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Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy
Yvonne Hui-Fang Teng, Wai-Jin Tan, Aye-Aye Thike, Poh-Yian Cheok, Gary Man-Kit Tse, Nan-Soon Wong, George Wai-Cheong Yip, Boon-Huat Bay, Puay-Hoon Tan
Breast Cancer Research , 2011, DOI: 10.1186/bcr2857
Abstract: Seventy samples were randomly chosen from a cohort of 653 triple negative breast tumours for EGFR mutation analysis. These samples were immunostained for EGFR protein expression and consisted of negatively stained and positively stained cases. DNA was extracted from paraffin blocks and polymerase chain reaction was performed to amplify exon regions 18 to 21 of the EGFR gene. Direct sequencing of the purified PCR products was performed.EGFR mutations were found in 8 of 70 samples (11.4%). Mutations were predominantly exon 19 deletions (4 of 70 samples, 5.7%), which clustered in the region spanning codons 746 to 759 within the kinase domain of EGFR. Two types of exon 19 deletions were seen: a 15 nucleotide deletion (del E746-A750) (2 of 70 samples) and a 24 nucleotide deletion (del S752 - I759) (2 of 70 samples). Other exon 19 mutations observed were the inversion of the complementary strand (1 of 70 samples). Exon 21 mutations included missense substitution, L858R (1 of 70 samples) and T847I (2 of 70 samples). Mutations observed were independent of EGFR protein expression determined by immunohistochemical staining.This study is among the first to document the presence and estimate the prevalence of EGFR mutations in triple negative breast cancer. These findings have potential implications for the design of clinical trials involving anti-EGFR directed therapy which currently do not select for patients based on presence of activating EGFR mutations, which may hence be underpowered to detect significant benefit in unselected populations. More complete sampling of EGFR mutation status in triple negative breast cancer is needed to determine the true mutation rate.Triple negative breast cancers, defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2/cerbB2/EGFR2) expression, account for 10 to 20% of all breast carcinomas in Asian and Western populations [1-7], but occur at much higher frequencies in individual
MicroRNAs and Triple Negative Breast Cancer  [PDF]
Elvira D'Ippolito,Marilena V. Iorio
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms141122202
Abstract: Triple Negative Breast Cancer (TNBC) is a very aggressive tumor subtype, which still lacks specific markers for an effective targeted therapy. Despite the common feature of negativity for the three most relevant receptors (ER, PgR and HER2), TNBC is a very heterogeneous disease where different subgroups can be recognized, and both gene and microRNA profiling studies have recently been carried out to dissect the different molecular entities. Moreover, several microRNAs playing a crucial role in triple negative breast cancer biology have been identified, providing the experimental basis for a possible therapeutic application. Indeed, the causal involvement of microRNAs in breast cancer and the possible use of these small noncoding RNA molecules as biomarkers has been extensively studied with promising results. Their application as therapeutic tools might represent an innovative approach, especially for a tumor subgroup still lacking an efficient and specific therapy such as TNBC. In this review, we summarize our knowledge on the most important microRNAs described in TNBC.
Differential Impact of EGFR-Targeted Therapies on Hypoxia Responses: Implications for Treatment Sensitivity in Triple-Negative Metastatic Breast Cancer  [PDF]
Abderrahim El Guerrab, Rabah Zegrour, Carine-Christiane Nemlin, Flavie Vigier, Anne Cayre, Frederique Penault-Llorca, Fabrice Rossignol, Yves-Jean Bignon
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025080
Abstract: Background In solid tumors, such as breast cancer, cells are exposed to hypoxia. Cancer cells adapt their metabolism by activating hypoxia-inducible factors (HIFs) that promote the transcription of genes involved in processes such as cell survival, drug resistance and metastasis. HIF-1 is also induced in an oxygen-independent manner through the activation of epidermal growth factor receptor tyrosine kinase (EGFR-TK). Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer characterized by negative expression of hormonal and HER2 receptors, and this subtype generally overexpresses EGFR. Sensitivity to three EGFR inhibitors (cetuximab, gefitinib and lapatinib, an HER2/EGFR-TK inhibitor) was evaluated in a metastatic TNBC cell model (MDA-MB-231), and the impact of these drugs on the activity and stability of HIF was assessed. Methodology/Principal Findings MDA-MB-231 cells were genetically modified to stably express an enhanced green fluorescent protein (EGFP) induced by hypoxia; the Ca9-GFP cell model reports HIF activity, whereas GFP-P564 reports HIF stability. The reporter signal was monitored by flow cytometry. HIF-1 DNA-binding activity, cell migration and viability were also evaluated in response to EGFR inhibitors. Cell fluorescence signals strongly increased under hypoxic conditions (> 30-fold). Cetuximab and lapatinib did not affect the signal induced by hypoxia, whereas gefitinib sharply reduced its intensity in both cell models and also diminished HIF-1 alpha levels and HIF-1 DNA-binding activity in MDA-MB-231 cells. This gefitinib feature was associated with its ability to inhibit MDA-MB-231 cell migration and to induce cell mortality in a dose-dependent manner. Cetuximab and lapatinib had no effect on cell migration or cell viability. Conclusion Resistance to cetuximab and lapatinib and sensitivity to gefitinib were associated with their ability to modulate HIF activity and stability. In conclusion, downregulation of HIF-1 through EGFR signaling seems to be required for the induction of a positive response to EGFR-targeted therapies in TNBC.
