BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 962-973 ◽  
Author(s):  
Amal Tazzite ◽  
Hassan Jouhadi ◽  
Abdellatif Benider ◽  
Sellama Nadifi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Susceptibility Gene ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Breast Cancer Susceptibility Gene ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

Evaluation of predictive biomarkers for AR therapy and to identify the LAR subtype of TNBC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 595-595
Author(s):  
Sahil Seth ◽  
James Crespo ◽  
Lei Huo ◽  
Alastair Mark Thompson ◽  
Elizabeth A. Mittendorf ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Predictive Biomarkers ◽  
Immunohistochemical Analysis ◽  
Predictive Biomarker ◽  
Molecular Profiling ◽  
Molecular Signature

595 Background: Androgen-receptor-like (LAR) triple-negative breast cancer (TNBC) is a subtype identified using Vanderbilt’s molecular signature. LAR subtype has the lowest pCR rate for NACT among all TNBC subtypes (10% vs. 28% for TNBC in general). We launched a clinical trial to determine the effectiveness of enzalutamide and paclitaxel (ZT) in improving this poor chemo. response in the neoadjuvant setting for pts with anthracycline-refractory, androgen receptor (AR)+ TNBC (NCT02689427). However, we do not yet have a robust predictive biomarker to detect an activated AR pathway and have not seen a robust correlation between molecular LAR subtype and AR IHC staining intensity. Methods: Molecular profiling and immunohistochemical analysis of key biomarkers (LAR, Ki67, and vimentin) was performed for all pts enrolled in A Randomized triple negative breast cancer enrolling Trial to Confirm Molecular Profiling Improves Survival (ARTEMIS; NCT02276443). Patients receive 4 cycles of AC, followed by an experimental arm or standard taxane, tailored using nuclear IHC staining. IHC staining of ≥30% AR+ was used as a threshold for selection for enzalutamide combination arm. We evaluated the concordance between LAR-subtype using molecular profiling vs % AR+ cells via IHC. Results: As part of the clinical trial, tumors with ≥30% AR+ cells were classified as LAR. In addition, we used RNA profiling to assign Vanderbilt subtype scores, resulting in classification of 15 tumors as LAR+. We observed a significant correlation (r=0.75) between LAR score and %AR+ cells, with 13 of 15 LAR tumors having ≥30% AR+ cells. Among patients with high % of AR+ tumor cells, 11 received enzalutamide, with 43% (3/7) having responses (pCR or RCB-I). Conclusions: Comparison on numerical scores for Vanderbilt subtype and IHC scores suggests ≥30% AR+ IHC staining as the threshold (ppv=0.65, npv=0.98, Table) to identify the molecular LAR subtype. We observed a trend where response rate was higher in patients with ≥ AR+ IHC scores treated with enzalutamide; however, these results need confirmation in a larger cohort of patients. Clinical trial information: NCT02689427, NCT02276443. [Table: see text]

MiRNAs-181a/b as Predictive biomarkers for olaparib sensitivity in triple-negative breast cancer cells.

2017 ◽  
Vol 12 (1) ◽  
pp. 221-229
Author(s):  
Abeer M. Ashmawy ◽  
Mona A. Sheta ◽  
Faten Zahran ◽  
Abdel Hady A. Abdel Wahab
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Predictive Biomarkers

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).

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 1 (3) ◽  
pp. 140-147
Author(s):  
Cynthia Villarreal-Garza ◽  
Ana S. Ferrigno ◽  
Alejandro Aranda-Gutierrez ◽  
Paul H. Frankel ◽  
Nora H. Ruel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Point Mutations ◽  
Treatment Resistance ◽  
Cancer Center ◽  
Breast Cancers ◽  
Entire Cohort ◽  
Pathogenic Variants ◽  
Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

scholarly journals Alteration in Steroid Hormone and HER2/neu Receptor Status Following Neoadjuvant Chemotherapy in Triple Negative Breast Cancer. Is There Any Hope?

2021 ◽  
Author(s):  
Rama Das ◽  
Parna Basu ◽  
Suman Ghosh ◽  
Debasish Guha
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Control Group ◽  
Study Group ◽  
Residual Tumour ◽  
Receptor Status ◽  
Platinum Based Chemotherapy

Introduction: Breast cancer continues to be the most common cancers among women in India. The Triple Negative Breast Cancer (TNBC) is a heterogeneous group of malignancy which is often aggressive and has a worse prognosis. Aim: The aim of this study was to assess the hormone receptor and HER2/neu status with platinum based chemotherapy in TNBC. Materials and Methods: The study was analysed retrospectively in a tertiary care centre of West Bengal from Januay 2017 to December 2019. Forty TNBC patients of Locally Advanced Breast Cancer (LABC) cases who received carboplatin along with neoadjuvant chemotherapy (study group) were compared with other group of 64 TNBC patients (control group) who did not receive any chemotherapy making a total of 104 cases of TNBC patients who were selected for the study. All the patients in both the groups had modified radical mastectomy. The study group of 40 TNBC patients who received chemotherapy also showed pathological partial response. Masterchart was prepared comprising patient’s age, menopausal status, family history, therapy history, histo-morphological features, hormone receptor and HER2/neu status after platinum added chemotherapy. Oestrogen Receptor (ER)/Progesterone Receptor (PR) were considered positive, if >1% tumour cell nuclei were immunoreactive and negative, if it was otherwise. HER-2/neu score of 3+ was taken as positive by Immunohistochemistry (IHC) method. Statistical analysis for descriptive purposes, percentages and mean were calculated. Comparison of both the groups was done by Pearson’s Chi-squared and Fisher’s-exact test. Significance level was considered at p-value <0.05. Results: TNBC patients (NACT group) showed hormone receptor positivity of 21 cases (52.50%) after chemotherapy along with carboplatin. HER2/neu positivity was detected in 9 (22.5%) cases. Non-NACT (64) cases were considered as control group for comparison. The effect of NACT in TNBC patients was found to be statistically significant with respect to change in HER2/neu (p=0.033, p<0.05) and ER status (p<0.05) while change in PR status was found to be statistically insignificant. Conclusion: The study showed significant alteration in hormonal and HER2/neu receptor status in TNBC patients receiving platinum added neoadjuvant chemotherapy. This study found statistical significance and justifies re-evaluation of these Hormone Receptor (HR) and HER2/neu markers in residual tumour after chemotherapy.

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