HEREDITARY BREAST-CANCER - PATHOBIOLOGY, PROGNOSIS, AND BRCA1 AND BRCA2 GENE LINKAGE

BACKGROUND. The purpose of this investigation was to determine if ther e are pathobiologic differences between BRCA1-related and BRCA2-relate d 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-rel ated'' (26 families, 90 breast cancer pathology cases) or ''Other'' (2 6 families, 85 cases), in which most BRCA2 cases were likely to reside . Cases were compared with 187 predominantly non-HBC cases. Tumors wer e assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and availab le follow-up data were obtained.RESULTS. BRCA1-related and Other HBC p atients 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 BRCAl-related HBC had a lowe r diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA ind ex (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rat es (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, inc luding patients in two BRCA2-linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were indepe ndent of age. A nonsignificant trend toward better crude survival in b oth 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 canc er patients at large. Other HBC patients, despite neutral prognostic i ndicators, fared worse. CONCLUSIONS, BRCA1-related HBCs are more frequ ently aneuploid and have higher tumor cell proliferation rates compare d with Other HBC. Despite these adverse prognostic features, BRCA1-rel ated HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the ''Other'' HBC group ma y be associated with BRCA2 linkage. (C) 1996 American Cancer Society.