Specific chromosomal alterations have been related to breast carcinoma risk as a result of the identification of mutations in the BRCA1 gene on the long arm of chromosome 17^2,3,4 and in the BRCA2 gene located on chromosome 13.⁵ BRCA1 is a pleiotropic DNA damage response protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination.⁶ The proteins expressed by these genes function together during DNA repair to shield the genome from double-strand DNA damage. Various types of mutations in different segments of these genes have been identified.^5,6,7,8,9 The lifetime risk of developing breast carcinoma as a result of a BRCA1 mutation has been reported in various studies to be 56% to nearly 90%.^10,11 A slightly lower risk of breast carcinoma associated with BRCA2 mutations has been reported to be 37% to 84%.^11,12 BRCA1 may account for up to 45% of cases of hereditary breast carcinoma as well as nearly 90% of patients with combined breast and ovarian carcinoma.^13,14 The lifetime risk of ovarian carcinoma attributed to BRCA1 mutations is about 45%.¹⁵

The risks associated with BRCA1 and BRCA2 mutations appear to be modified by other genes or genetic alterations, as suggested by a study of genotypes of the androgen receptor (AR).¹⁶ Reproductive factors such as parity and age of first live birth, well-established epidemiologic indicators of breast carcinoma risk, have been shown to interact with familial risk to a slight degree.¹⁷ Parity may influence BRCA1- associated breast carcinoma risk.¹⁸ Exogenous factors such as cigarette smoking and oral contraceptive hormones have also been identified as factors that might modify BRCA1 and/or BRCA2 penetrance.^19,20,21 Dietary, environmental, and other as yet undefined factors appear to influence the penetrance of BRCA1 and BRCA2 in individual women. This is illustrated by data from a study of 403 BRCA1 mutation carriers summarized by Rebbeck.²² Breast carcinoma alone had been diagnosed in 209 (52%) women with a mean age at diagnosis of 42.6 years, but there was a broad range of age (19 to 96 years). Among the other women, 40 (10%) developed ovarian carcinoma, and 22 (5%) had ovarian and breast carcinoma. Nine (7%) of the remaining 132 women who had not developed breast or ovarian carcinoma were older than 70 years. The relationship between particular BRCA1 and BRCA2 mutations and susceptibility to breast or ovarian carcinoma or to specific types of carcinoma are under investigation.^23,24

In the clinical screening situation, 16% of women who had breast carcinoma and reported a family history of breast and/or ovarian carcinoma were found to have detectable
BRCA1 mutations.²⁵ BRCA1 mutations were found in 7% women with breast carcinoma and a positive family history. No association was detected between bilateral breast carcinoma in the patient or the number of breast carcinomas in a family and the presence of a BRCA1 mutation. These data add further support to the notion that BRCA mutations have variable penetrance and also suggest that alterations of other BRCA gene sites or entirely different genes are responsible for breast carcinoma in some women with a positive family history.

Various reports indicate that BRCA1-associated breast carcinomas have distinctive pathologic features, although they are not unique to these patients.^26,27,28,29 The intraductal and infiltrating duct carcinomas are typically poorly differentiated (grade 3) and have high-grade nuclei.^30,31,32 A relatively high frequency of medullary carcinomas and of ductal carcinomas with medullary features has been reported in these patients.³⁰ The tumors are also characterized by high proliferative rates when studied by flow cytometry or by MIB-1 immunohistochemistry (IHC).^26,28 BRCA1-associated breast carcinomas typically do not express estrogen receptor (ER)²⁶ or human epidermal growth factor 2/neu (HER2/neu) receptor,²⁶ but they exhibit p53 nuclear reactivity.²⁶ Angiogenesis may also be enhanced in BRCA1-associated carcinomas.²⁶

A study from the Breast Cancer Linkage Consortium examined breast carcinomas from 118 BRCA1 patients, 78 BRCA2 patients, 244 non-BRCA familial carcinoma patients, and 547 controls.³¹ BRCA1 and BRCA2 tumors had significantly higher grade than control tumors. Medullary carcinoma was significantly more frequent in the BRCA1 than in the BRCA2 and control groups. Lobular carcinoma in situ (LCIS) was significantly less frequent in the entire familial carcinoma group than in the controls, but there was not a significant difference between BRCA1 and BRCA2 mutation carriers in the frequency of LCIS. BRCA1 carcinomas had significantly higher mitotic counts and greater pleomorphism than BRCA2 or control tumors.

In a study of women with carcinomas diagnosed before age 40, Armes et al.³⁰ found that carcinomas associated with BRCA1 mutations had significantly higher mitotic rates than carcinomas associated with BRCA2 mutations and control tumors from women without BRCA mutations. BRCA1-related carcinomas were also more likely to have necrosis. No differences were observed between the three groups with regard to tumor size, the frequency of or number of nodal metastases, or the presence of lymphatic invasion in the breast.

Using tissue microarrays (TMAs), Palacios et al.³² compared the immunohistochemical expression of a panel of markers in BRCA1-associated (n = 20) and BRCA2- associated (n = 18) breast carcinomas to the expression of these markers in breast carcinomas negative for BRCA1 and BRCA2 mutations (n = 37). In this study of relatively few cases, there was no statistically significant difference in the distribution of histologic types between the three groups. Non-BRCA1 and non-BRCA2 carcinomas were characterized by lower grade, more tubule formation, less nuclear pleomorphism, and fewer mitoses than the combined group of BRCA1 or BRCA2 mutation-associated carcinomas. When compared with BRCA1 mutation tumors alone, the non-BRCA1 or non-BRCA2 mutation tumors had significantly less nuclear pleomorphism, fewer mitoses, and more tubule formation. When compared with BRCA2 mutation tumors, the non-BRCA1 or non-BRCA2 tumors
were only significantly different in having fewer mitoses. Non-BRCA1 or non-BRCA2 mutation tumors had significantly more frequent expression of ER, progesterone receptor (PR), and bcl-2 and less frequent expression of p53 than BRCA1 mutation-associated carcinomas. They also had a lower proliferation index with the Ki67 immunostain. Non-BRCA1 or non-BRCA2 mutation tumors differed from those with BRCA2 mutations only in having a low Ki67 index. There were no significant differences in the distribution of HER2/neu