Clinical management of women with genomic BRCA1 and BRCA2 mutations

Purpose. There is increasing evidence that BRCA1 and BRCA2 associated tumor s may differ from sporadic cancers. The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associat ed tumors, and possible risk reduction strategies in women with these delet erious mutations. Design and methods. We conducted an extensive literature search of all publ ished articles (including Medline) on preclinical data on the function of B RCA1 and BRCA2, associated tumor pathology, and the clinical management for both unaffected carriers and affected patients. Results. BRCA1 and BRCA2 are likely to act as tumor suppressor genes, and t ogether with RAD51 operate in a common DNA damage response pathway implicat ed in double-strand repair. Breast cancers associated with BRCA1 are freque ntly of a higher grade, steroid hormone receptor negative, and appear to ha ve a higher proportion of atypical or typical medullary subtype. Conversely , BRCA2 associated breast cancers do not differ significantly from sporadic cancers. No special tumor phenotype has been ascribed to BRCA1 or BRCA2 as sociated ovarian cancers. Guidelines for risk reduction strategies for the high risk unaffected carrier have been recommended by expert panels in the USA and Europe. Lifestyle changes, multi-modality screening, chemopreventio n, and prophylactic oophorectomy and mastectomy, with their possible benefi ts and attendant risks are described. Finally, locoregional and systemic tr eatment in breast and ovarian cancers associated with these mutations, and differences between these and sporadic cancers are discussed. Conclusions. Although the incidence of breast or ovarian cancers that can b e attributed to BRCA1 or BRCA2 mutations account for less than 5% of all ca ncers, these cancers may differ from sporadic cases in terms of tumor biolo gy and phenotype. These differences may impact directly on clinical managem ent of breast and ovarian cancer patients, and their relatives. Further rec ommendations of these patients are constantly changing as new information e merges on the clinical behavior of these cancers.