Hereditary breast cancer: Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage

BACKGROUND. The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1-related and BRCA2-related hereditary breast cancer (HBC) and non-HBC. METHODS. On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either 'BRCA1-related' (26 families, 90 breast cancer pathology cases) or 'Other' (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained. RESULTS. BRCA1- related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P <0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR] = 4.42; P = 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P <0.0001). Other HBC patients, including patients in two BRCA2-linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age and stage- dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS. BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1- related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the 'Other' HBC group may be associated with BRCA2 linkage.