Non-BRCA familial breast cancer: review of reported pathology and molecular findings

The majority of women evaluated for a clinical concern of possible hereditary breast cancer syndromes have no identified pathogenic variants in genes predisposing them to breast cancer. Non-BRCA1- or BRCA2-related familial breast cancer, also called 'BRCAX', thus comprises a sizeable proportion of familial breast cancer but it is poorly understood. In this study, we reviewed 14 studies on histopathology and molecular studies of BRCAX to determine if there were differences between 'sporadic' breast cancers and compared to cancers arising in women harbouring variants in known cancer predisposition genes. Across available literature, there was inconsistency on inclusion and exclusion criteria, reported parameters, and use of controls. Cohorts were small, and while several studies reported findings that appeared to distinguish the BRCAX cases from sporadic and/or gene-positive controls, no findings were reported in more than one study. To determine whether the BRCAX families might still contain important genetic subsets awaiting discovery will require prospective ascertainment of a large number of women with familial breast cancer who are screened for all currently established predisposition genes, whose tumours are assessed for multiple parameters in a uniform manner, and in which controls (BRCA1/2+ and non-familial 'sporadic' cases) are collected from the same population.