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Kumar H, Gupta NV, Jain R, Madhunapantula SV, Babu CS, Kesharwani SS, Dey S, Jain V. A review of biological targets and therapeutic approaches in the management of triple-negative breast cancer. J Adv Res 2023; 54:271-292. [PMID: 36791960 DOI: 10.1016/j.jare.2023.02.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/23/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of breast cancer with associated chemoresistance. The development of chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression of membrane proteins (transporters), epigenetic changes, and alteration of the cell signaling pathways/genes associated with the development of cancer stem cells (CSCs). AIM OF REVIEW Due to the diverse and heterogeneous nature of TNBC, therapeutic response to the existing modalities offers limited scope and thus results in reccurance after therapy. To establish landmark therapeutic efficacy, a number of novel therapeutic modalities have been proposed. In addition, reversal of the resistance that developed during treatment may be altered by employing appropriate therapeutic modalities. This review aims to discuss the plethora of investigations carried out, which will help readers understand and make an appropriate choice of therapy directed toward complete elimination of TNBC. KEY SCIENTIFIC CONCEPTS OF REVIEW This manuscript addresses the major contributory factors from the tumor microenvironment that are responsible for the development of chemoresistance and poor prognosis. The associated cellular events and molecular mechanism-based therapeutic interventions have been explained in detail. Inhibition of ABC transporters, cell signaling pathways associated with CSCs, and epigenetic modification offers promising results in this regard. TNBC progression, invasion, metastasis and recurrence can also be inhibited by blocking multiple cell signaling pathways, targeting specific receptors/epigenetic targets, disrupting bioenergetics and generating reactive oxygen species (ROS).
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Affiliation(s)
- Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - N Vishal Gupta
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - Rupshee Jain
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - SubbaRao V Madhunapantula
- Department of Biochemistry, Centre of Excellence in Molecular Biology & Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - C Saravana Babu
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | | | - Surajit Dey
- Roseman University of Health Sciences, College of Pharmacy, Henderson, NV, USA
| | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India.
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Fuso P, Muratore M, D’Angelo T, Paris I, Carbognin L, Tiberi G, Pavese F, Duranti S, Orlandi A, Tortora G, Scambia G, Fabi A. PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives. Cancers (Basel) 2022; 14:2161. [PMID: 35565291 PMCID: PMC9103982 DOI: 10.3390/cancers14092161] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.
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Affiliation(s)
- Paola Fuso
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Margherita Muratore
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Tatiana D’Angelo
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
| | - Ida Paris
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Luisa Carbognin
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Giordana Tiberi
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Francesco Pavese
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
| | - Simona Duranti
- Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Armando Orlandi
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Unit of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (T.D.); (A.O.); (G.T.)
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giovanni Scambia
- Department of Woman and Child Health and Public Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.M.); (I.P.); (L.C.); (G.T.); (F.P.); (G.S.)
- Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
- Istituto di Ginecologia e Ostetricia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessandra Fabi
- Precision Medicine in Breast Cancer Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
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3
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Burguin A, Diorio C, Durocher F. Breast Cancer Treatments: Updates and New Challenges. J Pers Med 2021; 11:808. [PMID: 34442452 PMCID: PMC8399130 DOI: 10.3390/jpm11080808] [Citation(s) in RCA: 195] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/31/2022] Open
Abstract
Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence, a deeper understanding of the development of new treatments that are more specific and effective in treating each BC subgroup is key. New approaches have recently emerged such as immunotherapy, conjugated antibodies, and targeting other metabolic pathways. This review summarizes current BC treatments and explores the new treatment strategies from a personalized therapy perspective and the resulting challenges.
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Affiliation(s)
- Anna Burguin
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada;
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
| | - Caroline Diorio
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
- Department of Preventive and Social Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada
| | - Francine Durocher
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1T 1C2, Canada;
- Cancer Research Center, CHU de Québec-Université Laval, Quebec City, QC G1V 4G2, Canada;
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Palleschi M, Tedaldi G, Sirico M, Virga A, Ulivi P, De Giorgi U. Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer. Int J Mol Sci 2021; 22:ijms22157884. [PMID: 34360649 PMCID: PMC8346118 DOI: 10.3390/ijms22157884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/15/2021] [Accepted: 07/20/2021] [Indexed: 12/27/2022] Open
Abstract
Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms “PARP inhibitors” and “breast cancer”, was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.
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Affiliation(s)
- Michela Palleschi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.P.); (M.S.); (U.D.G.)
| | - Gianluca Tedaldi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.V.); (P.U.)
- Correspondence: ; Tel.: +39-0543-739232; Fax: +39-0543-739221
| | - Marianna Sirico
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.P.); (M.S.); (U.D.G.)
| | - Alessandra Virga
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.V.); (P.U.)
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.V.); (P.U.)
| | - Ugo De Giorgi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.P.); (M.S.); (U.D.G.)
