Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer
BackgroundData supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune-responsive tumor microenvironment (TME) in metastatic breast cancer (MBC) are weak, yet tumor agnostic approval in TMB-H advanced tumors provides immune checkpoint inhibition (ICI) as a clinical option....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1235902/full |
| _version_ | 1797744482072920064 |
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| author | Sarah Sammons Sarah Sammons Sarah Sammons Andrew Elliott Romualdo Barroso-Sousa Romualdo Barroso-Sousa Saranya Chumsri Antoinette R. Tan George W. Sledge Sara M. Tolaney Sara M. Tolaney Sara M. Tolaney Evanthia T. Roussos Torres |
| author_facet | Sarah Sammons Sarah Sammons Sarah Sammons Andrew Elliott Romualdo Barroso-Sousa Romualdo Barroso-Sousa Saranya Chumsri Antoinette R. Tan George W. Sledge Sara M. Tolaney Sara M. Tolaney Sara M. Tolaney Evanthia T. Roussos Torres |
| author_sort | Sarah Sammons |
| collection | DOAJ |
| description | BackgroundData supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune-responsive tumor microenvironment (TME) in metastatic breast cancer (MBC) are weak, yet tumor agnostic approval in TMB-H advanced tumors provides immune checkpoint inhibition (ICI) as a clinical option. We evaluated concurrent predictors of immune-responsive and non-responsive TME within MBC.MethodsTumor samples from patients with MBC (N=5621) were analyzed by next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). TMB-H threshold was set to ≥ 10 muts/Mb. PDL-1 was evaluated using SP142 antibody. Gene expression profiling and RNA deconvolution were used to estimate immune and stromal cell population abundance in the TME, and transcriptomic signature of immunotherapy response (T cell-inflamed score).Results461 (8.2%) TMB-H MBC samples were identified. Consistent with prior studies, TMB-H tumors exhibited significant dMMR/MSI-H enrichment (7 vs. 0%, p<0.0001) and PD-L1+ expression (36 vs. 28%, p<0.05) compared to TMB-L. Across all samples, T cell-inflamed scores were weakly correlated with TMB. TMB-H was not associated with significantly increased immune responsive cell types (CD8+ T-cells, NK cells, or B cells) or immune response gene signatures (e.g. antigen presentation), yet positive trends were observed, while immunosuppressive fibroblasts were significantly decreased in TMB-H tumors (0.84-fold change compared to TMB-L, P<0.05). HR+/HER2- breast cancer was the only subtype in which TMB-H tumors exhibited increased T cell-inflamed scores vs. TMB-L. Concurrent PD-L1+ or dMMR/MSI-H with TMB-H was associated with high T cell-inflamed scores in both HR+/HER2- and TNBC. Among several associated biomarkers, B2M mutations and CD274 amplifications were positively associated with T-cell inflamed scores in TMB-H tumors; CDH1 and ERBB2 mutations were negatively associated.ConclusionHigh TMB alone does not strongly correlate with immune infiltrate or immune-related gene signatures in MBC. TMB-H predicts T-cell inflamed signature compared to TMB-L in HR+/HER2- tumors only. Along with MSI-H and PD-L1+, several biomarkers, including B2M mutation and CD274 amplification, may help predict ICI benefit amongst TMB-H tumors. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in larger cohorts for response or resistance to ICI to develop composite predictive biomarkers in MBC. |
| first_indexed | 2024-03-12T15:10:18Z |
| format | Article |
| id | doaj.art-8b0d35ab3ce5400f8a02d8f094918d24 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-12T15:10:18Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-8b0d35ab3ce5400f8a02d8f094918d242023-08-11T17:53:30ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-08-011310.3389/fonc.2023.12359021235902Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancerSarah Sammons0Sarah Sammons1Sarah Sammons2Andrew Elliott3Romualdo Barroso-Sousa4Romualdo Barroso-Sousa5Saranya Chumsri6Antoinette R. Tan7George W. Sledge8Sara M. Tolaney9Sara M. Tolaney10Sara M. Tolaney11Evanthia T. Roussos Torres12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United StatesBreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, United StatesHarvard Medical School, Boston, MA, United StatesClinical and Translational Research, Caris Life Sciences, Phoenix, AZ, United