Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers. Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE-).Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE-tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE-tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival. Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (inTN tumors) to define BLBC.

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1 , or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1 , p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

Background: Basal-like breast cancer has been extensively characterized on the basis of gene expression profiles, but it is becoming increasingly common for these tumors to be defined on the basis of immunohistochemical (IHC) staining patterns, particularly in retrospective studies where material for expression profiling may not be available. The IHC pattern that best defines basal-like tumors is under investigation and various combinations of ER, PR, HER2-, CK5/6+ and EGFR+ have been tested.

Approximately 12% of breast cancers in the Ashkenazi Jewish population are attributable to mutations in the BRCA1 or BRCA2 gene. Genetic testing may be useful when Jewish women with breast cancer are diagnosed before age 50 years or have a close relative with ovarian or early-onset breast cancer. An association between breast and prostate cancers was observed in our study population.

Oral-contraceptive use may reduce the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene.

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor^and KIP1 (p27 Kip1)^negative tumors, with expression of cytokeratin 5/6, cyclin E,TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node^negative and^positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

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These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers.