Abstract P4-09-08: Tumor mutational burden in Japanese patients with triple negative breast cancer

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.

Download Full-text

Abstract P5-12-02:PTENalterations and tumor mutational burden (TMB) as potential predictors of resistance or response to immune checkpoint inhibitors (ICI) in metastatic triple-negative breast cancer (mTNBC)

10.1158/1538-7445.sabcs18-p5-12-02 ◽

2019 ◽

Author(s):

R Barroso-Sousa ◽

S Tyekucheva ◽

S Pernas-Simon ◽

P Exman ◽

E Jain ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Mutational Burden ◽

Tumor Mutational Burden

Download Full-text

Abstract PS6-49: Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden

10.1158/1538-7445.sabcs20-ps6-49 ◽

2021 ◽

Author(s):

Eriko Katsuta ◽

Li Yan ◽

Mateusz Opyrchal ◽

Pawel Kalinski ◽

Kazuaki Takabe

Keyword(s):

Breast Cancer ◽

T Lymphocyte ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cytotoxic T Lymphocyte ◽

Term Survival ◽

Long Term Survival ◽

Mutational Burden ◽

Tumor Mutational Burden

Download Full-text

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

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-19-3507 ◽

2020 ◽

Vol 26 (11) ◽

pp. 2565-2572 ◽

Cited By ~ 15

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

Download Full-text

Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22137154 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7154

Author(s):

Martina Dameri ◽

Lorenzo Ferrando ◽

Gabriella Cirmena ◽

Claudio Vernieri ◽

Giancarlo Pruneri ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Gene Testing ◽

Repair Deficiency ◽

Targeted Treatments ◽

Recombination Repair ◽

Tumor Mutational Burden ◽

Next Generation Sequencing Ngs

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).

Download Full-text

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

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211006680 ◽

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.

Download Full-text

Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

JCO Precision Oncology ◽

10.1200/po.17.00211 ◽

2018 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Masayuki Nagahashi ◽

YiWei Ling ◽

Tetsu Hayashida ◽

Yuko Kitagawa ◽

Manabu Futamura ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Ethnic Diversity ◽

Triple Negative ◽

Asian Population ◽

Japanese Patients ◽

The United States ◽

The Cancer Genome Atlas ◽

Cancer Genes ◽

Asian Patients

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

Download Full-text