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 Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0223725 ◽  
Author(s):  
Kevin J. Lee ◽  
Cortt G. Piett ◽  
Joel F. Andrews ◽  
Elise Mann ◽  
Zachary D. Nagel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Base Excision Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Excision Repair ◽  
Dna Damaging Agents ◽  
Base Excision

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

scholarly journals Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer

2017 ◽  
Vol 78 (3) ◽  
pp. 742-757 ◽  
Author(s):  
Jason. P.W. Carey ◽  
Cansu Karakas ◽  
Tuyen Bui ◽  
Xian Chen ◽  
Smruthi Vijayaraghavan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Synthetic Lethality ◽  
Parp Inhibitors

scholarly journals Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer

2021 ◽  
Vol 14 (12) ◽  
pp. 1270
Author(s):  
Mariya Yordanova ◽  
Audrey Hubert ◽  
Saima Hassan
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Breast Cancer Patients ◽  
Homologous Recombination Deficiency ◽  
Dosing Strategies

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is known to be associated with a poor prognosis and limited therapeutic options. Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics that have demonstrated efficacy as monotherapy in metastatic BRCA-mutant (BRCAMUT) TNBC patients. Improved efficacy of PARPi has been demonstrated in BRCAMUT breast cancer patients who have either received fewer lines of chemotherapy or in chemotherapy-naïve patients in the metastatic, adjuvant, and neoadjuvant settings. Moreover, recent trials in smaller cohorts have identified anti-tumor activity of PARPi in TNBC patients, regardless of BRCA-mutation status. While there have been concerns regarding the efficacy and toxicity of the use of PARPi in combination with chemotherapy, these challenges can be mitigated with careful attention to PARPi dosing strategies. To better identify a patient subpopulation that will best respond to PARPi, several genomic biomarkers of homologous recombination deficiency have been tested. However, gene expression signatures associated with PARPi response can integrate different pathways in addition to homologous recombination deficiency and can be implemented in the clinic more readily. Taken together, PARPi have great potential for use in TNBC patients beyond BRCAMUT status, both as a single-agent and in combination.

scholarly journals Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Giacomo Barchiesi ◽  
Michela Roberto ◽  
Monica Verrico ◽  
Patrizia Vici ◽  
Silverio Tomao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Targeted Agents

Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer—olaparib and talazoparib—based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

scholarly journals Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

2019 ◽  
Author(s):  
Kevin J. Lee ◽  
Cortt G. Piett ◽  
Joel F Andrews ◽  
Elise Mann ◽  
Zachary D. Nagel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Lines ◽  
Base Excision Repair ◽  
Triple Negative ◽  
Excision Repair ◽  
Dna Damaging Agents ◽  
Tnbc Cell ◽  
Base Excision

AbstractDNA repair defects have been increasingly focused on as therapeutic targets. In hormone positive breast cancer, XRCC1-deficient tumors have been identified and proposed as targets for combination therapies that damage DNA and inhibit DNA repair pathways. XRCC1 is a scaffold protein that functions in base excision repair (BER) by mediating essential interactions between DNA glycosylases, AP endonuclease, poly(ADP-ribose) polymerase 1, DNA polymerase β (POL β), and DNA ligases. Loss of XRCC1 confers BER defects and hypersensitivity to DNA damaging agents. BER defects have not been evaluated in triple negative breast cancer (TNBC), for which new therapeutic targets and therapies are needed. To evaluate the potential of XRCC1 as an indicator of BER defects in TNBC, we examined XRCC1 expression and localization in the TCGA database and in TNBC cell lines. High XRCC1 expression was observed for TNBC tumors in the TCGA database and expression of XRCC1 varied between TNBC cell lines. We also observed changes in XRCC1 subcellular localization in TNBCs that alter the ability to repair base lesions and single-strand breaks. Subcellular localization changes were also observed for POL β that did not correlate with XRCC1 localization. Basal levels of DNA damage were also measured in the TNBC cell lines, and damage levels correlated with observed changes in XRCC1 expression, localization, and repair functions. The results confirmed that XRCC1 expression changes may indicate DNA repair capacity changes but emphasize that basal DNA damage levels along with expression and localization are better indicators of DNA repair defects. Given the observed over-expression of XRCC1 in TNBC preclinical models and the TCGA database, XRCC1 expression levels should be considered when evaluating treatment responses of TNBC preclinical model cells.

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