Triple Negative Breast Carcinoma and the Basal Phenotype: From Expression Profiling to Clinical Practice

ArticleinAdvances in Anatomic Pathology 14(6):419-30 · December 2007with16 Reads
DOI: 10.1097/PAP.0b013e3181594733 · Source: PubMed
Triple negative breast carcinomas (TNBCs) are a group of primary breast tumors with aggressive clinical behavior. Most TNBCs possess a basal phenotype (BP) and show varying degrees of basal cytokeratin and myoepithelial marker expression. The importance of recognizing these tumors came to light largely as the result of gene expression profiling studies that categorized breast cancer into 3 major groups. Two of these groups are defined by their respective expression of estrogen receptor and HER2. TNBCs represent a third group and are defined by negativity for hormone receptors and HER2. TNBCs currently lack effective targeted therapies and are frequently resistant to standard chemotherapeutic regimens. These tumors tend to occur in premenopausal women and members of specific ethnic groups and a subset are associated with heritable BRCA1 mutations. For patients with sporadic TNBCs and BP tumors, BRCA1 dysfunction seems to play a major role in the development and progression of disease. The pathologist's role in the diagnosis and characterization of TNBCs and BP tumors is currently being defined as we are acquiring knowledge of the biologic and genetic underpinnings that drive this heterogeneous group of diseases. This review will provide a historical prospective on TNBCs and tumors that express basal cytokeratins and myoepithelial makers. Additionally, we will discuss the molecular biologic, genetic and pathologic aspects of these tumors. Guidelines will be provided on how to best approach the diagnosis of these cases and on what input pathologists should provide clinicians to help develop optimal therapeutic and preventative strategies against this aggressive group of breast cancers.
    • "Triple-negative breast cancer (TNBC), characterized by absence of expression of estrogen and progesterone receptors (ER, PR), and human epidermal growth factor receptor 2 (HER2), has been shown to be molecularly heterogeneous in gene expression analyses [1,2]. The majority of TNBC is with aggressive clinical course, higher rate of metastases, and shorter survival, thus requiring aggressive multidisciplinary treatment with surgery, radiation and chemotherapy [3,4,5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Triple-negative breast cancer (TNBC) is highly diverse group of cancers, and generally considered an aggressive disease associated with poor survival. Stratification of TNBC is highly desired for both prognosis and treatment decisions to identify patients who may benefit from less aggressive therapy. Methods: This study retrieved 192 consecutive non-metastasis TNBC patients who had undergone a resection of a primary tumor from 2008 to 2012. All samples were negative for ER, PR, and HER2/neu. Disease-free-survival (DFS) and overall-survival (OS) were evaluated for expression of immunohistochemical biomarkers (P53, Ki-67, CK5/6 and EGFR), as well as clinicopathological variables including age, tumor size, grade, lymph node status, pathologic tumor and nodal stages. The cutoff values of the basal biomarkers, EGFR and CK5/6, were estimated by time-dependent ROC curves. The prognostic values of combinatorial variables were identified by univariate and multivariate Cox analysis. Patients were stratified into different risk groups based on expression status of identified prognostic variables. Results: Median age was 57 years (range, 28-92 years). Patients' tumor stage and nodal stage were significantly associated with OS and DFS. EGFR and CK5/6 were significant prognostic variables at cutoff points of 15% (p = 0.001, AUC = 0.723), and 50% (p = 0.006, AUC = 0.675), respectively. Multivariate Cox analysis identified five significant variables: EGFR (p = 0.016), CK5/6 (p = 0.018), Ki-67 (p = 0.048), tumor stage (p = 0.010), and nodal stage (p = 0.003). Patients were stratified into low basal (EGFR≤15% and CK5/6≤50%) and high basal (EGFR>15% and/or CK5/6>50%) expression groups. In the low basal expression group, patients with low expressions of Ki-67, low tumor and nodal stage had significantly better survival than those with high expressions/stages of three variables, log-rank p = 0.015 (100% vs 68% at 50 months). In the high basal expression group, patient with high basal expression of both biomarkers (EGFR >15% and CK5/6 >50%) had worse survival (mean DFS = 25 months, 41.7% event rate) than those patient with high expression of either one marker (mean DFS = 34 months, 25.5% event rate). Conclusions: Immunoexpression of basal biomarkers, EGFR and CK5/6, is useful in predicting survival of TNBC patients. Integrated with Ki-67, tumor and nodal stages, combinatorial biomarker analysis provides a feasible clinical solution to stratify patient risks and help clinical decision-making with respect to selecting the appropriate therapies for individual patients.
    Full-text · Article · Mar 2016
    • "It should be noted that although TNBC and BLBC are not the same entity, practically, TNBC takes the place of BLBC in the application of clinical diagnosis and treatment because immunohistochemical characterization is more feasible compared to examination of the gene expression signature. Although many molecules are involved in the development of BLBCs, changes of the breast cancer susceptibility gene BRCA-related pathway are the key event leading to the formation of the BLBC phenotype [4, 16]. If loss of hormone receptor expression in breast cancer develops following the disruption of BRCA without HER2 amplification, it might result in triple-negative BLBC (TN-BLBC). "
    [Show abstract] [Hide abstract] ABSTRACT: Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC.
    Article · Jul 2015
    • "ER and/or PR receptors are expressed in a majority of breast cancers, and HER2 is amplified in approximately 20 % of cases [1] . Triple-negative breast cancer (TNBC) is an aggressive phenotype comprising 10–20 % of all breast cancers [1] . Triple-negative breast tumors lack ER, PR, and HER2 expression. "
    [Show abstract] [Hide abstract] ABSTRACT: Circulating tumor cells (CTCs) can be identified in approximately 25 % of stage I-III breast cancer patients; CTCs presence is a predictor of poor outcome in metastatic breast cancer, but little is known regarding the prognostic significance of CTCs in non-metastatic triple-negative breast cancer (TNBC) patients. The aim of this study was to determine whether CTCs predict worse outcome in non-metastatic TNBC patients. We evaluated CTCs in 113 patients with stages I-III TNBC at the time of definitive surgery. CTCs were assessed using the CellSearch System(®). Progression-free and overall survival were defined as time elapsed between date of diagnosis and either date of clinical disease progression, death, or last follow-up. Log-rank test and Cox regression analysis were used to determine associations of CTCs with progression-free and overall survival. The median follow-up was 40 months. CTCs were identified in 23/113 (20 %) of patients. No primary tumor characteristic or lymph node status predicted the presence of CTCs. The identification of ≥2 CTCs predicted shorter progression-free (log rank P ≤ 0.001; hazard ratio 8.30, 95 % CI 2.61-26.37) and overall survival (log rank P = 0.0004; hazard ratio 7.19, 95 % CI 1.98-26.06) versus survival for patients with <2 CTCs. Two or more CTCs predict shorter progression-free and overall survival in TNBC patients. Larger studies are needed to determine whether CTC assessment provides beneficial information that could be used in stratifying TNBC patients at increased risk for disease progression. Finally, CTCs characterization could facilitate the development of novel treatment approaches for TNBC.
    Full-text · Article · Aug 2014
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