The Implications of Breast Cancer Molecular Phenotype for Radiation Oncology  [PDF]
Shirin Sioshansi,Kathryn E. Huber,David E. Wazer
Frontiers in Oncology , 2011, DOI: 10.3389/fonc.2011.00012
Abstract: The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence, and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence (LR) in the hormone receptor (HR) positive luminal subtypes compared to HR negative subtypes [triple negative (TN) and HER2-enriched]. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of LR. Unfortunately, no such remedy exists to address the increased risk of LR for patients with TN tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and LR following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased LR in TN breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation, and the appropriateness of accelerated partial breast irradiation.
Triple Negative Breast Cancer-An Overview and Review of Literature  [PDF]
Amit Gupta, Jyotika Jain, Ajay Kumar, Sunil Kumar, Neelam Wadhwa
Asian Journal of Medical Sciences , 2012, DOI: 10.3126/ajms.v3i2.5384
Abstract: Triple-negative breast cancer refers to a specific subtype of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu. About 12-17 % of ca breast? have triple negative ca breast This subtype of breast cancer is clinically characterized as more aggressive and less responsive to standard treatment and associated with overall poorer prognosis. Chemotherapy is the choice of systemic therapy for triple-negative tumors. They are more susceptible to non-receptor mediated therapies than other tumors. A number of new strategies are currently being tested in clinical trials. DOI: http://dx.doi.org/10.3126/ajms.v3i2.5384 Asian Journal of Medical Sciences 3(2012) 16-20
Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin
Danica L. Rowe,Tuba Ozbay,Ruth M. O’Regan,Rita Nahta
Breast Cancer: Basic and Clinical Research , 2009,
Abstract: In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.
Triple-negative (basal-like) breast cancer: a new entity
LA Carey
Breast Cancer Research , 2007, DOI: 10.1186/bcr1696
Abstract: Basal-like breast cancer has some unique characteristics. It is the type of breast cancer that BRCA1 mutation carriers generally develop, although most basal-like breast cancers are sporadic. It comprises approximately 15% of all breast cancers, but is overrepresented among young African-American women who develop breast cancer, in whom it comprises 39%. Although it does not occur at higher stages than other breast cancer subtypes, it is usually high grade and highly proliferative, which may explain the poor prognosis associated with this subtype in several series. Given the triple-negative status of basal-like breast cancer, it cannot be treated with ER-targeted or HER2-targeted therapies, so is primarily treated with chemotherapy. Fortunately, advances in adjuvant therapy appear to benefit ER-negative breast cancer even more than ER-positive breast cancer, and women with the basal-like subtype have similarly benefited. In addition, in cohorts of breast cancer treated with neoadjuvant chemotherapy, the pathologic complete response to anthracycline/taxane-based therapy was significantly higher among basal-like breast cancers than luminal breast cancers. The women with pathologic complete response have good outcome; the poor prognosis of basal-like breast cancer appears to relate to a particularly high risk of early distant relapse among those that had residual disease. Among the targeted agents for breast cancer, bevacizumab added to paclitaxel in a randomized phase III trial appeared to have similar benefit in the triple-negative subset as the other breast cancer phenotypes, suggesting effectiveness in basal-like breast cancer. Current investigations into other therapeutic options for this subtype include confirmation of effectiveness of VEGF targeting, examination of EGFR-targeted strategies, determining whether the association of basal-like breast cancer with BRCA1 mutations means that this DNA repair pathway is dysfunctional in all basal-like breast cancer, and
Neoadjuvant Therapy in Operable Breast Cancer: Application to Triple Negative Breast Cancer  [PDF]
Foluso O. Ademuyiwa,Matthew J. Ellis,Cynthia X. Ma
Journal of Oncology , 2013, DOI: 10.1155/2013/219869
