Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.
Document Type
Article
Publication Date
3-25-2024
Publication Title
Nat Cancer
Keywords
california; sjci
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.
Clinical Institute
Cancer
Department
Oncology
Recommended Citation
Muquith, Maishara; Espinoza, Magdalena; Elliott, Andrew; Xiu, Joanne; Seeber, Andreas; El-Deiry, Wafik; Antonarakis, Emmanuel S; Graff, Stephanie L; Hall, Michael J; Borghaei, Hossein; Hoon, Dave S B; Liu, Stephen V; Ma, Patrick C; McKay, Rana R; Wise-Draper, Trisha; Marshall, John; Sledge, George W; Spetzler, David; Zhu, Hao; and Hsiehchen, David, "Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers." (2024). Articles, Abstracts, and Reports. 8593.
https://digitalcommons.providence.org/publications/8593