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Therapeutic Strategies for Metastatic Triple-Negative Breast Cancers: From Negative to Positive. Pharmaceuticals (Basel) 2021; 14:ph14050455. [PMID: 34065837 PMCID: PMC8150754 DOI: 10.3390/ph14050455] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 04/28/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Metastatic triple-negative breast cancer (TNBC) is a distinct and immensely complex form of breast cancer. Among all subtypes of breast cancers, TNBC has a comparatively high rate of relapse, a high rate of distant metastasis, and poor overall survival after standard chemotherapy. Chemotherapy regimens are an essential component of the management of this estrogen receptor-negative, progesterone receptor-negative, and epidermal growth factor receptor2 negative subtype of breast cancers. Chemotherapy is critical for preventing the recurrence of the disease and for achieving long-term survival. Currently, a couple of agents are approved for the management of this disease, including chemotherapy like eribulin, targeted therapy like PARP inhibitor, as well as an antibody-drug conjugate (ADC) to target TROP2. Like many other metastatic cancers, immune checkpoint inhibitors (ICIs) have also been approved for TNBC patients with PD-L1 positive tumors and high tumor mutational burden. In this review article, we discuss these newly approved and promising novel agents that may change the therapeutic landscape for advanced/metastatic TNBC patients.
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Metastatic Triple Negative Breast Cancer: The New Era of Thinking. FORUM OF CLINICAL ONCOLOGY 2021. [DOI: 10.2478/fco-2018-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The heterogeneity of triple negative breast cancer (TNBC) is reflected in a bizarre response to therapy. Although it is chemotherapy sensitive, the failure is the usual pathway either in local or distance status. With progression in Gene Expression Profile (GEP) and other molecular techniques, TNBC is divided into sub-types with unique pathways. In the current review, we are trying to highlight based on the molecular classification of TNBC and the management based on every type.
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O'Reilly D, Sendi MA, Kelly CM. Overview of recent advances in metastatic triple negative breast cancer. World J Clin Oncol 2021; 12:164-182. [PMID: 33767972 PMCID: PMC7968109 DOI: 10.5306/wjco.v12.i3.164] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/02/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Metastatic triple negative breast cancer (TNBC) has an aggressive phenotype with a predilection for visceral organs and brain. Best responses to chemotherapy are predominately in the first line. Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC. However, a recent trial in a similar population showed no benefit for atezoli-zumab and paclitaxel which led to a Food and Drug Administration alert. Two phase III trials (OLYMPIAD and BROCADE3) demonstrated a benefit in progression free survival (PFS) but not overall survival in patients with BRCA-associated metastatic TNBC treated with Olaparib or Talazoparib respectively. For those treated with Talazoparib, the time to deterioration in health related-quality of life was also longer compared to chemotherapy. The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity. There are no head-to-head comparisons of a poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinums. There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCA-associated ovarian cancer. Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway, protein kinase B, mammalian target of rapamycin or utilising antibody drug conjugates. This review focusses on recent and emerging therapeutic options in metastatic TNBC. We searched PubMed, clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology, San Antonio Breast Cancer Conference and the European Society of Medical Oncology.
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Affiliation(s)
- David O'Reilly
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 1, Ireland
| | - Maha Al Sendi
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 1, Ireland
| | - Catherine M Kelly
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 1, Ireland
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8
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Stenehjem DD, Telford C, Unni SK, Bauer H, Sainski A, Deka R, Schauerhamer MB, Ye X, Tak CR, Ma J, Dalvi TB, Gutierrez L, Kaye JA, Tyczynski JE, Brixner DI, Biskupiak JE. BRCA testing and outcomes in women with breast cancer. Breast Cancer Res Treat 2021; 186:839-850. [PMID: 33389410 DOI: 10.1007/s10549-020-06038-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/25/2020] [Indexed: 12/27/2022]
Abstract
MAIN PURPOSE Germline BRCA mutations (BRCAm) strongly influence the risk of developing breast cancer. This study aimed to understand the role of BRCAm testing in affected individuals and to assess its impact on the outcome of BRCAm carriers compared to non-carriers (BRCAwt) with breast cancer. RESEARCH QUESTION The research question is "Does standard of care testing for BRCAm improve survival outcomes of breast cancer patients?" METHODS In a single institution observational cohort study, demographic and clinical characteristics were compared between breast cancer patients with and without BRCAm. Frequency of BRCA testing was assessed. Survival outcomes were assessed by initial treatment setting stratified by BRCA status. RESULTS Of 5712 identified women with breast cancer, 14.6% (n = 835) were tested for a BRCA mutation and had a documented result. The total number and proportion of women tested for a BRCAm increased between 2000 and 2014, resulting in an increased number of BRCAm carriers identified. However, the proportion of women who underwent testing and had a BRCAm decreased during the study period from 27.5% in 2000-2004 to 13.3% in 2010-2014. Disease-free survival was similar in the adjuvant and neoadjuvant treatment settings between BRCAm and BRCAwt patients. Progression-free survival on first line treatment and overall survival for patients with metastatic disease was also similar between BRCAm and BRCAwt patients. CONCLUSIONS The proportion of women tested and the number of BRCAm identified increased during the study period despite a decreasing proportion of positive results among women tested.
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Affiliation(s)
- David D Stenehjem
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA. .,Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, 1110 Kirby Drive, 232 Life Science, Duluth, MN, 55812, USA.
