BACKGROUND.: Triple‐negative breast cancer (estrogen receptor‐negative, progesterone receptor‐negative, and HER2‐negative) is a high risk breast cancer that lacks the benefit of specific therapy that targets these proteins.METHODS.: In this study, the authors examined a large and well characterized series of invasive breast carcinoma (n = 1944) with a long‐term clinical follow‐up (median, 56 months) by using tissue microarray. The series were also stained with concurrent immunohistochemical prognostic panels (estrogen receptor, progesterone receptor, HER‐2, androgen receptor, epidermal growth factor receptor (EGFR), P‐cadherin, E‐cadherin, and basal (CK5/6, CK14), and p53), to characterize this specific subgroup of breast cancer and to identify prognostic markers that can identify tumors with more aggressive behavior.RESULTS.: Of informative cases, 16.3% were of the triple‐negative phenotype. The majority of these tumors were grade 3, ductal/no‐specific‐type carcinomas. There were positive associations with larger size, pushing margins, poorer Nottingham Prognostic Index, development of recurrence and distant metastasis, and poorer outcome. In addition, associations were found with loss of expression of androgen receptor and E‐cadherin, and positive expression of basal cytokeratins (basal phenotype), P‐cadherin, p53, and EGFR. In all tumors, tumor size, lymph node stage, and androgen receptor were the most useful prognostic markers. In the lymph node‐positive subgroup, both size and androgen receptor retained their prognostic significance. However, in the lymph node‐negative tumors, basal phenotype was the sole prognostic marker identified in this subgroup. Other parameters including age, histological grade, tumor size, vascular invasion or other biomarkers included in the current study were not significant.CONCLUSIONS.: The authors concluded that assessment of androgen receptor and basal phenotype, in addition to the established pathologic variables, mainly lymph node status and tumor size, can be used to select high‐risk and low‐risk patients at the time of primary surgery and can provide valuable information on treatment options in these triple‐negative tumors. Cancer 2007. © 2006 American Cancer Society

The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is characterized by an expression signature similar to that of the basal/myoepithelial cells of the breast and is reported to have transcriptomic characteristics similar to those of tumors arising in BRCA1 germline mutation carriers. They are associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 (“triple-negative” phenotype). Therefore, patients with basal-like cancers are unlikely to benefit from currently available targeted systemic therapy. Although basal-like tumors are characterized by distinctive morphologic, genetic, immunophenotypic, and clinical features, neither an accepted consensus on routine clinical identification and definition of this aggressive subtype of breast cancer nor a way of systematically classifying this complex group of tumors has been described. Different definitions are, therefore, likely to produce variable and contradictory results that may hamper consistent identification and development of treatment strategies for these tumors. In this review, we discuss definition, heterogeneity, morphologic spectrum, relation to BRCA1, and clinical significance of this important class of breast cancer.

T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37−0.79] versus CD8−negative tumours (HR = 0.87; 95% CI 0.55–1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P_{heterogeneity} = 0.04) and approached significance in imputed data (P_{heterogeneity} = 0.1). The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [ supplementary Figure S1, available at Annals of Oncology online ] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NCT00003577.