Estrogen Rececptor (ER)-Positive Breast Cancers in BRCA1 Mutation Carriers: Mutation-Related or Sporadic?

Abstract Background: Most invasive breast cancers (IBC) in BRCA1 mutation carriers are ER negative (-) and have a basal-like phenotype by expression array analysis. These tumors also have a characteristic constellation of histologic features including high grade, high mitotic rate, prominent lymphoid infiltrate, circumscribed or pushing margins, and geographic necrosis or a central fibrotic focus and typically lack ER, PR and HER2 expression (triple negative). ER positive (+) breast cancers also occur in women with germline BRCA1 mutations, but these tumors are less frequent and less well characterized. We previously reported that ER+ BRCA1-associated IBC show a wider spectrum of histologic types and grades than ER- cancers that occur in these patients. We raised the possibility that at least some ER+ BRCA1-associated IBC may be sporadic rather than mutation-related. However, it is not known how the features of these ER+ BRCA1-associated IBC compare with those of sporadic ER+ IBC.Design: To address this issue, we performed a case-control study of 60 ER+ BRCA1-associated IBC (cases) matched on age and year of diagnosis with 174 ER+ sporadic breast cancers (controls). Histologic sections of cases and controls were reviewed and the pathologic features were compared with each other as well with those of 85 ER- IBC that developed in BRCA1 mutation carriers.Results: Histologic features are summarized in the Table. When compared with ER+ controls, ER+ BRCA1-associated IBC were significantly more likely to be invasive ductal carcinomas (78% vs 58%;p=0.005), histologic grade 3 (47% vs 27%;p=0.006), and to have a high mitotic rate (29% vs 9%;p=0.0003). However, all of these features were significantly less frequent in ER+ BRCA1-associated IBC than in ER- BRCA1-associated IBC (p<0.001 for all comparisons). ER+ BRCA1-associated IBC and ER+ controls were not significantly different from each other with regard to the frequency of moderate-severe lymphoid infiltrate, the presence of geographic necrosis or the presence of a fibrotic focus, but the frequency of all of these features in both groups was significantly lower than in ER- BRCA1-associated IBC (p<0.01 for all comparisons). ER+ ControlsER+ BRCA1ER- BRCA1 N=174N=60N=85Histologic Type   Invasive Ductal58%78%96%Other42%22%4%Histologic Grade   327%47%96%1 or 273%53%4%Mitotic Rate   ≥10/10 HPF9%29%93%<10/10 HPF91%71%7%Tumor Margin   Invasive96%90%37%Pushing/Circumscribed4%10%63%Lymphoid Infiltrate   Moderate-Severe16%7%30%Other84%93%70%Fibrotic Focus   Present7%12%56%Absent93%88%44%Geographic Necrosis   Present2%5%50%Absent98%95%50% Conclusions: ER+ breast cancers arising in women with BRCA1 germline mutations appear to be pathologically "intermediate" between ER- BRCA1-associated breast cancers and ER+ sporadic breast cancers. This raises the possibility that some ER+ BRCA1-associated invasive breast cancers are mutation-related and others are sporadic or that there is a unique mechanism by which ER+ cancers develop in mutation carriers. Immunophenotypic and molecular studies are in progress to further characterize this interesting group of tumors.This work was supported by a grant from the Breast Cancer Research Foundation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5162.