Introduction: Many breast cancer (BC) patients develop the disease bilaterally. The emergence of two tumors in the same host is unlikely to be a random co-incidence: bilateral BC (biBC) patients are enriched by women who are susceptible to this disease due to genetic or non-genetic factors.Areas covered: Data on molecular pathogenesis and translational aspects of biBC research are summarized.Expert opinion: Studies on concordant and discordant molecular events occurring in paired tumors resemble twin studies, as they help to reveal core components of BC pathogenesis and to analyze interactions between host factors and tumor phenotype. Mutation profiling of biBC pairs suggested that most biBCs are clonally independent malignancies, although some instances of presumably contralateral metastatic spread were shown as well. Many biBCs, especially synchronous ones, demonstrate the similarity of essential tumor characteristics, which can be explained by sharing of genetic background, hormonal milieu, metabolic environment, and external exposures. biBC is strongly associated with BC-predisposing germline mutations; therefore, clinical management of biBC patients must include comprehensive genetic testing. Some contralateral metachronous BCs demonstrate high-level microsatellite instability (MSI-H). MSI-H is sometimes observed in radiation- and chemotherapy-induced tumors; therefore, it is possible that some second BCs are causally related to the therapy applied for the first cancer. MSI-H tumors are responsive to immune checkpoint blockade; hence, MSI-H analysis is advisable for biBC molecular testing. Systematic cataloging of biBC molecular portraits is likely to provide valuable information on fundamental aspects of cancer pathogenesis.
Keywords: BRCA1; BRCA2; Bilateral breast cancer; hereditary cancer syndromes; molecular portraits; review; twins.