Hereditary Breast Cancer: Part II. Management of Hereditary Breast Cancer: Implications of Molecular Genetics and Pathology

Abstract:  Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation‐positive breast cancers wherein those with BRCA1 mutations are frequently estrogen receptor (ER)‐negative in contrast to BRCA2 mutations which are more frequently ER‐positive; therein, significant differences exist with respect to anti‐estrogen therapy which will be more amenable to BRCA2 versus BRCA1 mutation carriers manifesting breast cancer. In turn, tumors that are negative for ER, PR, and Her2‐neu, often referred to as “triple negative” tumors, may also harbor a unique basal‐like gene expression profile and are characterized by poor prognosis wherein endocrine and/or Her2‐neu‐targeted therapies are not effective treatment options. A further confounder pertains to the lifetime risk for ovarian cancer, which differs strikingly between BRCA1 mutation carriers, who show a 40–60% lifetime risk, and their BRCA2 counterparts, who carry a lifetime risk of approximately 12–15% for ovarian cancer. It is clear that as we learn more about the biology and the molecular aspects of hereditary forms of breast cancer, it will be compelling for the clinician to integrate this knowledge with pharmacologic, radiologic, and surgical treatment options for these high‐risk patients.