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Dissecting the Heterogeneity of Triple-Negative Breast Cancer

Published on May 20, 2012in Journal of Clinical Oncology28.349
· DOI :10.1200/JCO.2011.38.2010
Otto Metzger-Filho19
Estimated H-index: 19
,
Andrew Tutt56
Estimated H-index: 56
+ 11 AuthorsMartine Piccart-Gebhart112
Estimated H-index: 112
Abstract
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.
  • References (125)
  • Citations (226)
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References125
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#1Jacek GronwaldH-Index: 55
#2Tomasz ByrskiH-Index: 39
Last. Steven A. NarodH-Index: 115
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502 Background: Neoadjuvant chemotherapy is administered to control disease, make surgical resection possible and increase the possibility of breast tissue conservation. A further advantage of neoadjuvant therapy is that it helps to assess chemo-sensitivity to a particular agent. Induction of a pathological complete response (pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a better disease-free and overall survival. Experimental data suggest that BRCA1 related breast ...
55 Citations
#1Adam Brufsky (University of Pittsburgh)H-Index: 59
#2Sara A. Hurvitz (UCLA: University of California, Los Angeles)H-Index: 37
Last. Hope S. Rugo (UCSF: University of California, San Francisco)H-Index: 76
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Purpose This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) –negative metastatic breast cancer.
281 CitationsSource
#1M. A. VolleberghH-Index: 8
#2Esther H. LipsH-Index: 18
Last. Sabine C. LinnH-Index: 41
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Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. Patie...
132 CitationsSource
#1Maggie C.U. CheangH-Index: 51
#2D. VoducH-Index: 3
Last. Torsten O. NielsenH-Index: 75
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1032 Background: Recent studies have suggested that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We assigned intrinsic subtypes to breast t...
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1007 Background: A randomized phase II study in mTNBC suggested that iniparib (I), an anticancer agent with PARP inhibitory activity, added to GC improved overall survival (OS), without potentiating GC toxicity (O’Shaughnessy et al. NEJM 2011). This confirmatory study evaluated the safety and efficacy of GC with or without I in a similar mTNBC pt population. Methods: This randomized, open-label phase III study enrolled pts ≥18 years with mTNBC, measurable disease, and ≤2 prior cytotoxic regimens...
214 CitationsSource
#1Andrea RoccaH-Index: 19
#2A. ParadisoH-Index: 15
Last. Rosella SilvestriniH-Index: 39
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1031 Background: Anthracycline-containing regimens are considered superior to cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant therapy for early breast cancer, but predictors of a...
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#1Emilio AlbaH-Index: 34
#2Jose Ignacio ChaconH-Index: 11
Last. Joan AlbanellH-Index: 26
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1015 Background: Platinum salts are active in basal-like breast cancer in preclinical models and has been widely used in clinical trials in this subtype. However its utility added to conventional d...
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#1Christine DesmedtH-Index: 45
#2Angelo Di LeoH-Index: 48
Last. Christos SotiriouH-Index: 78
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Purpose Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) –negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II- (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Patients and Me...
127 CitationsSource
#1Jiuping Ji (SAIC: Science Applications International Corporation)H-Index: 20
#2Maxwell P. LeeH-Index: 24
Last. James H. DoroshowH-Index: 74
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Poly (ADP-ribose) (PAR) polymerases (PARP1 and PARP2) are activated in response to DNA single-strand breaks and are pivotal to the base excision repair pathway for homologous recombination-defective cells or for the chemotherapy-damaged genome. ABT-888, AZD2281, and BSI201 are three presumed PARP inhibitors currently being evaluated in phase 1-3 clinical trials; each has demonstrated therapeutic activity either as a single agent for patients with BRCA-deficient malignancies or in combination wit...
21 CitationsSource
Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), t...
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Cited By226
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#1Francesca Sanges (University of Sassari)H-Index: 4
#2Matteo Floris (University of Sassari)H-Index: 15
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Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing “special types” to high-grade invasive breast carcinomas of no special type (IBC-NST). This study was performed on data obtained from TNBC Database, including pathological features and clinical re...
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#1Salma Begum Bhyan (University of the Sunshine Coast)H-Index: 2
#2YongKiat Wee (University of the Sunshine Coast)H-Index: 2
Last. Min Zhao (University of the Sunshine Coast)H-Index: 28
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Abstract Triple negative breast cancer (TNBC) is a sub type of breast cancers, and is responsible for numerous deaths worldwide. Due to lack of any of the three hormone receptors (ER, PR and HER2) commonly existing in other breast cancers, current targeted drug therapies are unavailable for this disease. Therefore, by exploring molecular regulatory network of TNBC, which includes transcription factors (TFs), modulators and target genes, it can be possible to determine treatment measures for this...
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#1Kan Zhu (University of California, Berkeley)
#2Nicholas R. Hum (UCM: University of California, Merced)H-Index: 7
Last. Min Zhao (University of California, Berkeley)H-Index: 41
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Cancer growth interferes with local ionic environments, membrane potentials, and transepithelial potentials, resulting in small electrical changes in the tumor microenvironment. Electrical fields (EFs) have significant effects on cancer cell migration (galvanotaxis/electrotaxis), however, their role as a regulator of cancer progression and metastasis is poorly understood. Here, we employed unique probe systems to characterize the electrical properties of cancer cells and their migratory ability ...
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#1Anke Janssen (UU: Utrecht University)H-Index: 2
#2Jose Villacorta Hidalgo (University of Freiburg)H-Index: 3
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γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCRs) from tumor-infiltrating γδ T lymphocytes (γδ TILs) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion o...
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The genetically heterogeneous triple-negative breast cancer (TNBC) continues to be an intractable disease, due to lack of effective targeted therapies. Gene amplification is a major event in tumorigenesis. Genes with amplification-dependent expression are being explored as therapeutic targets for cancer treatment. In this study, we have applied Analytical Multi-scale Identification of Recurring Events analysis and transcript quantification in the TNBC genome across 222 TNBC tumors and identified...
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#1Zhonghao Wang (Xinxiang Medical University)H-Index: 1
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Triple negative breast cancer (TNBC) comprises 15–20% of all invasive breast cancer and is associated with a poor prognosis. As therapy options are limited for this subtype, there is a significant need to identify new targeted approaches for TNBC patient management. The expression of the folate receptor alpha (FRα) is significantly increased in patients with TNBC and is therefore a potential biomarker and therapeutic target. We optimized and validated a FRα immunohistochemistry method, specific ...
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