scholarly journals Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110066
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Mateusz Opyrchal ◽  
Pawel Kalinski ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Patient Survival ◽  
Cytotoxic T Lymphocyte ◽  
Breast Cancer Patients ◽  
Mutational Burden ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Tumor Mutational Burden ◽  
Patient Prognosis

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC.

Functional hotness score based on three genes predicts long-term survival of triple-negative breast cancer independent from tumor mutational burden.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12583-e12583
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Mateusz Opyrchal ◽  
Pawel Kalinski ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Cancer Prognosis ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Expression Levels ◽  
Cancer Immunity ◽  
Anti Cancer

e12583 Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.

Correlation of the tumor mutational burden with the composition of the immune cell subpopulations in peripheral blood of triple-negative breast cancer patients undergoing neoadjuvant therapy with durvalumab: Results from the prospectively randomized GeparNuevo trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 588-588
Author(s):  
Barbara Seliger ◽  
Thomas Karn ◽  
Carsten Denkert ◽  
Andreas Schneeweiss ◽  
Claus Hanusch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Neoadjuvant Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Effector Memory ◽  
Cell Counts ◽  
Mutational Burden ◽  
Tumor Mutational Burden

588 Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard chemotherapy with nab-Paclitaxel (nab-Pac) followed by Epirubicin plus Cyclophosphamid (EC; Loibl S et al. ASCO 2018). Since the tumor mutational burden (TMB) has been suggested to be associated with a better outcome of patients undergoing immunotherapy and an increased T cell response, we determined whether there exists a link between TMB and immune cell composition, frequency and function in patients of the GeparNuevo trial. Methods: In order to determine possible predictive and / or prognostic biomarkers, tumor biopsies taken at recruitment from 149 patients out of the 174 enrolled patients underwent deep sequencing in order to determine the TMB. In addition, for 120 patients blood samples were taken at recruitment and during different time points of treatment (after durvalumab pre-treatment, after Nab-Pac and at surgery after EC) and evaluated using multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations. Results: The TMB of the GeparNuevo cohort was in line with published data with a mean of 1.8 mutations/MB (range 0.02 – 7.65), respectively. Preliminary evaluation demonstrated a significant correlation of TMB with blood parameters, in particular with subsets of CD8+ T cells. Interestingly, the data suggest a negative correlation of TMB with the frequency of effector cells while a positive correlation exists with the effector memory cells at recruitment. In depth analyses of a correlation with treatment arm and clinical responses are currently performed. Conclusions: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Clinical trial information: NCT02685059.

scholarly journals Tumor Mutational Burden and PTEN Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer

2020 ◽  
Vol 26 (11) ◽  
pp. 2565-2572 ◽  
Author(s):  
Romualdo Barroso-Sousa ◽  
Tanya E. Keenan ◽  
Sonia Pernas ◽  
Pedro Exman ◽  
Esha Jain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mutational Burden ◽  
Tumor Mutational Burden
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