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 Translating the role of PARP inhibitors in triple-negative breast cancer

Oncoscience ◽  
2019 ◽  
Vol 6 (1-2) ◽  
pp. 287-288 ◽  
Author(s):  
Michèle Beniey ◽  
Takrima Haque ◽  
Saima Hassan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitors

scholarly journals PARP Inhibitor Olaparib Use in a BRCA1-Positive Patient With Metastatic Triple-Negative Breast Cancer, Without the Initial Use of Platinum-Based Chemotherapy, Showing Significant Rapid Near Resolution of Large Liver Metastasis While Patient Experienced Gout-Like Symptoms

2019 ◽  
Vol 7 ◽  
pp. 232470961986498 ◽  
Author(s):  
Trevanne Matthews Hew ◽  
Lara Zuberi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Management Options ◽  
Federal Drug Administration ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers diagnosed worldwide. This subtype of breast cancer tends to behave more aggressively, and unlike other breast cancer subtypes, there are no standard targeted treatments for most patients. However, up to 20% of patients with TNBC harbor a breast cancer gene (BRCA) mutation, particularly in BRCA1. For patients who carry this gene mutation, this opens the door for new management options by the use of newer agents such as polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the metastatic setting. Given that this is uncommon and that PARP inhibitors have only recently received Federal Drug Administration approval, the experience with these drugs is relatively new. In this article, we present a case of a patient treated in this setting with olaparib who developed an unanticipated side effect as a result of the high efficacy of the drug.

scholarly journals The Role of Platinum Based Chemotherapy in Neoadjuvant Treatment of Locally Advanced Triple Negative Breast cancer

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
H M Abdelaziz ◽  
D R Diab ◽  
A M Adel ◽  
M Y Mostafa ◽  
M M Gaddalla
Keyword(s):  
Breast Cancer ◽  
Clinical Oncology ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Phase Iii ◽  
End Point ◽  
Platinum Based Chemotherapy

Abstract Background The treatment of patients with TNBC is the biggest challenge in the breast cancer (BC) scenario. TNBC remains the poorest prognosis breast cancer (BC) subtype, usually high-grade tumors with higher incidence of visceral and cerebral metastases. Cytotoxic chemotherapy is the backbone of triple-negative breast cancer treatment. Objective A phase III prospective study designed to investigate the role of addition the platinum based chemotherapy to the neoadjuvant setting in treatment of locally advanced triple negative breast cancer, Considering pathological response, complete (pCR) and partial (pPR) as a primary end point, and toxicity, disease free survival as a secondary end point. Patients and Methods This study was a phase III prospective one. 51 female patients Included with locally advanced triple negative Breast Cancer referred to Clinical Oncology& Radiotherapy Department, AIN SHAMS University Hospitals. Results A total of 51 female patients between ages 23-73 years with median age was 45 years old and with locally advanced features of breast cancer, (stage IIIa-IIIb-IIIc) were enrolled in the study during a recruiting period from October 2013 till October 2017 at Ain Shams University, clinical oncology department. Six patients (11.8%) were excluded from the analysis after enrollment, they didn’t receive neoadjuvant treatment because they underwent surgery or they developed metastasis So, only 45 patients received the neoadjuvant treatment. The median follow-up duration was 19 months after surgery. Conclusion Clearly, there were no statistical significance neither survival benefit in addition of the platinum to the NST comparison with the classic anthracyclines + taxens treatment. Even there was more clinical regression with platinum, but more recurrence and relapse occurred. There for, there is a major need to better understand the characteristics and the clinical behavior of TNBCs with an aim to develop effective treatments for this BC subtype.

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.

Role of Poly ADP-Ribose Polymerase (PARP) Inhibitors in Triple-Negative Breast Cancer (TNBC)

2015 ◽  
pp. 73-80
Author(s):  
Enrico Ricevuto ◽  
Katia Cannita ◽  
Gemma Bruera ◽  
Eleonora Palluzzi ◽  
Valentina Cocciolone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitors

scholarly journals Sacituzumab Govitecan for Treatment of Refractory Triple-Negative Metastatic Breast Cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Patrick J. Fleming Jr., PharmD, BCOP ◽  
Sylvia Karpio, PharmD candidate ◽  
Nicholas Lombardo, PharmD candidate
Keyword(s):  
Breast Cancer ◽  
Metastatic Disease ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Phase Iii Trial ◽  
Accelerated Approval

Sacituzumab govitecan was initially approved in April 2020 under accelerated approval for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease. A confirmatory phase III trial evaluating sacituzumab govitecan vs. chemotherapy of the provider’s choice was published in April 2021. Based on this trial, the FDA granted sacituzumab govitecan full regulatory approval. This antibody-drug conjugate is composed of a monoclonal antibody targeted at Trop-2 and contains the active metabolite of irinotecan, SN-38, as a cytotoxic side moiety. In a phase III clinical trial, sacituzumab govitecan demonstrated a median progression-free survival of 5.7 months vs. 1.7 months with chemotherapy. It is now an additional option for patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease.

