The Pathology of Familial Breast Cancer: Histological Features of Cancers in Families Not Attributable to Mutations in BRCA1 or BRCA2

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2 , differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non- BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non- BRCA1 / 2 families. Breast cancers in non- BRCA1/2 families were of lower grade ( P = 0.0018), showed fewer mitoses ( P < 0.0001), less nuclear pleomorphism ( P = 0.0014), less lymphocytic infiltrate ( P < 0.0001), a lesser extent of the tumor with a continuous pushing margin ( P = 0.004), a lesser extent of the tumor composed of solid sheets of cells ( P = 0.0047), less necrosis ( P = 0.002), and were more likely to be of invasive lobular type ( P = 0.0003) than breast cancers arising in BRCA1 mutation carriers. In comparison with BRCA2 tumors, non- BRCA1 /2 tumors were lower grade ( P = 0.017) and exhibited less pleomorphism ( P = 0.01) and more tubule formation ( P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non- BRCA1 /2 tumors were of significantly lower grade ( P = 0.001), showed less pleomorphism ( P = 0.0002), and had a lower mitotic count ( P = 0.003). The results indicate that non- BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non- BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.