| | - Claire Telford
- AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA.,GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA
| | - Sudhir K Unni
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.,Daiichi-Sankyo, Basking Ridge, NJ, USA
| | - Hillevi Bauer
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Amy Sainski
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.,Truven Health, Ann Arbor, MN, USA
| | - Rishi Deka
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.,University of Southern California, San Diego, CA, USA
| | - Marisa B Schauerhamer
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Xiangyang Ye
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Casey R Tak
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.,Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
| | - Junjie Ma
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.,Amgen Inc, Thousand Oaks, CA, 91320, USA
| | | | | | | | - Jerzy E Tyczynski
- AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA.,AbbVie Inc, Pharmacovigilance and Patient Safety, North Chicago, IL, USA
| | - Diana I Brixner
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Joseph E Biskupiak
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
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Han Y, Yu X, Li S, Tian Y, Liu C. New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer. Front Oncol 2020; 10:578095. [PMID: 33324554 PMCID: PMC7724080 DOI: 10.3389/fonc.2020.578095] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/15/2020] [Indexed: 12/19/2022] Open
Abstract
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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Affiliation(s)
- Ye Han
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaopeng Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuqiang Li
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ye Tian
- Department of Biomedical Informatics, College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
| | - Caigang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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10
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Robbe J, Moretta J, Vicier C, Sabatier R, Noguès C, Gonçalves A. Inhibiteurs de PARP dans les cancers du sein : développement clinique actuel et perspectives. Bull Cancer 2020; 107:1024-1041. [DOI: 10.1016/j.bulcan.2020.07.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/25/2020] [Accepted: 07/05/2020] [Indexed: 12/16/2022]
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Abstract
PARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since 2014, four PARP inhibitors have been approved in various indications: olaparib, niraparib, and rucaparib in high-grade serous ovarian cancer, and olaparib and talazoparib in metastatic breast cancer. The exact indications and study populations vary slightly between the different approvals in both disease states but there is significant overlap. PARP inhibitors continue to be investigated in ongoing clinical trials. In line with other targeted therapies, benefit appears to be strongest in a distinct population of patients with BRCA mutations or other defects in homologous recombination repair. Combination therapies, which include anti-angiogenesis agents and immunotherapy, show promise as a strategy to broaden efficacy for unselected patients. Initial studies of PARP inhibitors in combination with chemotherapy were limited by toxicity, but further studies are underway. To date, head-to-head trials comparing various PARP inhibitors have not been conducted, so questions remain in terms of choosing a PARP inhibitor to administer when indications overlap, as well as how to sequence these medications. Here we review both completed and ongoing clinical trials involving PARP inhibitors and mechanisms of resistance to this class of drugs.
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12
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Vidula N, Dubash T, Lawrence MS, Simoneau A, Niemierko A, Blouch E, Nagy B, Roh W, Chirn B, Reeves BA, Malvarosa G, Lennerz J, Isakoff SJ, Juric D, Micalizzi D, Wander S, Spring L, Moy B, Shannon K, Younger J, Lanman R, Toner M, Iafrate AJ, Getz G, Zou L, Ellisen LW, Maheswaran S, Haber DA, Bardia A. Identification of Somatically Acquired BRCA1/2 Mutations by cfDNA Analysis in Patients with Metastatic Breast Cancer. Clin Cancer Res 2020; 26:4852-4862. [PMID: 32571788 DOI: 10.1158/1078-0432.ccr-20-0638] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 05/15/2020] [Accepted: 06/17/2020] [Indexed: 01/11/2023]
Abstract
PURPOSE Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as BRCA1/2, but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired BRCA1/2 mutations in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic BRCA1/2 mutations were classified as known germline pathogenic mutations or novel variants, and linked to clinicopathologic characteristics. The effect of the PARP inhibitor, olaparib, was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation. RESULTS Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA BRCA1/2 mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic BRCA1/2 mutations were common in younger patients (P = 0.008), those with triple-negative disease (P = 0.022), and they were more likely to be protein-truncating alterations and be associated with TP53 mutations. Functional analysis of a CTC culture harboring a somatic BRCA1 mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the "BRCA" mutational signature (COSMIC Signature 3) were present in BRCA1/2-mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC. CONCLUSIONS Somatic BRCA1/2 mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.
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Affiliation(s)
- Neelima Vidula
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
| | - Taronish Dubash
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | | | - Antoine Simoneau
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Andrzej Niemierko
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Erica Blouch
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Becky Nagy
- Guardant Health, Inc., Redwood City, California
| | - Whijae Roh
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Brian Chirn
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Brittany A Reeves
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Giuliana Malvarosa
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jochen Lennerz
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Steven J Isakoff
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Dejan Juric
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Douglas Micalizzi
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Seth Wander
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Laura Spring
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Beverly Moy
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Kristen Shannon
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jerry Younger
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | | | - Mehmet Toner
- Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - A John Iafrate
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Gad Getz
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Lee Zou
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Leif W Ellisen
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Shyamala Maheswaran
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Daniel A Haber
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Aditya Bardia
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
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13
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Delving into PARP inhibition from bench to bedside and back. Pharmacol Ther 2020; 206:107446. [DOI: 10.1016/j.pharmthera.2019.107446] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023]
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Elmeliegy M, Láng I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D. Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours. Br J Clin Pharmacol 2020; 86:771-778. [PMID: 31770456 PMCID: PMC7098856 DOI: 10.1111/bcp.14178] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 10/21/2019] [Accepted: 10/29/2019] [Indexed: 01/24/2023] Open
Abstract
Aims In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed. Methods Thirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B). Results Coadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose. Conclusion Coadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited.
