scholarly journals Homologous recombination deficiency in breast cancer

2020 ◽  
Vol 13 (4) ◽  
pp. 375-379 ◽  
Author(s):  
Thomas Bartl ◽  
Alex Farr
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Scientific Evidence ◽  
Predictive Marker ◽  
Parp Inhibitors ◽  
Therapeutic Benefit ◽  
Molecular Characteristics ◽  
Mutational Status ◽  
The Individual

SummaryBRCA mutation-related DNA repair deficiencies increase the individual sensitivity to DNA-targeting agents. Therefore, the patient’s BRCA mutational status is evaluated in clinical practice as a predictive marker in response to platinum salts and poly-ADP-ribose polymerase (PARP) inhibitors for breast cancer treatment. A substantial subset of BRCA wild-type breast cancer lesions, however, share both prominent molecular characteristics and clinical behavior patterns with cancer that harbors BRCA mutations, including DNA repair deficiencies. Also referred to as “BRCAness”, this observation is related to aberrations of the homologous recombination (HR) repair pathway, which deprive cancer cells of the ability to adequately mend potentially lethal double-strand breaks and result in a BRCA-like genomic instability. Hence, HR deficiency is a promising target for related therapeutic options and the predictive potential of HR testing for treatment response has been increasingly studied. Several HR deficiency-testing assays have been proposed and prospectively validated for various cancer types; however, preliminary results in early breast cancer are inconsistent. As scientific evidence for a potential therapeutic benefit in breast cancer is scarce, HR testing remains highly experimental and should be limited to the boundaries of clinical studies until results of ongoing phase 3 trials are available.

scholarly journals Characterisation of PALB2 tumours through whole-exome and whole-transcriptomic analyses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pei Sze Ng ◽  
Jia Wern Pan ◽  
Muhammad Mamduh Ahmad Zabidi ◽  
Pathmanathan Rajadurai ◽  
Cheng Har Yip ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Peripheral Blood Lymphocytes ◽  
Molecular Characteristics ◽  
Breast Cancer Patients ◽  
Mutational Status ◽  
Whole Exome ◽  
Increased Risk ◽  
Fresh Frozen ◽  
Somatic Alterations

AbstractRare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.

scholarly journals Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1315 ◽  
Author(s):  
Michela Camilla Milanesio ◽  
Silvia Giordano ◽  
Giorgio Valabrega
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Parp Inhibitors ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancers ◽  
Mutational Status

Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.

scholarly journals Survivin contributes to DNA repair by homologous recombination in breast cancer cells

2015 ◽  
Vol 155 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Eloïse Véquaud ◽  
Grégoire Desplanques ◽  
Pascal Jézéquel ◽  
Philippe Juin ◽  
Sophie Barillé-Nion
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells

scholarly journals Rucaparib in patients presenting a metastatic breast cancer with Homologous Recombination Deficiency, without germline BRCA1/2 mutation

2020 ◽  
Author(s):  
Anne Patsouris ◽  
M'boyba Khadija DIOP ◽  
Olivier Tredan ◽  
Daniel Nenciu ◽  
Anthony Goncalves ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Homologous Recombination ◽  
Statistical Significance ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Small Subset ◽  
Durable Response ◽  
Homologous Recombination Deficiency

Abstract Breast cancer may present genomic alterations leading to homologous recombination deficiency. PARP inhibitors have proved their efficacy in patients with HER2-negative metastatic breast cancer (mBC) harboring germline (g) BRCA1/2 mutations. We conducted the phase 2 RUBY trial to assess the efficacy of rucaparib in HER2-negative mBC with high genomic loss of heterozygosity (LOH) score or somatic, without gBRCA1/2 mutation. 220 of 711 patients with mBC screened for LOH presented high LOH score which was associated with a higher likelihood of death (HR = 1.39, 95% CI: 1.11-1.75, p = 0.005). The primary objective was not reached with a clinical benefit rate (objective response or SD>16 weeks) of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (14 and 32 months). HRDetect tended to be associated with response to rucaparib, whithout reaching statistical significance (median HRDetect responders versus non responders: 0.465 versus, 0.040, p = 0.2135). Our data suggests that a small subset of patients with high LOH score could derive benefit from PARP inhibitors.

scholarly journals WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1258 ◽  
Author(s):  
Kamila Burdova ◽  
Radka Storchova ◽  
Matous Palek ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Dna Lesion ◽  
Cycle Checkpoint ◽  
G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel R. Principe ◽  
Matthew Narbutis ◽  
Regina Koch ◽  
Ajay Rana
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Wide Range ◽  
Recombination Pathway ◽  
Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

scholarly journals Update Breast Cancer 2019 Part 4 – Diagnostic and Therapeutic Challenges of New, Personalised Therapies for Patients with Early Breast Cancer

2019 ◽  
Vol 79 (10) ◽  
pp. 1079-1089 ◽  
Author(s):  
Florian Schütz ◽  
Peter A. Fasching ◽  
Manfred Welslau ◽  
Andreas D. Hartkopf ◽  
Achim Wöckel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Homologous Recombination ◽  
Early Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Further Development

AbstractThe further development of therapies for women with early breast cancer is progressing far more slowly than in the case of patients with advanced breast cancer and is additionally delayed compared to developments in metastatic breast cancer. Nonetheless, significant advancements have been able to be recorded recently. This review summarises the latest developments in view of the most recent publications and professional conferences. For hormone-receptor-positive patients, new aspects for the duration of antihormone therapy and with regard to the benefits of multigene tests have been published. In the case of HER2-positive patients, the value of post-neoadjuvant therapy and de-escalation of the therapy is discussed. In patients with triple-negative breast cancer, there is a question of whether the knowledge of the biological background of a homologous recombination deficiency (HRD) helps develop new therapies for this subtype. In particular the “use” of a BRCA1/2 mutation or the biological characteristic HRD as a potential motive for therapy plays a role here in specifying the significance of platinum therapy and therapy with PARP inhibitors.

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