Abstract: Systemic treatment for triple negative breast cancer (TNBC: negative for the expression of estrogen receptor and progesterone receptor and HER2 amplification) has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today’s standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed. 1. Introduction Neoadjuvant chemotherapy, also known as preoperative or primary systemic therapy, is an option for patients with breast cancers who require cytotoxic chemotherapy. It was initially used for patients with locally advanced inoperable breast cancers [1]. Subsequently tumor regression induced by chemotherapy allows a proportion of patients with large operable cancers who hitherto required a mastectomy to achieve breast conservation. For example, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 clinical trial randomized a large number of women to receive chemotherapy either pre- or postoperatively [2]. Although there were no survival differences, preoperative chemotherapy improved the rate of breast conservation. In those who are already candidates for breast conservation, neoadjuvant chemotherapy may also result in a more desirable cosmetic outcome by allowing less extensive surgery. In addition, neoadjuvant treatment provides a critical opportunity to assess the in vivo responsiveness to chemotherapy and a research platform for investigations of tissue or imaging predictors of response and novel therapeutic targets. Neoadjuvant chemotherapy has therefore increasingly become a preferred strategy for patients with Stage II or III breast cancers. Triple negative breast cancer (TNBC) is defined clinically by the absence of estrogen receptor (ER), progesterone receptor (PgR), and HER2/neu overexpression and encompasses a molecularly diverse group of diseases. As TNBC lacks a clearly defined therapeutic target, patients receive chemotherapy for their systemic management. Since chemotherapy-resistant TNBC carries a
Triple-Negative Breast Cancer: Adjuvant Therapeutic Options  [PDF]
Ayca Gucalp,Tiffany A. Traina
Chemotherapy Research and Practice , 2011, DOI: 10.1155/2011/696208
Abstract: Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents. 1. Triple-Negative Breast Cancer: Adjuvant Therapeutic Options Each year more than 1.3 million new cases of breast cancer are diagnosed worldwide. In spite of numerous advances in prevention, surgical resection, and adjuvant radiotherapy and chemotherapy, it is estimated that approximately 450,000 women will die of this disease globally each year [1]. Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2), represents approximately 15% of all breast cancers. Patients diagnosed with TNBC generally experience a more aggressive clinical course exacerbated by the lack of effective targeted therapies. Moreover, despite best available therapy, TNBC accounts for a disproportionate number of breast cancer-related deaths, further highlighting the need for novel therapeutic approaches for the management of this high-risk subset of patients [2–4]. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents. 2. Clinicopathologic and Molecular Features of TNBC Human breast cancers represent a heterogenous disease group characterized by varied clinical presentations
Identification of Prognostic Genes for Recurrent Risk Prediction in Triple Negative Breast Cancer Patients in Taiwan  [PDF]
Lee H. Chen, Wen-Hung Kuo, Mong-Hsun Tsai, Pei-Chun Chen, Chuhsing K. Hsiao, Eric Y. Chuang, Li-Yun Chang, Fon-Jou Hsieh, Liang-Chuan Lai, King-Jen Chang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028222
Abstract: Discrepancies in the prognosis of triple negative breast cancer exist between Caucasian and Asian populations. Yet, the gene signature of triple negative breast cancer specifically for Asians has not become available. Therefore, the purpose of this study is to construct a prediction model for recurrence of triple negative breast cancer in Taiwanese patients. Whole genome expression profiling of breast cancers from 185 patients in Taiwan from 1995 to 2008 was performed, and the results were compared to the previously published literature to detect differences between Asian and Western patients. Pathway analysis and Cox proportional hazard models were applied to construct a prediction model for the recurrence of triple negative breast cancer. Hierarchical cluster analysis showed that triple negative breast cancers from different races were in separate sub-clusters but grouped in a bigger cluster. Two pathways, cAMP-mediated signaling and ephrin receptor signaling, were significantly associated with the recurrence of triple negative breast cancer. After using stepwise model selection from the combination of the initial filtered genes, we developed a prediction model based on the genes SLC22A23, PRKAG3, DPEP3, MORC2, GRB7, and FAM43A. The model had 91.7% accuracy, 81.8% sensitivity, and 94.6% specificity under leave-one-out support vector regression. In this study, we identified pathways related to triple negative breast cancer and developed a model to predict its recurrence. These results could be used for assisting with clinical prognosis and warrant further investigation into the possibility of targeted therapy of triple negative breast cancer in Taiwanese patients.
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