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Affiliation(s)
| | - István Láng
- National Institute of Oncology, Budapest, Hungary
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15
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Tutt A. Inhibited, trapped or adducted: the optimal selective synthetic lethal mix for BRCAness. Ann Oncol 2019; 29:18-21. [PMID: 29300815 PMCID: PMC5834033 DOI: 10.1093/annonc/mdx775] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Affiliation(s)
- A Tutt
- Breast Cancer Now Research Centre, Institute of Cancer Research, London, UK.,Research Oncology, Kings College London, London, UK
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16
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Abstract
Talazoparib (TALZENNA™) is an oral inhibitor of the polyadenosine 5'-diphosphoribose polymerase (PARP) enzymes, which play a critical role in repairing DNA single-strand breaks. It has been developed by Pfizer and was recently approved in the USA for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer (as detected by a US FDA-approved assay). A regulatory assessment for talazoparib in this patient population is underway in the EU, with talazoparib also undergoing development for use in metastatic castration-resistant prostate cancer and various solid tumours, and as neoadjuvant therapy in early triple negative breast cancer. This article summarizes the milestones in the development of talazoparib leading to its first approval for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative, locally advanced or metastatic breast cancer.
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Affiliation(s)
- Sheridan M Hoy
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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17
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Armstrong AC, Clay V. Olaparib in germline-mutated metastatic breast cancer: implications of the OlympiAD trial. Future Oncol 2019; 15:2327-2335. [PMID: 31304797 DOI: 10.2217/fon-2018-0067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Breast cancer remains a leading cause of death worldwide. Our increased understanding of cellular mechanisms inherent to cancer has led to the development of new therapeutic targets. One such therapy is that of poly(ADP-ribose) polymerase (PARP) inhibitors, with PARP playing a key role in the repair of single stranded DNA breaks. The development of drugs able to inhibit PARP led to their investigation in tumors that have defective DNA repair, including that of BRCA1/2-associated cancers. The PARP inhibitor Olaparib, has recently been evaluated in the Phase III OlympiAD trial, and demonstrated a significant progression-free survival advantage in patients with HER2-negative metastatic breast cancer and a germline BRCA-mutation. This article will review the findings and potential implications of the trial.
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Affiliation(s)
- Anne C Armstrong
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road Manchester, M20 4BX, UK
| | - Vanessa Clay
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road Manchester, M20 4BX, UK
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18
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Abstract
Triple-negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the phosphoinositide 3 (PI3)-kinase and AKT signalling pathway is one of the most frequent oncogenic aberrations of TNBC. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in phosphatase and tensin homologue, occur in ∼25%‒30% of advanced TNBC. Recent randomised trials suggest improved progression-free survival (PFS) with AKT-inhibitors in combination with first-line chemotherapy for patients with TNBC and pathway genetic aberrations. We review the evidence for PI3K pathway activation in TNBC, and clinical trial data for PI3K, AKT and mammalian target of rapamycin inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.
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Affiliation(s)
- J Pascual
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London
| | - N C Turner
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London; Breast Unit, The Royal Marsden Hospital, London, UK.
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19
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McCann KE. Advances in the use of PARP inhibitors for BRCA1/2-associated breast cancer: talazoparib. Future Oncol 2019; 15:1707-1715. [DOI: 10.2217/fon-2018-0751] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Poly-ADP-ribosyl polymerase (PARP) enzymes PARP-1 and PARP-2 recognize DNA damage and set off a cascade of cellular mechanisms required for multiple types of DNA damage repair. PARP inhibitors are small molecule mimetics of nicotinamide which bind to PARP’s catalytic domain to inhibit poly-ADP-ribosylation (PARylation) of target proteins, including PARP-1 itself. PARP inhibitors olaparib, veliparib, talazoparib, niraparib and rucaparib have predominantly been studied in women with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2 (gBRCA1/2+). The BRCA1 and BRCA2 proteins are involved in DNA repair by homologous recombination. This review will focus on talazoparib, a PARP inhibitor approved by the US FDA for the treatment of metastatic gBRCA1/2+ breast cancers in October 2018.
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Affiliation(s)
- Kelly E McCann
- Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA
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20
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PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. J Clin Med 2019; 8:jcm8040435. [PMID: 30934991 PMCID: PMC6517993 DOI: 10.3390/jcm8040435] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/16/2019] [Accepted: 03/27/2019] [Indexed: 02/07/2023] Open
Abstract
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.
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21
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Nicolas E, Bertucci F, Sabatier R, Gonçalves A. Targeting BRCA Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives? Cancers (Basel) 2018; 10:cancers10120506. [PMID: 30544963 PMCID: PMC6316565 DOI: 10.3390/cancers10120506] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 11/27/2018] [Accepted: 12/09/2018] [Indexed: 12/24/2022] Open
Abstract
Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of BRCA1/2-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the BRCA1/2-wild type population, the BRCAness concept.
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Affiliation(s)
- Emanuel Nicolas
- Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.
| | - François Bertucci
- Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.
- CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm U1068, CNRS UMR7258, Aix-Marseille Univ, 13009 Marseille, France.
| | - Renaud Sabatier
- Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.
- CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm U1068, CNRS UMR7258, Aix-Marseille Univ, 13009 Marseille, France.
| | - Anthony Gonçalves
- Department of Medical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.
- CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm U1068, CNRS UMR7258, Aix-Marseille Univ, 13009 Marseille, France.
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22
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Nur Husna SM, Tan HTT, Mohamud R, Dyhl-Polk A, Wong KK. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol 2018; 10:1758835918808509. [PMID: 30542378 PMCID: PMC6236629 DOI: 10.1177/1758835918808509] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 09/27/2018] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the global leading cause of cancer-related death in women and it
represents a major health burden worldwide. One of the promising breast cancer
therapeutic avenues is through small molecule inhibitors (SMIs) which have
undergone rapid progress with successful clinical trials. Recently, three
emerging and vital groups of proteins are targeted by SMIs for breast cancer
treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine
diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K).
