Immunology · Year 2 · from Immunology
Case 3: MSI-High Colorectal Cancer Responding to Immunotherapy
Patient Presentation
Demographics: 52-year-old female
Chief Complaint: Follow-up for metastatic colorectal cancer treatment
History of Present Illness: The patient was diagnosed with metastatic colorectal cancer 6 months ago. Molecular testing revealed the tumor is microsatellite instability-high (MSI-H) with deficient mismatch repair (dMMR). She was started on pembrolizumab (anti-PD-1) as first-line therapy. After 4 cycles, she reports feeling well with improved energy and appetite.
Past Medical History:
- Colorectal cancer with liver metastases
- No family history of Lynch syndrome
- No prior chemotherapy
Physical Examination:
- General: Well-appearing, improved from prior visits
- Abdomen: Soft, non-tender, no hepatomegaly
- No lymphadenopathy
Workup and Results
Laboratory Studies:
- CEA: 12 ng/mL (down from 156 ng/mL at diagnosis)
- LFTs: Normal
- CBC: Normal
Imaging:
- CT chest/abdomen/pelvis: 70% reduction in liver metastases
Molecular Testing (at diagnosis):
- MSI-H (microsatellite instability-high)
- dMMR (deficient mismatch repair: MLH1 loss)
- Tumor mutational burden: 42 mutations/Mb (high)
Clinical Image
CT comparison showing significant tumor regression in MSI-H colorectal cancer liver metastases after pembrolizumab treatment, demonstrating the excellent response of high tumor mutational burden tumors to checkpoint inhibitor therapy.
Diagnosis
MSI-High Metastatic Colorectal Cancer with Excellent Response to Checkpoint Inhibitor
Discussion
This case illustrates predictors of immunotherapy response:
- MSI-H/dMMR Predicts Response: The lecture describes how MSI-H tumors have deficient mismatch repair, leading to accumulation of mutations and high tumor mutational burden (TMB). This generates numerous neoantigens that make tumors highly immunogenic.
- TMB Correlates with Response: The lecture notes that tumor mutational burden correlates with neoantigen load and checkpoint inhibitor response. MSI-H colorectal cancers have 10-100x higher TMB than microsatellite stable tumors.
- Tissue-Agnostic Approval: The lecture explains that pembrolizumab has tissue-agnostic FDA approval for MSI-H/dMMR tumors regardless of site of origin - the first such approval based on a biomarker rather than tumor type.
- "Hot" vs "Cold" Tumors: MSI-H tumors are typically "hot" (T-cell infiltrated) due to their high neoantigen load, making them excellent candidates for checkpoint inhibitors.
Treatment Plan
- Continue Pembrolizumab:
- Standard dosing every 3 weeks
- Continue for up to 2 years if responding
- Monitoring:
- CEA every 6 weeks
- CT imaging every 3 months
- Monitor for irAEs
- Genetic Counseling:
- Consider Lynch syndrome evaluation
- MLH1 promoter methylation testing (sporadic vs germline)
- Family history assessment
- Future Considerations:
- If complete response: consider treatment discontinuation at 2 years
- Surveillance protocol after completion
Teaching Points
- MSI-H/dMMR tumors have high TMB and are highly responsive to checkpoint inhibitors
- Pembrolizumab has tissue-agnostic approval for MSI-H/dMMR tumors
- Hot tumors (T-cell infiltrated) respond better to immunotherapy than cold tumors
- Testing for MSI/MMR status should be routine in colorectal cancer
- Lynch syndrome should be considered in patients with dMMR tumors
Image Reference
For visual reference of tumor immunology concepts, see:
- Radiopaedia: Immunotherapy - Overview
- Wikipedia: Checkpoint inhibitor - Mechanisms
- Radiopaedia: CAR-T cell therapy - Complications
Learning Points
- irAEs Mechanism: Result from T cell activation against normal tissues when checkpoints are blocked
- CRS Treatment: Tocilizumab (anti-IL-6R) is first-line; corticosteroids for ICANS
- MSI-H Predicts Response: High tumor mutational burden generates neoantigens making tumors immunogenic
- Hot vs Cold Tumors: Hot (T-cell infiltrated) tumors respond better to checkpoint inhibitors
- Tissue-Agnostic Approval: Pembrolizumab approved for MSI-H/dMMR tumors regardless of site of origin