Beyond failure of endocrine-based therapies in HR+/HER2 negative advanced breast cancer: What before chemotherapy? A glimpse into the future

Despite the impressive improvements achieved by endocrine therapy and CDK4/6 inhibitors (CDK4/6i) and the forthcoming availability of alternative endocrine manipulations and targeted therapies, hormone-receptor positive/HER2 negative (HR+/HER2-) advanced breast cancer (ABC) is almost inevitably destined to become endocrine- refractory. At this time chemotherapy has been recently challenged and partly replaced by new targeted options as antibody-drug conjugated (ADCs). Trastuzumab-deruxtecan has been proven meaningfully superior to chemotherapy either in 1st and later lines after progression to CDK4/6i in HER2-low ABC and results with other ADCs as Sacituzumab Govitecan and Datopotamab-deruxtecan are promising, but the definition of cross-resistance between these drugs sharing either antibody or payload is crucial before implementing them in a useful sequence. While PARP inhibitors are the standard 2nd line in patients with gBRCA mutation, it is not still known whether patients with mutations of PALB2 or of other homologous recombinant defect (HRD)-related genes will benefit of the same treatment. On the other hand, the results obtained with immune checkpoint inhibitors (ICIs) in HR+ /HER2-ABC contrarily to the early setting are disappointing up to now, but investigations of ICIs in combination with other targeted drugs which may increase immune response and the search for better markers of activity are under way. Moreover the anticipation in upfront treatment of ADCs or PARPi in patients with features of putative endocrine resistance and/or of less sensitiviy to CDK4/6i and the choice of therapy in patients recurring during or soon after adjuvant CDK4/6i and olaparib represent further challenges for the future.