Several of these inhibitors have been approved for the treatment of breast
cancer patients or progressed into late-stage clinical trials. Thus, modeling
from these successful clinical trials, as well as their limitations, is pivotal
for future development and trials of other inhibitors or therapeutic regimens
targeting breast cancer patients. In this review, we discuss eight recently
approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib),
PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib).
The mechanisms of action, series of clinical trials and limitations are
described for each inhibitor.
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Affiliation(s)
- Siti Muhamad Nur Husna
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Hern-Tze Tina Tan
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Anne Dyhl-Polk
- Department of Oncology, Herlev-Gentofte University Hospital, Herlev, Denmark
| | - Kah Keng Wong
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, 16150, Malaysia
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23
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Prasanna T, Wu F, Khanna KK, Yip D, Malik L, Dahlstrom JE, Rao S. Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy. Cancer Sci 2018; 109:3383-3392. [PMID: 30230653 PMCID: PMC6215877 DOI: 10.1111/cas.13799] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 09/05/2018] [Accepted: 09/09/2018] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine-specific histone demethylase-1A inhibitors or histone deacetylase inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
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Affiliation(s)
- Thiru Prasanna
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
| | - Fan Wu
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia
| | - Desmond Yip
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
| | - Laeeq Malik
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
| | - Jane E. Dahlstrom
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
- Department of Anatomical PathologyACT PathologyThe Canberra HospitalCanberraACTAustralia
| | - Sudha Rao
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
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24
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Liposits G, Loh KP, Soto-Perez-de-Celis E, Dumas L, Battisti NML, Kadambi S, Baldini C, Banerjee S, Lichtman SM. PARP inhibitors in older patients with ovarian and breast cancer: Young International Society of Geriatric Oncology review paper. J Geriatr Oncol 2018; 10:337-345. [PMID: 30333088 DOI: 10.1016/j.jgo.2018.10.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 09/16/2018] [Accepted: 10/10/2018] [Indexed: 01/28/2023]
Abstract
Breast and ovarian cancer are common malignancies among older adults, causing significant morbidity and mortality. Although most cases of breast and ovarian cancer are sporadic, a significant proportion is caused by mutations in cancer susceptibility genes, most often breast cancer susceptibility genes (BRCA) 1 and 2. Furthermore, some breast and ovarian tumors are phenotypically similar to those with BRCA mutations, a phenomenon known as "BRCAness". BRCA mutations and "BRCAness" lead to defects in DNA repair, which may be a target for therapeutic agents such as Poly ADP-Ribose Polymerase (PARP) inhibitors. PARP inhibitors are novel medications which lead to double-strand breaks resulting in cell death due to synthetic lethality, and which have been shown to be effective in patients with advanced breast and ovarian cancers with or without BRCA mutations. Three different PARP inhibitors (olaparib, niraparib, and rucaparib) have been approved for the treatment of ovarian cancer and one (olaparib) for breast cancer harboring BRCA mutations. Here, we review the currently available evidence regarding the use of PARP inhibitors for the treatment of patients with breast and ovarian cancer, with a particular focus on the inclusion of older adults in clinical trials of these therapies. Additionally, we provide an overview of currently ongoing studies of PARP inhibitors in breast and ovarian cancer, and include recommendations for increasing the evidence-base for using these medications among older patients.
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Affiliation(s)
- Gabor Liposits
- Department of Oncology, Region Hospital West Jutland, Gl. Landevej 61, Herning, 7400, Denmark.
| | - Kah Poh Loh
- Division of Hematology/Oncology, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
| | - Enrique Soto-Perez-de-Celis
- Enrique Soto-Perez-de-Celis Department of Geriatrics, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
| | - Lucy Dumas
- Gynaecology Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
| | | | - Sindhuja Kadambi
- Division of Geriatrics/Aging, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
| | - Capucine Baldini
- Drug Development Department (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.
| | - Susana Banerjee
- Gynaecology Unit, The Royal Marsden NHS Foundation Trust Sutton, United Kingdom.
| | - Stuart M Lichtman
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, NY, USA.
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25
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Noor ZS, Master A. Updates on Targeted Therapy for Triple-Negative Breast Cancer (TNBC). CURRENT BREAST CANCER REPORTS 2018. [DOI: 10.1007/s12609-018-0291-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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26
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Triple-Negative Breast Cancers: Systematic Review of the Literature on Molecular and Clinical Features with a Focus on Treatment with Innovative Drugs. Curr Oncol Rep 2018; 20:76. [PMID: 30128845 DOI: 10.1007/s11912-018-0726-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Triple-negative breast cancer (TNBC) accounts for 15-20% of diagnosed breast tumours, with higher incidence in young and African-American women, and it is frequently associated with BRCA germline mutations. Chemotherapy is the only well-established therapeutic option in both early- and advanced-stages of the disease. TNBC tumours relapse earlier after standard anthracycline- and/or taxane-based chemotherapy treatments, generally within 1-3 years after the diagnosis, and often develop visceral metastases, representing the subtype with a worse prognosis among all breast cancers. In the present review, we will provide an updated overview of the available results of recent clinical trials for this disease and we will describe the implications of the known molecular pathways representing novel targets for development of future therapies for TNBC patients. RECENT FINDINGS Over the past decade, the advent of gene expression micro-array technology has led to the identification of different actionable targets including various genomic alterations, androgen receptor, PARP, PI3K, VEGF and other proteins of the angiogenic pathway. Thus, novel targeted drugs have been tested in clinical trials reporting promising results in specific TNBC molecular subgroups. Although cytotoxic chemotherapy remains the mainstay of treatment for TNBC patients, the identification of novel 'drugable' targets and pathways for developing personalized treatments represents a promising investigational approach in the management of the TNBC subtype.
