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

Abstract

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. Cancer 1996; 697‐709.