Molecular profile of ductal carcinoma in situ of the breast in BRCA1 and BRCA2 germline mutation carriers

Abstract

Ductal carcinoma in situ (DCIS) is an established late precursor of sporadic invasive breast cancer and to a large extent parallels its invasive counterpart with respect to molecular changes and immunophenotype. Invasive breast cancers in germline BRCA1 and BRCA2 mutation carriers have a distinct “basal” respectively luminal immunophenotype, but immunophenotype of their precursor lesions has hardly been studied, which was the aim of this study.

DCIS lesions of 25 proven BRCA1 and 9 BRCA2 germline mutation carriers and their respectively 22 and 6 accompanying invasive lesions were stained by immunohistochemistry for ER, PR, HER-2/neu, CK5/6, CK14, EGFR and Ki67.

DCIS lesions in BRCA1 mutation carriers were mostly of the “basal” molecular type with low ER/PR/HER2 expression, while they frequently expressed CK5/6, CK14 and EGFR, were mostly grade 3 and highly proliferative. DCIS lesions in BRCA2 mutation carriers were mostly of “Luminal” molecular type with frequent expression of ER/PR, and infrequent expression of CK5/6, CK14 and EGFR, were mostly grade 3 and showed low proliferation. There was in both BRCA1 and BRCA2 mutation carriers a high concordance between DCIS lesions and their concomitant invasive counterpart with regard to expression of individual markers as well as “molecular” subtype.

In conclusion, although the number of cases studied was low, DCIS lesions in BRCA1 and BRCA2 mutations carriers are usually of the Basal respectively Luminal molecular type, similar to their accompanying invasive cancers, thereby providing evidence that DCIS is a direct precursor lesion in these hereditary predisposed patients. This also suggests that crucial carcinogenetic events leading to these phenotypes in hereditary predisposed patients occur before the stage of invasion.