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27
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Tong CWS, Wu M, Cho WCS, To KKW. Recent Advances in the Treatment of Breast Cancer. Front Oncol 2018; 8:227. [PMID: 29963498 PMCID: PMC6010518 DOI: 10.3389/fonc.2018.00227] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/01/2018] [Indexed: 12/15/2022] Open
Abstract
Breast cancer (BC) is the most common malignancy in women. It is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. Over the past few years, substantial advances have been made in the discovery of new drugs for treating BC. Improved understanding of the biologic heterogeneity of BC has allowed the development of more effective and individualized approach to treatment. In this review, we provide an update about the current treatment strategy and discuss the various emerging novel therapies for the major molecular subtypes of BC. A brief account of the clinical development of inhibitors of poly(ADP-ribose) polymerase, cyclin-dependent kinases 4 and 6, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, histone deacetylation, multi-targeting tyrosine kinases, and immune checkpoints for personalized treatment of BC is included. However, no targeted drug has been approved for the most aggressive subtype-triple negative breast cancer (TNBC). Thus, we discuss the heterogeneity of TNBC and how molecular subtyping of TNBC may help drug discovery for this deadly disease. The emergence of drug resistance also poses threat to the successful development of targeted therapy in various molecular subtypes of BC. New clinical trials should incorporate advanced methods to identify changes induced by drug treatment, which may be associated with the upregulation of compensatory signaling pathways in drug resistant cancer cells.
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Affiliation(s)
- Christy W. S. Tong
- Faculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Mingxia Wu
- Faculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - William C. S. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong
| | - Kenneth K. W. To
- Faculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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28
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Duma N, Gast KC, Choong GM, Leon-Ferre RA, O'Sullivan CC. Where Do We Stand on the Integration of PARP Inhibitors for the Treatment of Breast Cancer? Curr Oncol Rep 2018; 20:63. [PMID: 29884921 DOI: 10.1007/s11912-018-0709-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW To provide an overview of the clinical development of poly(ADP-ribose) polymerase inhibitors (PARPi) in breast cancer to date and to review existing challenges and future research directions. RECENT FINDINGS We summarize the clinical development of PARPi in breast cancer from bench to bedside, and discuss the results of recent phase 3 trials in patients with metastatic breast cancer (MBC) and germline mutations in BRCA1/2 (gBRCAm). We will also provide an update regarding mechanisms of action and resistance to PARPi, and review clinical trials of PARPi as monotherapy or in combination regimens. PARPi are a novel treatment approach in persons with gBRCA1/2m-associated MBC. Going forward, the clinical applicability of these compounds outside the gBRCAm setting will be studied in greater detail. The identification of accurate predictive biomarkers of response is a research priority.
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Affiliation(s)
- Narjust Duma
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Kelly C Gast
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Grace M Choong
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA
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BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer 2018; 119:141-152. [PMID: 29867226 PMCID: PMC6048046 DOI: 10.1038/s41416-018-0127-5] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 04/10/2018] [Accepted: 04/24/2018] [Indexed: 12/15/2022] Open
Abstract
Testing for germline BRCA1/2 mutations has an established predictive role in breast cancer risk assessment. More recently, studies have also identified BRCA1/2 status as clinically relevant in the selection of therapy for patients already diagnosed with breast cancer. Emerging breast and ovarian cancer research indicate that BRCA status predicts responsiveness to platinum-based chemotherapy, as well as to inhibitors of poly(ADP-ribose) polymerase (PARP), owing to the ability of these interventions to inhibit DNA repair pathways. BRCA1/2 mutation testing thus has important and expanding roles in treatment planning for subsets of patients with breast cancer. Recent studies have demonstrated different activity of platinum salts in BRCA-mutated compared with non-BRCA-mutated breast cancer. Furthermore, phase II/III studies of single-agent PARP inhibitors (PARPi) have shown encouraging progression-free survival results in patients with BRCA1/2-mutated breast cancer, which led to the recent approval of olaparib, the first PARPi to be approved in breast cancer. Determining BRCA1/2 mutation status in this breast cancer subgroup could potentially expand treatment options beyond the current standard of taxane and anthracycline-based chemotherapy. Although attempts have been made to develop scoring systems that measure defects in homologous recombination repair pathways to predict response to platinum or PARPi, none have yet made it into clinical use. In this review, we summarise the recent and ongoing preclinical and clinical studies on the treatment of BRCA-associated breast cancer, and discuss efforts to identify other breast cancer patients who may be responsive to therapies effective in BRCA mutation carriers, including platinum-containing chemotherapy and PARPi.