StatesDepartment of Oncology, Dasa Institute for Education and Research (IEPD), Brasilia, BrazilDasa Oncology/Hospital Brasilia, Brasilia, BrazilDepartment of Hematology Oncology and Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United StatesLevine Cancer Institute, Atrium Health, Charlotte, NC, United StatesClinical and Translational Research, Caris Life Sciences, Phoenix, AZ, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United StatesBreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, United StatesHarvard Medical School, Boston, MA, United StatesDivision of Oncology, Department of Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United StatesBackgroundData supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune-responsive tumor microenvironment (TME) in metastatic breast cancer (MBC) are weak, yet tumor agnostic approval in TMB-H advanced tumors provides immune checkpoint inhibition (ICI) as a clinical option. We evaluated concurrent predictors of immune-responsive and non-responsive TME within MBC.MethodsTumor samples from patients with MBC (N=5621) were analyzed by next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). TMB-H threshold was set to ≥ 10 muts/Mb. PDL-1 was evaluated using SP142 antibody. Gene expression profiling and RNA deconvolution were used to estimate immune and stromal cell population abundance in the TME, and transcriptomic signature of immunotherapy response (T cell-inflamed score).Results461 (8.2%) TMB-H MBC samples were identified. Consistent with prior studies, TMB-H tumors exhibited significant dMMR/MSI-H enrichment (7 vs. 0%, p<0.0001) and PD-L1+ expression (36 vs. 28%, p<0.05) compared to TMB-L. Across all samples, T cell-inflamed scores were weakly correlated with TMB. TMB-H was not associated with significantly increased immune responsive cell types (CD8+ T-cells, NK cells, or B cells) or immune response gene signatures (e.g. antigen presentation), yet positive trends were observed, while immunosuppressive fibroblasts were significantly decreased in TMB-H tumors (0.84-fold change compared to TMB-L, P<0.05). HR+/HER2- breast cancer was the only subtype in which TMB-H tumors exhibited increased T cell-inflamed scores vs. TMB-L. Concurrent PD-L1+ or dMMR/MSI-H with TMB-H was associated with high T cell-inflamed scores in both HR+/HER2- and TNBC. Among several associated biomarkers, B2M mutations and CD274 amplifications were positively associated with T-cell inflamed scores in TMB-H tumors; CDH1 and ERBB2 mutations were negatively associated.ConclusionHigh TMB alone does not strongly correlate with immune infiltrate or immune-related gene signatures in MBC. TMB-H predicts T-cell inflamed signature compared to TMB-L in HR+/HER2- tumors only. Along with MSI-H and PD-L1+, several biomarkers, including B2M mutation and CD274 amplification, may help predict ICI benefit amongst TMB-H tumors. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in larger cohorts for response or resistance to ICI to develop composite predictive biomarkers in MBC.https://www.frontiersin.org/articles/10.3389/fonc.2023.1235902/fullbreast cancertumor mutational burdengenetic profilingmicroenvironmentimmune checkpoint inhibitors |
| spellingShingle | Sarah Sammons Sarah Sammons Sarah Sammons Andrew Elliott Romualdo Barroso-Sousa Romualdo Barroso-Sousa Saranya Chumsri Antoinette R. Tan George W. Sledge Sara M. Tolaney Sara M. Tolaney Sara M. Tolaney Evanthia T. Roussos Torres Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer Frontiers in Oncology breast cancer tumor mutational burden genetic profiling microenvironment immune checkpoint inhibitors |
| title | Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer |
| title_full | Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer |
| title_fullStr | Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer |
| title_full_unstemmed | Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer |
| title_short | Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer |
| title_sort | concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden high breast cancer |
| topic | breast cancer tumor mutational burden genetic profiling microenvironment immune checkpoint inhibitors |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1235902/full |
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