BRCA 1 / 2 - Associated and Sporadic Breast Cancers : Fellow Travelers or Not ? Perspective on

How useful are hereditary cancer susceptibility syndromes for modeling sporadic cancers? If the biology of cancers developing within hereditary syndromes follows the same pathways to malignancy as does a substantial proportion of sporadic cancers, then prevention trials focused on hereditary high-risk individuals can lead to important gains in the sporadic setting. McKusick struggled with this fundamental issue of genetics in his classic 1969 article “On lumpers and splitters, or the nosology of genetic disease” (1). One of the first large studies to compare BRCA1/2-associated with sporadic breast cancers was reported by Lakhani et al. on behalf of the Breast Cancer Linkage Consortium. In univariate analyses, they found relatively less ductal carcinoma in situ (DCIS), a common precursor of sporadic invasive ductal cancers, and less lobular carcinoma in situ (LCIS), a histologic marker of increased breast cancer risk, in association with invasive breast cancer in BRCA1 or BRCA2 mutation carriers than in association with sporadic cancers (2). In the multivariate analysis, the differences for both DCIS and LCIS remained significant only for BRCA1-associated tumors. Tumors in women with BRCA1 mutations were more likely than were sporadic breast cancers to lack expression of estrogen receptors (ER) and progesterone receptors, to be high grade, and to have “pushing margins.” The BRCA1 tumors were also more often node negative than would be expected for tumors of their size, but without the relatively improved prognosis that node-negative status generally confers (2). In contrast, BRCA2-associated tumors could not be distinguished from the majority of sporadic breast cancers. Perou and colleagues made the fundamental observation that breast cancer can be reliably divided by molecular profiling into at least five subtypes (3). This observation has had a significant effect on the field. Up to 80% of BRCA1-associated breast cancers cluster in a basal-like gene expression pattern, or subtype, and share this subtype's characteristic absence of expression of ER and progesterone receptor (4, 5). In contrast, ∼80% of BRCA2-associated breast cancers cluster in a luminal gene expression pattern and share this subtype's characteristic expression of ER and progesterone receptor (6). Neither BRCA1nor BRCA2-associated breast cancers have amplified human epidermal growth factor receptor-2 as a rule, although all breast cancer subtypes can occur in the setting of either mutation (2). Given that BRCA1 and BRCA2 proteins are thought