How would you treat a patient with symptomatic and rapidly progressing metastatic HR+, HER2 low breast cancer with PIK3CA WT, ESR1 mutated, TMB high after progression on CDK 4/6 inhibitor, a taxane, and T-DXd?

With disease progressing on increasing number of systemic therapy lines, the likelihood of having a response diminishes. In the absence of an impending organ crisis, one could consider fulvestrant with alpelisib, elacestrant, or pembrolizumab. However, if the patient is facing an impending organ failure, I would choose a systemic regimen that is expected to produce response more rapidly than the above 3 options, such as a chemotherapy doublet. One could also consider adding pembrolizumab to chemotherapy doublet although getting it approved through the insurance could be difficult as the FDA label for patients with tumors with high TMB is for pembrolizumab monotherapy.