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Wang X, Shi Y, Huang D, Guan X. Emerging therapeutic modalities of PARP inhibitors in breast cancer. Cancer Treat Rev 2018; 68:62-68. [PMID: 29870916 DOI: 10.1016/j.ctrv.2018.05.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 12/26/2022]
Abstract
Inhibition of Poly (ADP-ribose) polymerase (PARP) has shown marked benefit for breast cancer with homologous recombination deficiency, whether driven by defects in BRCA1, BRCA2, or other pathway components. Since the initial approval of olaparib, a mostly investigated PARP inhibitor (PARPi), the clinical development of PARPi in breast cancer treatment has been a major emphasis. Researches in investigating platinum-PARPi combination use compared with platinum monotherapy demonstrated promising benefit in metastatic BRCA mutated breast cancer or TNBC, while no such superiority was observed in the neoadjuvant setting of TNBC. Moreover, the utility of PARP inhibition in BRCA1/2 mutated breast cancer with different platinum-free interval was investigated. There was a clear association between clinical benefit with PARPi and platinum sensitivity, whereas partial efficacy of PARPi still occurs in platinum-resistant patients. In addition, proof-of-principle studies of immunotherapy combined with PARPi in breast cancer have obtained promising results, indicating the potential benefit of the combination therapy in patients with breast cancer. These efforts, contributing to maximize the utility of PARPi, may drive a new era of this agent after its first routine use. In this review, we summarized the utility of combining platinum-PARPi in BRCA mutated breast cancer or TNBC compared with platinum monotherapy and provided promising prospects of PARPi as maintenance therapy in breast cancer, as well as providing a strong rationale for testing immunotherapy combined with PARPi in breast cancer to expand the clinical utility of PARPi.
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Affiliation(s)
- Xin Wang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Yaqin Shi
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Doudou Huang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Xiaoxiang Guan
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China; Department of Medical Oncology, Jinling Clinical College, Nanjing Medical University, Nanjing 210002, China.
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Papadimitriou M, Mountzios G, Papadimitriou CA. The role of PARP inhibition in triple-negative breast cancer: Unraveling the wide spectrum of synthetic lethality. Cancer Treat Rev 2018; 67:34-44. [PMID: 29753961 DOI: 10.1016/j.ctrv.2018.04.010] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 04/26/2018] [Accepted: 04/28/2018] [Indexed: 02/07/2023]
Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and is characterized by a lack of immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and HER2. TNBC is associated with poor long-term outcomes compared with other breast cancer subtypes. Many of these tumors are also basal-like cancers which are characterized by an aggressive biological behavior with a distant recurrence peak observed early at 3 years following diagnosis. Furthermore, metastatic TNBC bears a dismal prognosis with an average survival of 12 months. Although the prevalence of genetic alterations among women with TNBC differs significantly by ethnicity, race and age, BRCA mutations (including both germline mutations and somatic genetic aberrations) are found in up to 20-25% of unselected patients and especially in those of the basal-like immunophenotype. Therefore, defects in the DNA repair pathway could represent a promising therapeutic target for this subgroup of TNBC patients. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in BRCA1 or BRCA2 mutation carriers. Several PARP inhibitors are currently being evaluated in the adjuvant, neo-adjuvant, and metastatic setting for the treatment of breast cancer patients with a deficient homologous recombination pathway. In this article, we review the major molecular characteristics of TNBC, the mechanisms of homologous recombination, and the role of PARP inhibition as an emerging therapeutic strategy.
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Affiliation(s)
- Marios Papadimitriou
- Second Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Giannis Mountzios
- Department of Medical Oncology, 251 Airforce General Hospital, Athens, Greece
| | - Christos A Papadimitriou
- Second Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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32
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Guney Eskiler G, Cecener G, Egeli U, Tunca B. Triple negative breast cancer: new therapeutic approaches andBRCAstatus. APMIS 2018; 126:371-379. [DOI: 10.1111/apm.12836] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 02/28/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Gamze Guney Eskiler
- Deparment of Medical Biology; Faculty of Medicine; Sakarya University; Sakarya Turkey
| | - Gulsah Cecener
- Deparment of Medical Biology; Faculty of Medicine; Uludag University; Bursa Turkey
| | - Unal Egeli
- Deparment of Medical Biology; Faculty of Medicine; Uludag University; Bursa Turkey
| | - Berrin Tunca
- Deparment of Medical Biology; Faculty of Medicine; Uludag University; Bursa Turkey
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33
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Turk AA, Wisinski KB. PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside. Cancer 2018; 124:2498-2506. [PMID: 29660759 DOI: 10.1002/cncr.31307] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/30/2018] [Accepted: 02/02/2018] [Indexed: 12/29/2022]
Abstract
Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA-mutant, metastatic breast cancer demonstrated improved outcomes with single-agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA-mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498-506. © 2018 American Cancer Society.
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Affiliation(s)
- Anita A Turk
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
| | - Kari B Wisinski
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
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Abstract
OPINION STATEMENT The single agent activity of PARP inhibitors (PARPi) in germline BRCA mutated (gBRCAm) breast and ovarian cancer suggests untapped potential for this new class of drug in breast cancer. The US Food and Drug Administration has approved three PARPi (olaparib, rucaparib, and niraparib) so far to treat certain ovarian cancers, including those with gBRCAm and olaparib for treatment of gBRCAm breast cancers. Several PARPi are now under clinical development for breast cancer in the various treatment settings. Recently, two phase III trials of olaparib (OlympiaD) and talazoparib (EMBRACA) demonstrated 3-month progression-free survival improvement with PARPi compared to physician's choice single agent chemotherapy in metastatic gBRCAm breast cancer. To date, PARPi seems less efficacious in metastatic breast cancer patients than those with BRCA mutated platinum-sensitive recurrent ovarian cancer, perhaps reflecting the biologic heterogeneity and low somatic BRCA mutation rate in breast cancer. The use of PARPi is gradually evolving, including combination strategies with chemotherapy, targeted agents, radiotherapy, or immunotherapy in women with and without gBRCAm. The role of predictive biomarkers, including molecular signatures and homologous recombination repair deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to identify a subgroup of patients who may have benefit from PARPi. An improved understanding of the mechanisms underlying PARPi clinical resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which breast cancer patients we should treat with PARPi and where these agents should come in over the course of treatment.
