Summary of the Text: immunotherapy Biomarkers – MSI, TMB, and PD-L1
This text provides a practical guide to understanding and utilizing biomarkers – MSI-H/dMMR, TMB, and PD-L1 – when considering immunotherapy for cancer patients. Here’s a breakdown of the key takeaways:
1. MSI-H/dMMR (Microsatellite Instability-High/Mismatch Repair Deficient): The Most Reliable predictor
* Why it matters: MSI-H tumors have a high number of mutations, leading to a large number of neoantigens that the immune system can recognize and attack.
* Clinical significance: FDA-approved pembrolizumab for all solid tumors with MSI-H/dMMR in 2017. the KEYNOTE-177 trial confirmed its effectiveness in metastatic colorectal cancer.
* Testing is crucial: Especially in colorectal, endometrial, and gastric cancers.
* Crucial Note: MSI-H tumors can respond to immunotherapy irrespective of PD-L1 expression.
2. TMB (Tumor Mutational burden): Quantity Over Quality
* What it is: Measures the total number of mutations in a tumor. Higher TMB suggests more neoantigens.
* Limitations: Doesn’t assess whether mutations actually create effective neoantigens. Results can vary based on testing method.
* FDA Approval: pembrolizumab is approved for TMB-high tumors (≥10 mut/Mb), but only for previously treated patients with limited options.
* Best Use: Most informative in cancers linked to mutagenic exposures (melanoma, smoking-related NSCLC).Less reliable in other cancers.
3. PD-L1 (Programmed Death-Ligand 1): Moderate & Context-Dependent
* The text doesn’t focus heavily on PD-L1, but it’s presented as a biomarker that provides a moderate signal, but its predictive power is dependent on the specific cancer type and context.
4. Comparative Summary:
* MSI-H/dMMR: Most robust and biologically grounded predictor.
* PD-L1: Moderate,context-dependent signal.
* TMB: Variable predictive value.
* Stability: MSI is stable, PD-L1 is dynamic, and TMB is technically stable but biologically incomplete.
5. Common Mistakes Trainees Make:
* Assuming PD-L1 negativity rules out immunotherapy.
* Not testing for MSI outside of colorectal cancer.
* Over-relying on TMB.
* Ignoring tumor-specific guideline recommendations.
6. When Biomarkers Disagree:
* MSI-H takes precedence: If a tumor is PD-L1 negative but MSI-H, the MSI-H status should guide treatment decisions due to its strong association with immunotherapy response.
In essence, the text emphasizes that MSI-H/dMMR is the most reliable biomarker for predicting immunotherapy benefit, while TMB should be used cautiously and PD-L1 considered within the broader clinical context.
