EGFR in triple negative breast carcinoma: significance of protein expression and high gene copy number.

BACKGROUND: As up to 60 % of triple negative breast carcinomas are reported to express EGFR, the receptor is a potential target for biological therapy. The exact role EGFR plays in triple negative breast carcinoma (TNBC) biology, however, remains uncertain. We aimed to discover associations between EGFR protein expression as well as gene copy number changes and clinico-pathologic TNBC characteristics. METHODS: We performed an immunohistochemical and dual in situ hybridization study on a set of 52 archive cases of pre-treatment TNBC in order to detect EGFR protein expression and EGFR gene copy number changes. Clinico-pathologic and follow up data were compared with EGFR status for determining possible links between EGFR and tumor characteristics and/or behavior. RESULTS: 88.5 % of our cases showed EGFR expression. We found no significant links between EGFR expression and tumor grade (p = 0.204), lymph node status (p = 0.514) or p53 status (p = 0.078). Though EGFR gene amplification (EGFR gene:chromosome 7 ratio 2) was rare (1.9 % of all cases), a high gene copy number ( 4 copies per cell) was observed in 15.4 % of all cases. High EGFR gene copy number appeared to be more common in non-ductal, special-type carcinomas than in ductal carcinomas. Neither EGFR expression nor EGFR gene copy number was associated with event-free survival. CONCLUSION: EGFR changes do not appear to be associated with markers of aggressive behavior in TNBC. Further studies with much larger sample sizes are essential in understanding the role EGFR plays in TNBC biology in order to identify the patients that could benefit from EGFR targeted therapy.

[Hopes and pitfalls of the molecular classification of breast cancer]. / Nadeje a úskalí molekulární klasifikace karcinomu prsu.

Traditional histopathological diagnosis of breast cancer has been extended in recent years through the results of additional methods. Today, the results of the detection of hormone receptors, HER-2/neu, and Ki67 antigen are thus an integral part of the histopathological diagnosis. A critical factor for the success of these tests is the fulfillment of pre-analytical phase conditions - i.e. optimal fixation, as well as taking into account the heterogeneous nature of the neoplastic population. In addition to the above-mentioned markers - which have become a routine practice in recent years, there are many efforts to include the molecular characteristics of tumors both in tumor classification as well as in the prediction of results of cancer treatment. Most of the work is based on the use of gene expression profiles. On the basis of the detection of increased or decreased expression of a large number of genes, it is possible to find a set of multiple genes correlating with the biological behavior of the tumor. Using this approach, four basic subgroups of breast cancer have been identified - luminal, basal-like, HER-2 enriched and normal gland-like. Over the course of time, the number of molecular categories has expanded - originally a homogenous group of luminal cancers has been subclassified into the luminal A, B and C. Also within basal-like carcinomas additional subgroups have been identified. However, the results of studies dealing with the analysis of gene expression profiles suggest that our understanding of the biology of breast cancer is far from being complete. The individual categories are defined differently in various publications and thus the comparison of the results of these studies is very difficult. Another approach for the molecular classification of breast cancer is the immunohistochemical detection of various proteins used as a surrogate marker instead of the detection of the mRNA of individual genes. The advantage of this approach is the possibility to use even archive material, as well as much lower costs. On the other hand, its main limitation is the inability of parallel detection of thousands of markers, unlike in genomic profiling. The results of molecular classification are, however, not fundamentally surprising. The fact that breast cancer tumor stem cells can differentiate towards myoepithelial (or basal) and luminal cells has been known for a long time. These two lines of differentiation are - among others - characterized by differential expression of cytoskeletal proteins as well as of other molecules. These findings have been confirmed by the results of molecular studies - either those based on gene expression profiling or immunohistochemical ones. Research results in gene expression profiling have relatively quickly translated into clinical practice. At present, several commercially available certified tests serve as a complementary source of information for decisions about clinical treatment.

Predicting left atrial thrombi in atrial fibrillation.

BACKGROUND: The aim of the study was to determine whether CHADS(2) score is predictive of left atrial appendage thrombus (LAAT) in nonvalvular atrial fibrillation (AF). Strategies for effective stroke prevention in AF require tools capable of identifying those patients at greatest risk for embolization of LAAT and most likely to benefit from warfarin. Nearly half of strokes in AF are due to noncardioembolic mechanisms for which antiplatelet therapy would be more appropriate. Previous attempts to develop such tools have been limited by including patients without proven cardioembolism. METHODS: Nonanticoagulated, nonvalvular AF patients with (cases) or without (controls) LAAT by transesophageal echocardiography were identified using Mayo Clinic Echocardiography and Cardioversion Unit Databases (Rochester, MN). Type and duration of AF, CHADS(2) score, and echocardiography measures were compared to determine variables predictive of LAAT. RESULTS: The CHADS(2) score was significantly higher for cases (n = 110, mean +/- SD 2.8 +/- 1.6) compared to controls (n = 387, 1.6 +/- 1.3). By multivariate analysis, independent predictors of LAAT included heart failure (HR 5.78, P < 0001), prior stroke/transient ischemic attack (HR 3.94, P < .0001), diabetes mellitus (HR 1.98, P = .015), permanent AF (HR 3.02, P < .05), AF duration (HR 2.24, P < .05), and spontaneous echocardiographic contrast (HR 4.35, P = .005). Using these elements, a new scoring system provided cleaner case-control separation (C-index 0.90) and higher predictive power compared to CHADS(2) (C-index 0.71). CONCLUSIONS: The CHADS(2) score predicts the presence of LAAT in AF patients. Some, but not all, variables within this score are predictive of LAAT. By including only echo and clinical variables predictive of LAAT, our novel scoring system better identified those AF patients at greatest cardioembolic risk.