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Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Distinct outcome patterns according to RAS and BRAF status in MSI-H/dMMR mCRC treated with immune checkpoint
Andrea Pretta1, Riccardo Giampieri2, Andrea Bottelli3
1Medical Oncology Unit, University Hospital and University of Cagliari, Italy.
Background:
Immune checkpoint inhibitors (ICIs) are superior to chemotherapy in metastatic colorectal cancer (mCRC) with MSI-H/dMMR. However, whether oncogenic driver alterations contribute to clinically meaningful heterogeneity in outcomes within this immunotherapy-sensitive population remains unclear. We conducted a systematic review and meta-analysis to evaluate the association between RAS and BRAF mutational status and outcomes in ICI-treated MSI-H/dMMR mCRC.
Methods:
A systematic literature search identified studies reporting outcomes of ICI therapy according to RAS and/or BRAF status in MSI-H/dMMR mCRC. Study-level pooled analyses were conducted using random-effects models to estimate odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS).
Results:
Nine studies were included, comprising a total of 13 treatment cohorts and 2564 patients were analysed. ORR did not significantly differ across molecular subgroups. Compared with wild-type tumours, RAS-mutated disease was associated with modestly longer PFS (HR 0.81, 95% CI 0.66-0.99), whereas BRAF-mutated tumours showed shorter PFS (HR 1.37, 95% CI 1.11-1.69). Overall survival was significantly worse in BRAF-mutated disease (HR 1.74, 95% CI 1.17-2.59), while no significant OS differences were observed for RAS-mutated tumours. Exploratory analyses suggested that dual checkpoint blockade may increase response rates particularly in BRAF-mutated and molecularly wild-type subgroups.
Conclusions:
Within MSI-H/dMMR mCRC treated with ICIs, molecular subgroups show distinct survival patterns despite similar response rates. BRAF-mutated tumours retain an adverse prognostic impact, whereas RAS-mutated disease may exhibit more durable disease control. These findings support biological stratification within MSI-H/dMMR mCRC and provide a rationale for prospective biomarker-stratified studies of tailored immunotherapy strategies.
Insights
In metastatic colorectal cancer (mCRC) with MSI-H/dMMR treated with immune checkpoint inhibitors (ICIs), BRAF mutations indicate worse survival, while RAS mutations may offer more durable disease control. These findings highlight the importance of molecular stratification for tailored immunotherapy strategies.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) show superiority over chemotherapy for metastatic colorectal cancer (mCRC) patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors.
- The impact of oncogenic driver alterations (RAS, BRAF) on treatment outcomes within this specific patient population remains incompletely understood.
Purpose of the Study:
- To conduct a systematic review and meta-analysis evaluating the association between RAS and BRAF mutational status and clinical outcomes in patients with MSI-H/dMMR mCRC treated with ICIs.
Main Methods:
- A systematic literature search identified relevant studies reporting outcomes based on RAS and BRAF status in ICI-treated MSI-H/dMMR mCRC.
- Study-level pooled analyses using random-effects models were performed to estimate hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), and odds ratios (ORs) for objective response rate (ORR).
Main Results:
- Analysis of nine studies (13 cohorts, 2564 patients) revealed similar objective response rates across molecular subgroups.
- BRAF-mutated tumors were associated with significantly shorter PFS (HR 1.37) and worse OS (HR 1.74) compared to wild-type.
- RAS-mutated tumors showed a trend towards longer PFS (HR 0.81) but no significant difference in OS compared to wild-type.
Conclusions:
- Distinct survival patterns exist within MSI-H/dMMR mCRC based on molecular subgroups, despite comparable response rates to ICIs.
- BRAF mutations confer an adverse prognostic impact, while RAS mutations may be linked to more durable disease control.
- These results support biological stratification and warrant biomarker-stratified trials for personalized immunotherapy in mCRC.
