PATHOLOGY OF FAMILIAL BREAST-CANCER - DIFFERENCES BETWEEN BREAST CANCERS IN CARRIERS OF BRCA1 OR BRCA2 MUTATIONS AND SPORADIC CASES

Background A few breast cancer cases are attributable to a hereditary predisposition to the disease. We aimed to compare the histological fe atures of breast cancer in women carrying mutations in the susceptibil ity genes BRCA1 and BRCA2 with controls unselected for family history. Methods The morphological characteristics of specimens from 440 patie nts with familiar breast cancer, including 118 in carriers of BRCA1 mu tations and 78 in carriers of BRCA2 mutations, were compared with thos e from 547 age-matched controls, unselected for family history, by sev en pathologists. Findings Cancers in carriers of BRCA1 (p<0.0001) and BRCA2 mutations (p=0.04) were, on average, of a higher overall grade t han in controls, For example, the proportions in grade 3 were 66% of 1 39, 41% of 58 and 36% of 368 specimens, respectively. However, when th e three grade indices were considered independently, breast cancers in BRCA1-mutation carriers showed more pleomorphism (p=0.006), a higher mitotic count (p<0.0001), and less tubule formation than controls (p=0 .006), whereas cancers in BRCA2-mutation carriers showed less tubule f ormation (p=0.003), but no difference in pleomorphism or mitotic count , The occurrence of invasive lobular carcinoma and invasive ductal car cinoma was not significantly different between carriers of BRCA1 or BR CA2 mutations and controls. Medullary or atypical medullary carcinoma was, however, found more often in BRCA1 (13%, p<0.0001) than in BRCA2- mutation carriers (3%) or controls (2%). Tubular carcinoma was less co mmon in BRCA2-mutation carriers. The few mucoid carcinomas were all in familiar cases, Carriers of BRCA1 mutations showed less ductal carcin oma in situ around the invasive lesion than controls (41 vs 56%, p=0.0 01). Lobular carcinoma in situ was less common in familiar cancers (p= 0.013), but differences were not significant for BRCA1-mutations or BR CA2-mutation carriers, separately. Interpretation The histology of bre ast cancers in predisposed women differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings suggest that breast cancer due to BR CA1, has a different natural history to BRCA2 or apparently sporadic d isease, which may have implications for screening and management.