The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients With Mutations in BRCA1 and BRCA2

Abstract

T h e P a t h o l o g y o f F a m i l i a l B r e a s t C a n c e r : P r e d i c t i v e V a l u e o f I m m u n o h i s t o c h e m i c a l M a r k e r s E s t r o g e n R e c e p t o r , P r o g e s t e r o n e R e c e p t o r , H E R -2 , a n d p 5 3 i n P a t i e n t s W i t h M u t a t i o n s i n B R C A 1 a n d B R C A 2By Sunil R. Lakhani, Marc J. van de Vijver, Jocelyne Jacquemier, Thomas J. Anderson, Peter P. Osin, Lesley McGuffog, and Douglas F. Easton for the Breast Cancer Linkage ConsortiumPurpose: The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes.Materials and Methods: Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein.Results: Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls.Conclusion: BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined.

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

“…On the other hand, the ERBB2 subtype comprised only of BRCAX tumors (four cases, B14%) (Table 1). This finding is in concordance with the low incidence of ERBB2 amplification in BRCA1/2 mutation carriers described before (Grushko et al, 2002;Lakhani et al, 2002;Palacios et al, 2003;Adem et al, 2004). A significant association was found between most of BRCAX samples (45%) and luminal A phenotype, as seen in previous analyses (Oldenburg et al, 2006;Honrado et al, 2007).…”

Body weight and risk of breast cancer in BRCA1/2 mutation carriers

“…The reduced risk of breast cancer after a BPSO in BRCA1/2 carriers [37] suggests that hormonal influences are important in carriers, despite the fact that the majority of BRCA1 associated breast cancers have negative estrogen receptor status [38]. In vitro studies indicate that estrogens may play a role in BRCA1-related carcinogenesis [39] and suggest that BRCA1 may function as part of a feedback mechanism to regulate estrogen signaling [40].…”

BRCA1 gene in breast cancer

“…The incidence of over-expression of the HER2/neu and cyclin D1 proteins is even higher (about 25-30% and 30-40%, respectively); and these two genes are thought to function as essential oncogenes during the development of a subset of human breast cancer cases (reviewed in Barnes and Gillett, 1998;Lohrisch and Piccart, 2001). In contrast, BRCA1 mutant breast cancers rarely exhibit amplification of the HER2/ neu or cyclin D1 genes and show a very low incidence of HER2/Neu and cyclin D1 protein over-expression (Vaziri et al, 2001;Grushko et al, 2002;Lakhani et al, 2002). In addition to immunophenotypic characteristics, analysis of human breast cancers by DNA microarray analyses suggest a characteristic pattern of gene expression alterations in BRCA1 vs. BRCA2 cancers (Hedenfalk et al, 2001;van't Veer et al, 2002).…”

“…At this point, it is conjectural whether functional inactivation of BRCA1 through HER2/Neu and other pathways leading to c-Akt activation occurs and is of pathophysiologic importance during breast cancer progression. However, in contrast to sporadic tumors, BRCA1 mutant breast cancers show a very low incidence of HER2/Neu positivity, suggesting a lack of selection pressure for HER2/ Neu expression in this setting (Grushko et al, 2002;Lakhani et al, 2002).…”