Biology Of Triple-negative Breast Cancer Research Articles

Clinical trials in triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease against which targeted therapies that significantly improve the prognosis for hormone receptor-positive and HER2-overexpressing breast cancers are ineffective. This article summarizes our current understanding of the biology of TNBC as it relates to the efficacy of standard and investigational therapies. It reviews promising preliminary results that have been achieved with chemotherapeutic agents including the platinum analogs and agents that inhibit DNA repair by targeting poly ADP-ribose polymerase (PARP), while anti-angiogenic therapies and those that target the epidermal growth factor receptor (EGFR) have had more limited success. Agents that target a number of other pathways which appear to influence the biologic aggressiveness of TNBC, including src and PI3K, are in early stage clinical trials. As we learn more about TNBC, and which of its characteristics determine treatment response and resistance, we should become better able to select appropriate therapies for biologically defined patient subgroups, and reduce the clinical burden of this disease.

Abstract P6-10-04: Outcome of Triple Negative Breast Cancer in Patients with or without Deleterious BRCA Mutations

Abstract Background: Triple-negative breast cancer (TNBC) affects 10-17% of all breast cancers and is associated with a poor prognosis. The biology of TNBC is poorly understood; however, it has been shown that up to 60% of BRCA1 mutation carriers develop TNBC. The aim of this study was to determine if there were differences in the progression-free survival (PFS) and overall survival (OS) rates of BRCA mutation-associated TNBC and Non-BRCA mutation-associated TNBC. Methods: Patients with TNBC who were referred between 1997 and 2010 for genetic counseling were included in the analysis. Data was collected from a prospectively maintained IRB-approved research database. All patients with one primary breast cancer and negative expression of ER, PR, and Her2 were included in this study. A Kaplan-Meier survival analysis was performed to determine survival outcomes. Results: Out of 98 TNBC patients, 48 (48 %) were BRCA negative, and 47 (49%) were found to have a deleterious BRCA mutation (42 BRCA1 and 5 BRCA 2); 3 (3%) patients had a variant of uncertain significance in BRCA2 and were removed from study. The median age of diagnosis for BRCA positive TNBC was 42 years (range, 21-71) and for BRCA negative TNBC was 40.5 years (range, 21-64). There were no significant differences between age at diagnosis, nuclear grade, stage (I-III), or tumor histology of BRCA positive and BRCA negative TNBCs. The PFS for BRCA positive patients was 230.7 (range, 2-271) months and for BRCA negative was 203.1 (range, 2-258) months (p = 0.19). The overall survival (OS) for BRCA positive patients was 263.4 (range, 2-292) months and for BRCA negative 236.2 (2-279) months (p = 0.39). Conclusion: Outcome of triple-negative breast cancer is not different in BRCA mutation carriers versus non carriers. Further studies need to evaluate whether different therapies will change the outcome in these subgroups of TNBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-04.

Abstract 3852: Combination treatment of nab-paclitaxel and bevacizumab in a new model of triple-negative breast cancer

Abstract Background: Tumors that lack estrogen, progesterone, and Her2/nu (triple-negative) are one of the most aggressive, therapy-resistant and highly metastatic subtypes of breast cancer (BC). Most currently available models do not recapitulate expression profile of triple-negative BC, thus making it difficult to devise new treatments that target this tumor type. Here, we established and characterized a new model of triple-negative BC. We also tested the novel combination of nab-paclitaxel with bevacizumab, which has been successful in treating other metastatic cancer types. Methods: HCC1806 cells were obtained stably transfected with Red Fluorescent Protein (RFP) and Renilla luciferase to establish dual reporter termed RR (RFP and Renilla luciferase). The new derivative was designated as HCC1806-RR and characterized in proliferation and cytotoxicity assays. HCC1806-RR was also orthotopically implanted into mammary fat pads of immunodeficient mice to determine tumor cell sensitivity to chemotherapy alone or in combination with anti-VEGF-A antibody. Mice bearing orthotopic HCC1806-RR tumors of 150mm3 in size were treated with saline (control), bevacizumab (4mg/kg. i.p., twice a week, for 10 weeks), nab-paclitaxel (10mg/kg, i.v., qdx5), or with combination of nab-paclitaxel and bevacizumab. Tumor growth rate was monitored by using calipers. Metastasis was analyzed by measuring luciferase activity in the lymph nodes (LN) and lungs. Results: The parental HCC1806 and its derivative HCC1806-RR had identical morphology, proliferation rates and sensitivity to nab-paclitaxel. Luciferase measurements and imaging in vivo showed that HCC1806-RR tumors have predominant LN metastasis with lungs being a second metastatic site. Bevacizumab and nab-paclitaxel inhibited tumor growth by 0% and 90%, respectively. Combination therapy inhibited tumor growth by 100%. This result was highly significant compared with either control (P < 0.001) or nab-paclitaxel (P = 0.024) group. Importantly, only combination therapy reduced incidence of LN and lung metastases by 50% and 87%. This result was statistically significant as compared with all other groups, with P-values of 0.007 and 0.001 for LN and pulmonary metastases, respectively. Half of the mice in the combination therapy group (n =10) had complete regressions of primary tumors and metastases at both regional and distant sites. Conclusions: The HCC1806-RR is a new model double-tagged with RFP and Renilla luciferase. These tags allow for quantitative assessment of metastatic spread. This model can be used to study the biology of triple-negative breast cancer and for designing new approaches to treat this type of cancer. Preliminary studies demonstrated high sensitivity of HCC1806-RR to nab-paclitaxel combined with bevacizumab suggesting that this therapy could significantly improve the health outcome for patients with triple-negative breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3852.

Triple-Negative Breast Cancer: Risk Factors to Potential Targets

Triple-negative breast cancer has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, a molecularly distinct subtype of breast cancer, the basal-like subtype. We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms. Moreover, the established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Finally, because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay. Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets. This CCR focus article will review the current state of the art on triple-negative breast cancer.

Therapeutic Strategies for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a clinically relevant term referring to breast carcinomas that do not express the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 and became operational after human epidermal growth factor receptor type 2 testing was introduced. This is a challenging disease to treat because of the absence of a specific target, but these tumors are sensitive to chemotherapy. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs, specifically, platinum compounds, and several targeted agents, including poly(ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, microtubule inhibitors, Src inhibitors, checkpoint kinase I inhibitors, mammalian target of rapamycin inhibitors, androgen receptor blocker, tumor necrosis factor-related apoptosis-inducing ligand receptor agonists, and transforming growth factor-beta antagonists, that may lead to improved clinical outcomes. Ongoing clinical trials will further define the optimal chemotherapy regimen and most effective targeted therapeutic strategy for TNBC.

Triple negative breast cancer: current understanding of biology and treatment options

We have made remarkable advances in treatment of breast cancer with combination chemotherapies, hormonal therapies, and modern targeted therapies. Triple negative breast cancers carry a poor prognosis, however, and they are insensitive to most available hormonal or targeted therapeutic agents thus far developed. A better understanding of pathophysiology, natural history, and currently available treatment options is necessary to improve outcomes of patients with triple negative breast cancer. Gene expression profiling has allowed us to classify breast cancers into five subtypes based upon distinctive gene expression signatures. This subtyping is prognostic, and the recent literatures suggest that these 'molecular portraits' may be used to predict treatment outcomes in the future. As we prepare for an era of targeted and individualized medicine, limited understanding of triple negative breast cancer biology presents a challenge in developing novel therapies. Identification of more molecular predictive signatures and their prospective validation will enable us to characterize triple negative breast cancers better and design optimal treatment modalities.