scholarly journals Prevalence of tumor genomic alternations in homologous recombination genes among Taiwanese breast cancers

2021 ◽  
Author(s):  
Chi-Cheng Huang ◽  
Chun-Yu Liu ◽  
Yi-Fang Tsai ◽  
Pei-Ju Lien ◽  
Yen-Shu Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
Clinical Benefits ◽  
Cancer Tissues

Abstract Purpose Deleterious BRCA1 / 2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. PARP (poly ADP ribose polymerase) inhibitors selectively cause failure of single-strand but does not affect double-strand DNA break repair, and ant-tumor activity is observed in BRCA mutant breast cancers. Recently genes implicated into the homologous recombination repair (HRR) pathways are investigated extensively, as defective HRR genes may indicate potential clinical benefits from PARP inhibitors beyond BRCA1 / 2 mutations. Materials and Methods We evaluated the prevalence of BRCA1 / 2 mutations as well as alternations in HRR genes for Taiwanese breast cancers with targeted sequencing. Consecutive 648 breast cancer samples were assayed, and HRR genes by Heeke et al. and those interrogated in Talazoparib Beyond BRCA (TBB) trial were evaluated for prevalence from breast cancer tissues. Results Among 648 breast cancer samples, there were 18 truncating and 2 missense mutations in BRCA1 and 48 truncating and 2 missense mutations in BRCA2 , impacting 3% and 5% of study population (collectively altered in 6%) with co-occurrence of BRCA1 / 2 in 7 breast cancers. On the other hand, HRR genes defined by Heeke et al. were altered in 122 (19%) breast cancers while TBB interrogated genes (excluding BRCA1 / 2 ) were mutated in 107 (17%) patients. Beyond BRCA1/2 , the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%) and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples were impacted by at least one HRR gene. Conclusion The prevalence of high-penetrant BRCA1 / 2 mutations was far below one tenth of assayed samples while the prevalence of tumor DNA mutations in HRR pathways was much higher and approached one fifth among Taiwanese breast cancers. Further studies to evaluate the efficacy of PARP inhibitors in patients with defective HRR gene(s) are warranted to broaden the targeted population of synthetic lethality.

scholarly journals A novel BRCA1 duplication and new insights on the spectrum and frequency of germline large genomic rearrangements in BRCA1/BRCA2

2021 ◽  
Author(s):  
Ibrahim Sahin ◽  
Hanife Saat
Keyword(s):  
Breast Cancer ◽  
Clinical Results ◽  
Genomic Rearrangements ◽  
Breast Cancers ◽  
Cancer Syndrome ◽  
Large Genomic Rearrangements ◽  
Pathogenic Variants ◽  
Recurrent Mutations ◽  
History Of ◽  
Brca1 Brca2

Abstract Heritable breast cancers account for 5 to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All the 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles.

scholarly journals PARP inhibitors in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations. Experience of treatment with talazoparib in clinical practice

2020 ◽  
pp. 57-61
Author(s):  
M. A. Frolova ◽  
E. V. Glazkova ◽  
M. B. Stenina
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Base Excision Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Base Excision

Germline BRCA1/2 mutations account for about 10% of all breast cancer. BRCA1/2 proteins are involved in homologous recombination - DNA double-strand break repair mechanism. Poly-(ADP ribose) polymerases (PARP) are required to repair DNA single-strand breaks through base excision repair. PARP inhibitors represent a modern option of treatment of metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. Mechanism of action of PARP inhibitors is based on the concept of synthetic lethality under conditions of BRCA dysfunction, when both DNA repair mechanisms, homologous recombination and base excision repair, are impaired. This leads to the apoptosis of cancer cells. Currently two PARP inhibitors are registered in Russia for the treatment of BRCA-associated metastatic HER2 negative breast cancer – olaparib and talazoparib. Efficacy of PARP inhibitors olaparib and talazoparib versus standard chemotherapy has been studied in very similarly designed phase III trials OlympiAD и EMBRACA. Benefit in the progression free survival, acceptable toxicity profile and positive impact on quality of life support inclusion of PARP inhibitors in treatment schemes of metastatic BRCAassociated breast cancer. Very important is the role of PARP inhibitors in treatment of very aggressive triple negative breast cancer with limited number of effective therapy options. We represent here a clinical case of treatment of metastatic triple negative breast cancer with talazoparib in 4th line of therapy.

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 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 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 Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1918
Author(s):  
Yanyuan Wu ◽  
Marianna Sarkissyan ◽  
Ochanya Ogah ◽  
Juri Kim ◽  
Jaydutt V. Vadgama
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Akt Pathway ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Mesenchymal Transition ◽  
Cancer Tissues

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.

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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