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

Kosaka, Yoshimasa; Yamamoto, Yutaka; Tanino, Hirokazu; Nishimiya, Hiroshi; Yamamoto-Ibusuki, Mutsuko; Hirota, Yuko; Iwase, Hirotaka; Nakamura, Seigo; Akashi‐Tanaka, Sadako

doi:10.3390/diagnostics10020119

Cited by 6 publications

(3 citation statements)

References 35 publications

(38 reference statements)

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“…In TNBC, the functions of the genes are exploited to nurture tumor microenvironment and heterogeneity. BRCAness, or the trait of harbouring BRCA1/2 mutation, is deemed to be a hallmark for screening of BC or TNBC ( Kosaka et al, 2020 ). Some studies have shown that in TNBCs without BRCA1/2 mutations, TP53 seems commonly mutated, while the joint loss of p53 and BRCA1/2 activity could lead to poorer overall survival outcomes ( Kim et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of single-nucleotide polymorphisms in genes associated with triple-negative breast cancer

et al. 2022

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Triple-negative breast cancer (TNBC) is a rare variant of breast cancer (BC) known to be aggressive and refractory. TNBC lacks effective early diagnostic and therapeutic options leading to poorer outcomes. The genomic landscape and alterations leading to BC and TNBC are vast and unclear. Single nucleotide polymorphisms (SNPs) are a widespread form of genetic alterations with a multi-faceted impact on multiple diseases, including BC and TNBC. In this study, we attempted to construct a framework that could identify genes associated with TNBC and screen the SNPs reported in these genes using a set of computational predictors. This framework helped identify BRCA1, BRCA2, EGFR, PIK3CA, PTEN, and TP53 as recurrent genes associated with TNBC. We found 2%–29% of reported SNPs across genes to be typed pathogenic by all the predictors in the framework. We demonstrate that our framework prediction on BC samples identifies 99% of alterations as pathogenic by at least one predictor and 32% as pathogenic by all the predictors. Our framework could be an initial step in developing an early diagnosis of TNBC and potentially help improve the understanding of therapeutic resistance and sensitivity.

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Section: Discussionmentioning

confidence: 99%

Analysis of single-nucleotide polymorphisms in genes associated with triple-negative breast cancer

et al. 2022

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“…However, HRD can occur in tumors that do not carry BRCA1/2 mutation, defining a subgroup of patients referred to as BRCAness. BRCAness includes a series of traits in which BRCA1 dysfunction following gene mutation, methylation, or deletion accounts for DNA repair deficiency [125]. BRCAness refers to a phenotype common in TNBC that shares molecular characteristics, and the resulting clinical features are similar to those found in BRCA-mutated patients [126].…”

Section: Biomarkers Predicting Resistance To Platinum-based Therapymentioning

confidence: 99%

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Scatena

Ghilli

Bargagna

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

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“…Theoretically, detection of gene mutations associated with HR deficiency is highly recommended for diagnosing "BRCAness" and predicting the sensitivity to PARPi in TNBC. However, mutational signatures are not as stable as genomic changes but a "scar" on the genome caused by consecutive DNA damage attributable to diverse factors including previous systemic therapy, and this hinders their acuity as a marker for BRCAness (32). Consequently, fresh biopsy for HR status and functional assays for diagnosing BRCAness are necessary.…”

Section: Brcaness Molecular Traitmentioning

confidence: 99%

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Han

et al. 2020

Front. Oncol.

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Poly (ADP-ribose) polymerase (PARP) inhibitors are a therapeutic milestone exerting a synthetic lethal effect in the treatment of cancer involving BRCA1/2 mutation. Theoretically, PARP inhibitors (PARPi) eliminate tumor cells by disrupting DNA damage repair through either PARylation or the homologous recombination (HR) pathway. However, resistance to PARPi greatly hinders therapeutic effectiveness in triple-negative breast cancer (TNBC). Owing to the high heterogeneity and few genetic targets in TNBC, there has been limited therapeutic progress in the past decades. In view of this, there is a need to circumvent resistance to PARPi and develop potential treatment strategies for TNBC. We present, herein, a review of the scientific progress and explore the mechanisms underlying PARPi resistance in TNBC. The complicated mechanisms of PARPi resistance, including drug exporter formation, loss of poly (ADP-ribose) glycohydrolase (PARG), HR reactivation, and restoration of replication fork stability, are discussed in detail in this review. Additionally, we also discuss new combination therapies with PARPi that can improve the clinical response in TNBC. The new perspectives for PARPi bring novel challenges and opportunities to overcome PARPi resistance in breast cancer.

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

Cited by 6 publications

References 35 publications

Analysis of single-nucleotide polymorphisms in genes associated with triple-negative breast cancer

Analysis of single-nucleotide polymorphisms in genes associated with triple-negative breast cancer

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

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