High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types
| Autor: | Maarten Slagter, Marleen Kok, Amy B. Heimberger, Eric Jonasch, NT Ueno, Sy Lin, Renata Ferrarotto, Patrick G. Pilie, Bora Lim, Jeffrey T. Chang, S. L. Moulder, Naim U. Rashid, Jennifer K. Litton, Mustafa Khasraw, Leonie Voorwerk, Daniel J. McGrail |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty business.industry Melanoma Cancer Hematology Odds ratio medicine.disease Immune checkpoint Article Blockade 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Internal medicine medicine Cytotoxic T cell Biomarker (medicine) business CD8 |
| Zdroj: | Ann Oncol |
| Popis: | BACKGROUND: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted Foundation One CDx assay in 9 tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. PATIENTS AND METHODS: Data from over 10,000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N=1551) and overall survival (OS, N=1936). RESULTS: In cancer types where CD8 T cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB (95% CI 34.9–44.8), which was significantly higher than that observed in low TMB (TMB-L) tumors (odds ratio (OR) = 4.1, 95% CI 2.9–5.8, P < 2×10(−16)). In cancer types that showed no relationship between CD8 T cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2–23.4, P = 0.95), and also exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24–0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. CONCLUSIONS: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type specific studies are warranted. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|