Islam E Elkholi, William D Foulkes
More than three decades have passed since the identification of BRCA1 as the first breast cancer susceptibility gene (BCSG). Since then, substantial progress has been made in pinpointing BCSGs and estimating the associated risk of developing BC. Simultaneously, new challenges and open questions have also emerged, such as the potential associations between BCSGs and metastasis in BC patients. In this review, we discuss available data from clinical and experimental studies assessing the association between germline pathogenic variants (GPVs) in BCSGs and metastasis pattern. To help guide future studies addressing the current knowledge gaps, the review outlines clinical outcomes and four variables to be considered: 1) age and ethnicity; 2) clinical, molecular, and pathological characteristics; 3) treatment response; and 4) the specificity of BSCG variants. The synthesis of data from mouse models and human-derived materials supports a speculative model where the crosstalk between BC cells and the microenvironment defines the metastasis pattern in carriers of GPVs in BCSGs. An experimental framework is proposed for testing this model in future studies that could parallel comprehensive clinical studies addressing the outlined clinical outcomes and variables.