Inhibited, trapped or adducted: the optimal selective synthetic lethal mix for BRCAness

BRCA1 and BRCA2 proteins have important roles in DNA replication fork stabilisation and a specialised form of DNA repair termed homologous recombination (HR) [1]. They are components of the Fanconi anaemia protein network [2, 3]. A hallmark of deficiency in this network is sensitivity to DNA crosslinks induced by platinum agents and mitomycin C [4, 5]. Historically platinum chemotherapy has only shown modest activity in advanced breast cancer excepting those with chemotherapy naïve disease [6, 7] but recent uncontrolled studies have suggested significant activity for single agent platinum agents in BRCA1 and BRCA2 germline mutation carriers [8]. The TNT phase III trial has recently reported positive interaction between the presence of germline mutation but not epigenetic change in these genes and specific treatment effect; with a doubling of response to carboplatin but no effect of mutation on standard of care taxane response in advanced breast cancer [9].