High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology

Voutsadakis, Ioannis A.

doi:10.1016/j.ctarc.2023.100746

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…The prevalence of high TMB in the patient population was measured at 21.7%. Similar patient populations such as those reported by Voutsadakis reported prevalence of high TMB in metastatic CRC to be lower at 9.8% ( 13 ). The GeneTrails ® NGS which provided the data for our report has been internally validated for accuracy ( 20 ), though there are likely to be variations between different assays.…”

Section: Discussionsupporting

confidence: 77%

“…Treatment of high TMB solid tumors with an ICI was approved after the phase 2 trial KEYNOTE-158, which showed a higher objective response to treatment to ICI monotherapy in high TMB compared to non-high TMB solid tumor patients, though notably there were no patients with CRC included in this trial ( 10 ). Some studies suggest that TMB could be a valuable prognostic marker in CRC and could predict response to ICI therapy ( 11 ), though other studies have suggested that identifying specific mutations is more important than measuring the quantity of mutations ( 12 ), and a recent study looking at microsatellite-stable (MSS) CRC did not find a significant survival difference between patients with high or low TMB ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Survival in metastatic microsatellite-stable colorectal cancer correlated with tumor mutation burden and mutations identified by next-generation sequencing

Taflin,

Sandow,

Thawani

et al. 2024

J Gastrointest Oncol

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Background Next-generation sequencing (NGS) identifies mutations and molecular abnormalities within tumors, including tumor mutation burden (TMB). If a solid tumor has high TMB, immune checkpoint inhibitors (ICIs) are approved as an option for treatment. Studies have been inconclusive regarding how effective ICI are in treating patients with colorectal cancer (CRC), and it is unclear if high TMB is a good prognostic marker for CRC. We collected data from NGS of CRC and correlated survival to both TMB and mutations of interest, as well as investigated the efficacy of ICI. Methods This was a retrospective cohort analysis at a single institution, collecting NGS data from January 2018 to December 2020 in patients with CRC who were microsatellite-stable (MSS), n=161. Demographics, clinical data, and results from NGS were collected, and a survival analysis looking at TMB and selected mutations of interest was performed. Patients who were treated with ICI were assessed in a descriptive subset analysis. Results Patients with CRC who were MSS and had high TMB trended towards worse survival [hazard ratio (HR) =1.38] though the result was not significant (P=0.28). Survival was significantly worse in patients with a KRAS mutation (HR =1.71, P=0.04) and/or a CDKN2A mutation (HR =4.45, P<0.001). In this study population, 12 patients with high TMB had treatment with ICI, with nine of these patients having shorter progression-free survival (PFS) between 0.7 and 4.1 months, and three patients having longer PFS of 26.3, 24.7, and 13.2 months. Conclusions High TMB in MSS CRC did not show statistical difference in outcome. Mutations in KRAS and/or CDKN2A correlated with worse prognosis. Some patients with MSS CRC and high TMB responded to ICI, though there is a need to identify a better biomarker to predict which patients will have a good response to ICI therapy.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Survival in metastatic microsatellite-stable colorectal cancer correlated with tumor mutation burden and mutations identified by next-generation sequencing

Taflin,

Sandow,

Thawani

et al. 2024

J Gastrointest Oncol

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“…However, the lack of association of PD-L1 expression with response in the MHC-II reliant group seems to suggest a mechanism independent of alleviating PD-L1 based repression of CD8 T cells. A similar phenomenon has been observed in microsatellite instable colorectal cancers with B2M loss that paradoxically remain among the best responders to anti-PD1/anti-PD-L1 therapy 91 . It is intriguing to think that anti-PD1/anti-PD-L1 can be beneficial even if PD-L1 is not highly expressed or the class-I antigen presentation machinery is not functional.…”

Section: Mhc-i Damage On Cancer Cells Inherently Hampers the Cytotoxi...supporting

confidence: 68%

Integrated germline and somatic features reveal divergent immune pathways driving ICB response

Sears,

Pagadala,

Castro

et al. 2024

Preprint

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Immune Checkpoint Blockade (ICB) has revolutionized cancer treatment, however mechanisms determining patient response remain poorly understood. Here we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher T follicular helper infiltrates were robust to defects in the class-I Major Histocompatibility Complex (MHC-I). Further investigation uncovered different ICB responses in MHC-I versus MHC-II neoantigen reliant tumors across patients. Despite similar response rates, MHC-II reliant responses were associated with significantly longer durable clinical benefit (Discovery: Median OS=63.6 vs. 34.5 months P=0.0074; Validation: Median OS=37.5 vs. 33.1 months, P=0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC-II but not MHC-I reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses.

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“…mCRC that originates via Pol epsilon mutations displays relatively higher TMB, and these patients show increased response to ICB therapy [ 146 ]. Published genomic studies show that 7.5% of mCRC patients with MSS tumor display high TMB, and sequencing may identify candidates for ICB therapy not detected based on dMMR/MSI [ 147 ]. Clinical studies have investigated the potential of chemotherapy to improve the activity of immunotherapy in MSS mCRC, but no therapeutic benefit has been established for this approach [ 148 ].…”

Section: Immunotherapy Approaches For Mcrcmentioning

confidence: 99%

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

Gmeiner

2024

Cancers

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Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.

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High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology

Cited by 8 publications

References 49 publications

Survival in metastatic microsatellite-stable colorectal cancer correlated with tumor mutation burden and mutations identified by next-generation sequencing

Survival in metastatic microsatellite-stable colorectal cancer correlated with tumor mutation burden and mutations identified by next-generation sequencing

Integrated germline and somatic features reveal divergent immune pathways driving ICB response

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

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