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 A review of current progress in triple-negative breast cancer therapy

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1143-1149
Author(s):  
Meiying Shen ◽  
Huawen Pan ◽  
Yuxia Chen ◽  
Yu Hang Xu ◽  
Weixiong Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Brca Mutation ◽  
Complete Response ◽  
Parp Inhibitors ◽  
The Past ◽  
Germline Brca Mutation ◽  
Aggressive Subtype

AbstractTriple-negative breast cancer (TNBC) is a particularly aggressive subtype known for its extremely high drug resistance, progression, poor prognosis, and lack of clear therapeutic targets. Researchers are aiming to advance TNBC treatment worldwide. In the past 2–3 years, more positive results have emerged in the clinical research on TNBC treatment. Based on the results, several impressive drugs have been approved to benefit patients with TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation-associated breast cancer (gBRCAm-BC) and immunotherapy using the checkpoint inhibitor atezolizumab in combination with nab-paclitaxel for programmed cell death-ligand 1-positive (PD-L1+) advanced TNBC. Although neoadjuvant therapy has focused on combinations of systemic agents to optimize pathologically complete response, metastatic TNBC still has a poor prognosis. Innovative multidrug combination systemic therapies based on neoadjuvants and adjuvants have led to significant improvements in outcomes, particularly over the past decade.

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

2012 ◽  
Vol 30 (15) ◽  
pp. 1879-1887 ◽  
Author(s):  
Otto Metzger-Filho ◽  
Andrew Tutt ◽  
Evandro de Azambuja ◽  
Kamal S. Saini ◽  
Giuseppe Viale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Parp Inhibitor ◽  
High Sensitivity ◽  
Phase Iii ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

scholarly journals BSCI-15. Osteopontin plays a crucial role in invasiveness of triple negative breast cancer cells in the context of human microglia

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii4-iii4
Author(s):  
Kamil Wojnicki ◽  
Agata Kochalska ◽  
Katarzyna Poleszak ◽  
Adria-Jaume Roura ◽  
Ewa Matyja ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Microglia

Abstract The triple-negative breast cancer (TNBC) is the most malignant among breast cancers and has the high risk of developing metastasis into the brain. Metastases of breast cancers are increasing and pose a clinical challenge as the current treatments are not effective due to the unique brain microenvironment for metastatic breast cancer cells. While the contribution of brain macrophages to the formation of the metastatic niche is established, factors responsible for the crosstalk between cells remain elusive. SPP1 encoding a secreted phosphoprotein 1 (ostepontin) is highly overexpressed in malignant breast cancers. We evaluated the role of SPP1 in invasion and metastasis of human breast cancer cells. We found the increased invasion of triple-negative MDA-MB-231 (MDA-231) cells in the presence of human microglial HMSV40 cells. Using Western blot analysis demonstrated the elevated levels of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) in MDA-231 cells in co-cultures. Moreover, blocking SPP1 and integrin interactions with the synthetic RGD peptide, efficiently diminished both basic and microglia-induced invasion of MDA-231. To assess the role of SPP1 in cell invasion, we established the MDA-231 cells with knocked-down SPP1 expression using shRNA (shSPP1). Interestingly, the shSPP1 cells were unresponsive towards HMSV40 microglia. We have previously found that an antibiotic minocycline reduces SPP1 expression in glioma cells. We performed cell toxicity studies on 4 breast cancer cell lines and various non-malignant cells. All tested malignant cancer cells were more sensitize to minocycline than non-cancerous cells and breast cancer cells derived from TNBC were the most susceptible. Altogether, we demonstrate that microglia support invasion of breast cancer cells via SPP1/osteopontin triggering the integrin signalling, and minocycline by downregulating SPP1 expression may reduce both basic and microglia-induced cancer invasion. Therefore, we purpose that minocycline could be a new therapeutics targeting metastatic brain cancers.

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