Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo

Abstract

Background: The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. Patients and methods: We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). Results: Median TMB was 1.52 mut/Mb (range 0.02e7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P ¼ 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33e3.20, P ¼ 0.001] among all patients, 1.77 (95% CI 1.00e3.13, P ¼ 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21e6.54, P ¼ 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. Conclusions: TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis

“…Breast cancer immunotherapy based on immune checkpoint inhibitors is currently effective for some TNBCs. These patients with TNBC usually show a high TMB and specific characteristics of immune cell infiltration (21,22). In this study, to further explore the immunogenicity of TNBC, i) we investigated differences in immune cell infiltration between high and low tumor mutation loads, differences in key pathways, and correlation to the prognosis of TNBC; ii) we analyzed the difference in immune cell infiltration between the wild and mutation group; iii) In order to identify biomarkers related to the prognosis of TNBC, we screened and identified a prognostic gene related to TNBC, the key mutation gene FAT3.…”

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes

“…In a further study evaluating CXCL13 mRNA expression in the FinHER trial, CXCL13 as a marker of the humoral immune system was associated with favorable prognosis, particularly in triple-negative breast cancer (TNBC) [ 11 ]. One possible explanation for the finding that immune-related gene signatures have prognostic and predictive effects, particularly in the case of strongly proliferating tumors, especially TNBC or basal-like breast cancer, is the occurrence of an increased mutation load and neoepitopes that can induce or enhance an antitumor immune response [ 18 , 19 ]. In fact, TNBC, which is not synonymous with basal-like breast cancer but largely overlaps with it, has a higher level of tumor-infiltrating lymphocytes [ 2 , 3 ].…”

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

“…In addition, they performed a predefined analysis of 149 samples assessing the predictive value of TMB alone or in combination with an immune gene expression profile (GEP) for pCR. Results from multivariate analysis showed an odds ratio for pCR per mut/Mb of 2.06 (95% CI 1.33–3.20, P = 0.001) among all patients, 1.77 (95% CI 1.00–3.13, P = 0.049) in the Durvalumab treatment arm, and 2.82 (95% CI 1.21–6.54, P = 0.016) in the placebo treatment arm, confirming that further analyses of TMB in combination with other immune parameters are still necessary, as well as the choice of a standardized assay and a cut off value to define high mutational load [ 135 , 136 ]. Very recently, FDA approved FoundationOne ® CDx test to identify patients with solid tumors with TMB score who may benefit from immunotherapy treatment with Pembrolizumab monotherapy.…”