Douglas Macmillan

High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high‐throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well‐characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)‐artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c‐erbB‐2 protein overexpression. Two additional groups were characterized by high c‐erbB‐2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E‐cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.

Tubular Carcinoma of the Breast: Further Evidence to Support Its Excellent Prognosis

PURPOSE Although tubular carcinoma (TC) is known to have a favorable prognosis, it is still unknown whether this subtype represents a distinct type of breast carcinoma or whether it behaves like other low-grade luminal A-type breast carcinomas. METHODS In this study, we performed a retrospective analysis of a large well-characterized series of breast cancers (2,608 carcinomas) to assess the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast. Results When compared with grade 1 ductal carcinoma (n = 212), TC (n = 102) was more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (chi(2) = 13.25, P < .001) and breast cancer-specific survival (chi(2) = 8.8, P = .003). In this study, none of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type. CONCLUSION We conclude that the biologic behavior of TC is excellent and is more favorable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. In addition, patients with TC seem to have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management.

The prognostic significance of lymphovascular invasion in invasive breast carcinoma.

Although lymphovascular invasion (LVI) has been associated with a poor outcome in patients with breast cancer, it is not included in most internationally recognized staging systems, including the American Joint Committee on Cancer tumor, lymph node, metastasis (TNM) classification. This is mainly because it remains unclear whether the presence of LVI is an independent, high‐risk criterion in clinically relevant staging subgroups.

Encapsulated papillary carcinoma of the breast: an invasive tumor with excellent prognosis.

&NA;Papillary carcinoma (PC) of the breast, which accounts for 0.5% to 1% of breast cancer, is a distinct histologic subtype that is characterized by malignant epithelial proliferation supported by fibrovascular stalks. However, the classification of PC (whether they are in situ or invasive), its behavior, and management remain a matter of debate. MethodsIn this study, we reviewed 302 PCs including 247 pure PCs without coexisting conventional non-PCs collected from 3 institutions. This included 208 (84%) intracystic PCs (IPC), 30 (12%) solid PCs (SPC), and 9 (4%) papillary ductal carcinoma in situ (DCISs). In addition, previous studies of PC were reviewed. This included 339 pure PCs of a total of 521 PC patients. Clinical and outcome analyses were carried out to assess nature and behavior of these lesions and to determine their optimal outcome-based management. Results and ConclusionsSPC is more frequently associated with coexisting conventional invasive carcinoma than IPC (P<0.05). Although the majority of papillary DCIS and some cases of IPC and SPC (both called encapsulated PC) that are surrounded by an intact layer of myoepithelial cells are considered to be true in situ lesions, PC lacking a peripheral layer of myoepithelial cells can be regarded as a special type of invasive carcinoma associated with low incidence of stromal/skeletal muscle invasion, low frequency of lymph node metastasis (3%), and infrequent development of local or distant recurrence. These lesions are therefore characterized by indolent behavior and extremely favorable prognosis. Encapsulated PC can be treated with adequate local therapy. Routine use of adjuvant therapy, particularly chemotherapy, is clearly not appropriate in view of the very low risk of subsequent events. However, hormonal therapy may be indicated in certain cases such as recurrent PC.

Recommendations for the aesthetic evaluation of breast cancer conservative treatment

During the Turning Subjective Into Objective seminar held in Lisbon in May 2011, experts in the topic gathered to discuss the unsolved problems of aesthetic evaluation of breast-conserving treatment (BCT). The purpose of this study is to review the main methodological issues related to the aesthetic evaluation of BCT, to discuss currently used methods of evaluation and the lack of a gold standard, and to write a set of recommendations that can be used as guidance for the aesthetic evaluation of BCT.

The prognostic significance of early stage lymph node positivity in operable invasive breast carcinoma: number or stage

Aim The earlier detection of breast cancer through mammographic screening has resulted in a shift in stage distribution with patients who are node-positive tending to present with a lower number of positive lymph nodes (LN). This study aims to assess the prognostic value of absolute number of positive nodes in the pN1 TNM stage (1–3 positive LN) and whether the prognostic value of the number of nodes in this clinically important stage justifies its consideration in management decisions. Methods This study is based on a large and well-characterised consecutive series of operable breast cancer (3491 cases), treated according to standard protocols in a single institution, with a long-term follow-up. Results LN stages and the absolute number of LN are associated with both breast cancer specific survival (BCSS) and distant metastasis free survival (DMFS). In the pN1 stage, patients with three positive LN (14% of pN1) show shorter BCSS (HR=1.9, (95% CI 1.3 to 2.6)) and shorter DMFS (HR=2.2, (95% CI 1.6 to 2.9)) when compared with one and/or two positive nodes. This effect is noted in the whole series as well as in different subgroups based on tumour size (pT1c and pT2), histological grade (grade 2 and 3), vascular invasion and oestrogen receptor status (both positive and negative). Multivariable analyses showed that three positive LN, compared with one and two positive LN, are an independent predictor of shorter BCSS and DMFS. Conclusion The number of LN in the pN1 stage yielded potentially informative risk assignments with three positive LN providing an independent predictor of poorer outcome.