Pathology and heredity of breast cancer in younger women

The pathology of early-age onset breast cancer is considered here from three perspectives: 1) benign proliferative disease, 2) the cancers themselves, and 3) familial and hereditary breast cancer. Hereditary breast cancer, a subset of familial breast cancer featuring a strong autosomal dominant pedigree pattern and multiple primary cancers, has a strong predilection for younger women, accounting for about one half of breast cancers under age 30. With respect to benign proliferative disease, the increased relative risk of breast cancer associated with proliferative disease with atypia, about fourfold to fivefold for all ages, is doubled by the presence of a family history of breast cancer and amplified by young age. With respect to the carcinomas, the relative incidences of medullary carcinoma and ductal carcinoma in situ are increased in young women, while lobular and tubular carcinomas are decreased. Invasive breast cancer is higher grade and more proliferative in younger women, as measured by thymidine-labeling index, DNA flow cytometric S-phase fraction, and proliferation-associated proteins. The increased fraction of ductal carcinoma in situ and higher grade invasive cancers may help to account, respectively, for increased recurrence rates with conservative therapy, and more aggressive natural history in younger women. Familial breast cancers show trends for increased medullary type, but the effect is not independent of age. Weak associations of family history with tubular carcinoma have been reported, but data for associations with lobular carcinoma in situ and invasive lobular carcinoma are conflicting. Hereditary breast cancer as a class has higher tumor proliferation rates, an effect independent of age. Knowledge of the pathology and biomarker characteristics of BRCA1 gene-linked hereditary breast cancers, which account for a substantial fraction of breast cancers in younger women, should shed light on the nature of the responsible gene(s) and guide approaches to therapy and prophylaxis.