Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in
Maishara Muquith1, Magdalena Espinoza2, Andrew Elliott3
1Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Abstract:
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.
Insights
Immune checkpoint inhibitors (ICIs) show varied effectiveness. Tumor mutation burden (TMB) impacts survival outcomes in microsatellite-stable cancers, with specific associations noted in eight cancer types when treated with anti-PD-1/L1 therapies.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have advanced cancer treatment but benefit only a fraction of patients.
- Tumor mutation burden (TMB) is a proposed biomarker for ICI efficacy.
- Understanding TMB's role in diverse cancers is crucial for optimizing immunotherapy.
Purpose of the Study:
- To investigate the association between TMB and survival outcomes in microsatellite-stable cancers within a large, real-world cohort.
- To identify specific cancer types where TMB correlates with response to anti-PD-1/L1 therapies.
- To evaluate the utility of universal TMB cutoffs for guiding ICI treatment decisions.
Main Methods:
- Analysis of a real-world clinicogenomic dataset comprising 70,698 patients across 27 histologies.
- Assessment of microsatellite-stable cancers.
- Correlation of TMB levels with survival outcomes in patients treated with anti-PD-1/L1 therapies.
Main Results:
- TMB demonstrated context-dependent associations with survival, indicating both benefit and detriment.
- Eight cancer types showed a significant link between TMB and improved outcomes with anti-PD-1/L1 treatment.
- Survival benefits were observed across various TMB thresholds, with a dose-dependent relationship in some cancers.
Conclusions:
- The impact of TMB on ICI efficacy is highly dependent on cancer type and treatment context.
- Cancer-specific TMB assessments are more informative than universal cutoffs for guiding anti-PD-1/L1 therapy.
- Tissue context is critical for developing robust ICI biomarkers.
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