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Updated: Jul 28, 2025
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with
T Ratovomanana1, R Nicolle2, R Cohen3
1Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris.
Background:
Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy.
Patients And Methods:
We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS).
Results:
Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS.
Conclusions:
iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.
Insights
Predicting response to immune checkpoint inhibitors (ICIs) in mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) is crucial. A novel DNA and RNA signature, analyzing microsatellite mutations and TGFB-related markers, accurately predicts progression-free survival in these patients.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Mismatch repair-deficient (dMMR) tumors with microsatellite instability (MSI) respond well to immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC).
- However, some patients with dMMR/MSI mCRC are resistant to ICI therapy.
- Predictive tools are needed to optimize ICI treatment strategies for mCRC.
Purpose of the Study:
- To identify reliable DNA and RNA biomarkers for predicting patient response to ICI therapy in dMMR/MSI mCRC.
- To validate these predictors in independent patient cohorts.
Main Methods:
- High-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with ICIs (NIPICOL trial and ImmunoMSI cohort).
- Analysis of previously suggested biomarkers (MSIsensor, tumor mutational burden) and novel signatures.
- Validation of significant predictors from the discovery set in the validation set.
- Primary endpoint: progression-free survival (PFS) by immune RECIST (iPFS).
Main Results:
- Previously suggested biomarkers did not predict ICI response.
- A multiplex MSI signature (19 microsatellites) and an 182-RNA marker signature (non-epithelial, TGFB-related) were significantly associated with iPFS.
- Both DNA and RNA signatures independently predicted iPFS in MSI mCRC patients.
Conclusions:
- Progression-free survival in patients with MSI mCRC treated with ICIs can be predicted.
- The predictive signature involves analyzing DNA microsatellite gene mutations in epithelial tumor cells.
- The signature also incorporates non-epithelial, TGFB-related RNA markers.
