Role of endocrine therapy in combination with anti-HER2 therapy and CDK4/6 inhibitors in hormone receptor positive/HER2 positive breast cancer

In clinical practice, patients with advanced ER+/HER2+ BC are treated with a combination of anti-HER2 and chemotherapy as first choice but it is clear that a proportion of these derive prolonged benefit from the combination of hormonal therapy (HT) and anti-HER2 therapy (AH2T). Preclinical evidence from cellular models of BC indicates that ER and HER2 pathways are strictly interdependent and that targeting both pathways in ER+/HER2+ BC might be an effective therapeutic strategy; few trials investigated this combination showing a significant, albeit modest, clinical improvement. CDK4/6 pathway acts downstream of both the ER and HER2 pathways. CDK4/6 inhibitors (PD)have shown synergistic activity with HT or AH2T but data on the combination of PD with both HT and AH2T in ER+/HER2+ BC are lacking. PD activity is dependent on an intact RB pathway; therefore we analyzed whether Cyclin D/Rb/E2F pathway might help discriminating the subgroup of ER+/HER2+ BC resistant to PD therapy. We developed a gene expression signature of Rb-loss-of-function, the RBsig, that included a final set of 87 genes that is predictive of resistance to PD in BC cell lines. An in-silico analisys on a meta-dataset of neoadjuvant trials has also shown a good performance of RBsig in prediction of a better response to neoadjuvant chemotherapy. These data suggest RBsig as a potential marker for identifying patients with differential benefit from chemotherapy or HT+PD, both in combination with AH2T.