile of tumor immune microenvironment (TIME) amongst RASmut. By contrast, BRAF ^V600E tumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming, but similarly inflamed TIME compared to the wild type counterpart.

Conclusions

Overall, these data suggest that MSI/dMMR CRC harboring RAS mutations are less immunogenic and appear to contain a lower tumor inflammatory profile of TIME than RASwt or BRAF ^V600E mutated tumors. Further analysis and validation are needed to confirm our data.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

E. Mauer: Financial Interests, Personal, Full or part-time Employment: Tempus AI. S.M. El-Refai: Financial Interests, Personal, Full or part-time Employment: Tempus AI. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., Ikena Oncology, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. J. Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, Pierre Fabre, BeiGene; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo, Gilead, Arcus, Takeda, Illumina; Non-Financial Interests, Leadership Role, Working party chair: AGITG. S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GSK, Jazz, Xilis, Abbvie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata, Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis; Financial Interests, Personal, Other, Consultant: Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis; Financial Interests, Personal, Ownership Interest: Frontier Medicines. E. Van Cutsem: Financial Interests, Personal, Advisory Board: Abbvie, Agenus, ALX, Arcus Biosciences, Astellas, AstraZeneca, Bayer, BeiGene, Biontech, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Debiopharma, Elmedix, Eisai, GSK, Hoopika Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, MIrati, Novartis, Nordic, Pierre Fabre, Seattle Genetics, Servier, Simcere, Takeda, Taiho, Terumo; Financial Interests, Personal, Invited Speaker: Amgen, Pfizer. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, merck serono, lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Astellas, GSK, Takeda, Bayer, Rottapharm; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Servier, Amgen, Bristol-Myers Squibb, Incyte, Lilly, Merck Serono, MSD, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb; Non-Financial Interests, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. M.J. Overman: Financial Interests, Personal, Advisory Board: roche, bms, medimmune, merck, amgen, takeda, janssen, pfizer, array, gritstone, nouscom, atreca, bayer; Financial Interests, Institutional, Coordinating PI: roche, lilly, merck, bms, phanes, nouscom. All other authors have declared no conflicts of interest.