scholarly journals Commentary: Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Konstantinos Venetis ◽  
Nicola Fusco ◽  
Elham Sajjadi
Keyword(s):  
Breast Cancer ◽  
Retrospective Study ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency

scholarly journals Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-yu Ren ◽  
Yu Song ◽  
Jing Wang ◽  
Long-yun Chen ◽  
Jun-yi Pang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Low Frequency ◽  
Clinicopathological Parameters ◽  
Tissue Samples

PurposeTo investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters.MethodsWe retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed.ResultsThe median age of the cohort was 49 years (range: 24–90 years) with a median follow-up period of 68 months (range: 1–170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival.ConclusionsThe incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.

scholarly journals BRCAness as an Important Prognostic Marker in Patients with Triple-Negative Breast Cancer Treated with Neoadjuvant Chemotherapy: A Multicenter Retrospective Study

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 119 ◽  
Author(s):  
Yoshimasa Kosaka ◽  
Yutaka Yamamoto ◽  
Hirokazu Tanino ◽  
Hiroshi Nishimiya ◽  
Mutsuko Yamamoto-Ibusuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retrospective Study ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Complete Response ◽  
University Hospitals ◽  
Free Survival ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Triple-negative breast cancer (TNBC) has several subtypes. The identification of markers associated with recurrence and poor prognosis in patients with TNBC is urgently needed. BRCAness is a set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation, or deletion, results in DNA repair deficiency. In the current study, we evaluated the clinical significance and prognosis of BRCAness in a multicenter retrospective study. Ninety-four patients with TNBC treated with neoadjuvant chemotherapy were enrolled from three university hospitals for this retrospective study. BRCAness was evaluated in 94 core needle biopsy (CNB) specimens prior to neoadjuvant chemotherapy and 49 surgical specimens without pathological complete response (pCR). The samples were assessed using multiplex ligation-dependent probe amplification, and the amplicons were scored. Of the 94 patients, 51 had BRCAness in CNB specimens. There were no significant differences in pCR rates or recurrence between the BRCAness and non-BRCAness groups. Among surgical specimens, the BRCAness group had a significantly shorter recurrence-free survival and overall survival compared with the non-BRCAness group. The BRCAness of surgical specimens was found to be an important marker to predict prognosis in patients with TNBC after neoadjuvant chemotherapy. A clinical trial to assess the clinical impact of carboplatin with BRCAness is planned.

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

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).

Retrospective Study about the Prevalence of (TILs) Tumor Infiltrating Lymphocytes in Non-Metastatic Triple Negative Breast Cancer Patients and its Prognostic Value

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Hesham Ahmed ElGhazaly ◽  
Manal Mohamed El-Mahdy ◽  
Azza Mohamed Adel ◽  
Nermeen Mostafa ◽  
Aya Magdy Kamal Ali
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Retrospective Study ◽  
Triple Negative Breast Cancer ◽  
Prognostic Value ◽  
Triple Negative ◽  
Free Survival ◽  
Female Patients ◽  
Risk Of Death ◽  
Reduced Risk

Abstract Background TNBC comprises a distinct disease entity with a unique microenvironment of TILs, the immunogenic potential of TNBC is derived from its genetic instability and high mutation rate. Tumors from patients with TNBC are more likely than tumors from patients with other subtypes to exhibit chromosomal instability and potential mutations. Objectives The study aims to evaluate the prevalence of CD8+ TILs biomarker by IHC in triple negative breast cancer and its prognostic value. TILs are an important prognostic value for the response of patient to chemotherapy the greater number of TILS is associated with higher probability of response to chemotherapy also decrease recurrence. TILS in triple negative breast cancer suggest a likely option for immunotherapy in this disease. Patients and Methods This is a retrospective study, which was carried on 30 female patients, Clinical data and paraffin wax block of female patients with triple negative breast cancer are to be collected from the breast cancer unit, department of clinical Oncology and Nuclear medicine Ain Shams university and Matarya teaching hospital. Results Several large systematic reviews and meta-analyses have confirmed that high levels of TILs are associated with better disease free survival and overall survival only in triple negative and HER2 positive subtypes, with no significant benefit seen in estrogen receptor positive breast carcinoma. In the Breast International Group (BIG) 02-98 trial shows that for every 10% increase in the intertumoral TILs there was a 17% reduced risk of relapse, and 27% reduced risk of death regardless of chemotherapy type. Also in eastern cooperative oncology group trial (ECOG) 2197, and 1199 showed that for every 10% increase in TILs, a 14% reduction of risk of recurrence, and 19% reduction in risk of death were observed. Conclusion Our study showed that All our patients (100%) were positive for CD8+, with a minimum range of 1% and a maximum range of 60%, most of the patients (20 patients) had CD8% between (10% to 20%). High levels of CD8 + TILs are good prognostic indicators in TNBC. our study showed that there were associations of CD8+ TILs infiltrate status with longer progression free survival and better overall survival in triple-negative breast cancer, but were not statistically significant probably due to our small sample size.

scholarly journals Combined homologous recombination repair deficiency and immune activation analysis for predicting intensified responses of anthracycline, cyclophosphamide and taxane chemotherapy in triple-negative breast cancer

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gaoming Liao ◽  
Zedong Jiang ◽  
Yiran Yang ◽  
Cong Zhang ◽  
Meiting Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Immune Activation ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Homologous Recombination Repair ◽  
Repair Deficiency ◽  
Recombination Repair

Abstract Background Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Methods Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. Results HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). Conclusions These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

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