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Affiliation(s)
- Alexandra S Zimmer
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr. MSC1906 Building 10, Room 4B54, Bethesda, MD, 20892-1906, USA.
| | - Mitchell Gillard
- School of Medicine, Stony Brook University School of Medicine, 101 Nicolls Road Stony Brook, Bethesda, NY, 11794-8434, USA
| | - Stanley Lipkowitz
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr. MSC1906 Building 10, Room 4B54, Bethesda, MD, 20892-1906, USA
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr. MSC1906 Building 10, Room 4B54, Bethesda, MD, 20892-1906, USA
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Pettitt SJ, Lord CJ. PARP inhibitors and breast cancer: highlights and hang-ups. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2018. [DOI: 10.1080/23808993.2018.1438187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Stephen J. Pettitt
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
| | - Christopher J. Lord
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
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36
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Ferrara R, Simionato F, Ciccarese C, Grego E, Cingarlini S, Iacovelli R, Bria E, Tortora G, Melisi D. The development of PARP as a successful target for cancer therapy. Expert Rev Anticancer Ther 2017; 18:161-175. [DOI: 10.1080/14737140.2018.1419870] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Roberto Ferrara
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
- Medical Oncology Department, Gustave Roussy, Villejuif, France
| | - Francesca Simionato
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Chiara Ciccarese
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Elisabetta Grego
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Sara Cingarlini
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Roberto Iacovelli
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Emilio Bria
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Giampaolo Tortora
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Davide Melisi
- Section of Oncology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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37
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Anampa J, Sparano JA. New agents for the management of resistant metastatic breast cancer. Expert Opin Pharmacother 2017; 18:1815-1831. [DOI: 10.1080/14656566.2017.1409206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Jesus Anampa
- Department of Oncology, Section of Breast Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joseph A. Sparano
- Department of Oncology, Section of Breast Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
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38
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Wang C, Kar S, Lai X, Cai W, Arfuso F, Sethi G, Lobie PE, Goh BC, Lim LHK, Hartman M, Chan CW, Lee SC, Tan SH, Kumar AP. Triple negative breast cancer in Asia: An insider's view. Cancer Treat Rev 2017; 62:29-38. [PMID: 29154023 DOI: 10.1016/j.ctrv.2017.10.014] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/29/2017] [Accepted: 10/31/2017] [Indexed: 12/31/2022]
Abstract
While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC.
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Affiliation(s)
- Chao Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shreya Kar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xianning Lai
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wanpei Cai
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Peter E Lobie
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Tsinghua Berkeley Shenzhen Institute, Tsinghua University Graduate School at Shenzhen, Shenzhen, China
| | - Boon C Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore; National University Cancer Institute, National University Health System, Singapore
| | - Lina H K Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; NUS Immunology Program, National University of Singapore, Singapore
| | - Mikael Hartman
- Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore; Department of Surgery, National University Cancer Institute, National University Health System, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Ching W Chan
- Department of Surgery, National University Cancer Institute, National University Health System, Singapore
| | - Soo C Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore; National University Cancer Institute, National University Health System, Singapore
| | - Sing H Tan
- Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore; National University Cancer Institute, National University Health System, Singapore; OncoCare Cancer Centre, Gleneagles Medical Centre, Singapore.
| | - Alan P Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore; Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, Australia; Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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39
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Saraiva DP, Guadalupe Cabral M, Jacinto A, Braga S. How many diseases is triple negative breast cancer: the protagonism of the immune microenvironment. ESMO Open 2017; 2:e000208. [PMID: 29018573 PMCID: PMC5604720 DOI: 10.1136/esmoopen-2017-000208] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/21/2017] [Accepted: 07/24/2017] [Indexed: 12/22/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a type of breast cancer (BC) that does not express the oestrogen and the progesterone receptors and the human epidermal growth factor receptor type 2 (HER2). Since there are no positive markers to reliably classify TNBC, these tumours are not yet treated with targeted therapies. Perhaps for this reason they are the most aggressive form of breast carcinomas. However, the clinical observation that these patients do not carry a uniformly dismal prognosis, coupled with data coming from pathology and epidemiology, suggests that this negative definition is not capturing a single clinical entity, but several. We critically evaluate this evidence in this paper, reviewing clinical and epidemiological data and new studies that aim to subclassify TNBC. Moreover, evidence on the role of tumour infiltrating lymphocytes (TILs) on TNBC progression, response to chemotherapy and patient outcome have been published. The heterogeneity, observed even at TILs level, highlights the idea that TNBC is much more than a single disease with a unique treatment. The exploration of the immune environment present at the tumour site could indeed help in answering the question 'How many diseases is TNBC' and will help to define prognosis and eventually develop new therapies, by stimulating the immune effector cells or by inhibiting immunological repressor molecules. In this review, we focus on the prospect of the patient's diverse immune signatures within the tumour as potential biomarkers and how they could be modulated to fight the disease.
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Affiliation(s)
- Diana P Saraiva
- CEDOC, Nova Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal
| | - M Guadalupe Cabral
- CEDOC, Nova Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal
| | - António Jacinto
- CEDOC, Nova Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal
| | - Sofia Braga
- CEDOC, Nova Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal
- Instituto CUF de Oncologia, Lisbon, Portugal
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40
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PARP Inhibitors in Breast Cancer: Latest Evidence. CURRENT BREAST CANCER REPORTS 2017. [DOI: 10.1007/s12609-017-0251-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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