For patients who have progressed on or have exhausted frontline treatments for advanced disease (ie, endocrine therapy plus CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib), standard options include continuing endocrine-based therapies, cytotoxic chemotherapy, or antibody-drug conjugates (ADCs). When endocrine-based therapy is continued, it often involves switching from an aromatase inhibitor to fulvestrant, or from fulvestrant to exemestane, usually in combination with alpelisib for those tumors that harbor activating PIK3CA mutations (or the mTOR inhibitor everolimus if there is no such mutation). Another option would be monotherapy with elecestrant, especially in patients who are circulating tumor DNA assay positive for an ESR1 mutation and had response to or stable disease on a CDK4/6 inhibitor for at least 1 year. For those who require cytotoxic therapy, oral capecitabine is a commonly used option that can be effective and is generally well tolerated. A distinguishing feature of the new ADCs, such as trastuzumab deruxtecan and sacituzumab govitecan, has been their impact on improving overall survival in patients who have had progressive disease after prior endocrine therapy, CDK4/6 inhibitors, and chemotherapy.

Another evolving concept is being able to therapeutically target tumors that do not have HER2 gene amplification and high levels of protein expression, which has been called HER2-low disease and is defined by an HER2 immunohistochemistry (IHC) score of IHC1+ or IHC2+. In the past, HER2-low breast cancer was often treated much like HER2- breast cancer; however, we now know that patients with HER2-low disease can benefit from ADCs such as trastuzumab deruxtecan. 

Despite being HER2-, most of these tumors still harbor detectable amounts of the HER2 protein on cell membranes, with approximately two-thirds of HR+ tumors being HER2-low. Trastuzumab deruxtecan received US Food and Drug Administration (FDA) approval in 2022 and is composed of an anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload. Approval was based on the phase 3 DESTINY-Breast04 trial, which compared trastuzumab deruxtecan with chemotherapy treatment of physician’s choice in heavily pretreated patients with HER2-low, metastatic breast cancer. In this setting, trastuzumab deruxtecan improved objective response, progression-free survival, and overall survival compared with standard chemotherapy. This represents an important new treatment option for patients with estrogen receptor–positive (ER+)/HER2-low breast cancers. 

Another ADC that was also just FDA approved in this space is called sacituzumab govitecan, and it targets TROP2. This agent was initially approved in metastatic triple-negative breast cancer but has now been shown to have activity in ER+/HER2- breast cancers based on the results of the phase 3 TROPiCS-02 trial. In this study, sacituzumab govitecan produced significant improvements in overall survival compared with the physician’s choice of therapy. It has recently received FDA approval for the treatment of adults with unresectable, locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

In addition to these agents, there are multiple ongoing studies that are evaluating combinations of CDK4/6 inhibitors and PI3K inhibitors in the first and second line. There are also combinations of the new selective estrogen receptor degraders (eg, elacestrant and others) that are being compared with standard therapy, as well as new ADCs looking at different targets and different payloads. And, finally, although immunotherapy has not been shown to be effective in HR+ breast cancer, there are ongoing investigations that are attempting to combine immunotherapy with other agents that might result in the reversal of the resistance to immunotherapy.