While endocrine therapy is highly effective in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer, resistance to endocrine therapy occurs in a substantial proportion of patients. Thus, it is important to perform molecular testing to identify any actionable mutations that can inform the selection of second-line therapy.

The speed with which resistance to antiestrogen therapy occurs, and its mechanism, depend on whether resistance develops after antiestrogen therapy is used alone or in combination with a CDK4/6 inhibitor. Up to 40% have a mutation in the binding domain of the ESR1 gene, which results in ligand-independent activation or estrogen receptor (ER) signaling. Other mechanisms of resistance include the loss of the retinoblastoma tumor suppressor gene and the amplification of cyclin-dependent kinase enzymes, which may drive resistance to CDK4/6 inhibitors.

The use of circulating tumor DNA assays plays a central role in guiding therapy for those who have developed resistance to antiestrogen therapy. For patients with ESR1 mutations, elacestrant may be an effective option, especially if the duration of prior CDK4/6 inhibitor therapy was at least 1 year. For those with activating PIK3CA mutations, PIK3CA inhibitors have a role when added to second-line endocrine therapy. For those lacking ESR1 and PIK3CA mutations, the combination of the mTOR inhibitor everolimus with second-line endocrine therapy may be an effective option.

For patients who progress on first-line therapy with a CDK4/6 inhibitor plus endocrine therapy, it is important to perform a liquid or tissue biopsy for next-generation sequencing to determine whether there are any actionable mutations (eg, ESR1 and PIK3CA) that can determine therapeutic options.

Elacestrant is an oral selective ER degrader that was recently approved by the US Food and Drug Administration (FDA) for postmenopausal women or adult men with ER+/HER2- advanced breast cancer with ESR1 mutations and disease progression following at least 1 line of endocrine therapy. Elacestrant was FDA approved as a single agent based on the results of the phase 3 EMERALD trial, which randomized patients to elacestrant or to the investigator’s choice of endocrine therapy. Patients with ESR1 mutations who were receiving elacestrant monotherapy achieved a modest improvement in progression-free survival of approximately 1.9 months (3.79 vs 1.87 months). Thus, elacestrant is an option for patients with ESR1-mutated tumors who progress on first-line treatment with CDK4/6 inhibitor therapy plus endocrine therapy.

Alpelisib in combination with fulvestrant is a treatment option for patients with PIK3CA mutations, which are found in approximately 40% of patients with HR+/HER2- breast cancer, based on the results of the SOLAR-1 trial, although the clinical use of this regimen has been hampered by the high rate of hyperglycemia, which can be challenging in the context of patients with glucose intolerance. Capivasertib, a potent pan-AKT inhibitor, in combination with fulvestrant was approved by the FDA in November 2023 for patients with HR+/HER2- advanced breast cancer with PIK3CA/AKT1/PTEN alterations, after progression on at least 1 line of endocrine-based therapy.

For patients who are treated with endocrine therapy, we describe resistance as being either primary (de novo) or secondary (acquired). Unfortunately, we do not have perfect biomarkers that can predict which category patients are at risk for. Gene expression profiles are commonly used to identify those patients who are at risk for de novo endocrine resistance. One particular profile, the Prediction Analysis of Microarray 50 assay (commonly referred to as the PAM50 assay), identifies different molecular subtypes that include the luminal A, luminal B, HER2-enriched, basal, and normal-like subtypes. For tumors that are luminal and in which the ER is present, targeting the ER with endocrine therapy is crucial, and most patients will initially respond. However, there are subgroups of patients with ER-positive (ER+) disease who are at risk for de novo resistance, and these patients are potential candidates for other approaches. Luminal B and nonluminal subtypes (eg, HER2-enriched and basal-like subtypes) are more likely to be endocrine resistant and have a worse prognosis compared with luminal A tumors.

A secondary analysis of data from the MONALEESA trials found benefit with ribociclib in all subtypes except basal. One strategy that is being investigated in the ongoing, prospective HARMONIA trial is preselection based on tumor biology in patients with HR+/HER2- advanced breast cancer, with HER2-enriched tumors being the main cohort and basal-like tumors being the exploratory cohort. In the main HER2-enriched cohort, patients are being randomized to either ribociclib plus endocrine therapy (ie, letrozole or fulvestrant) or palbociclib plus endocrine therapy. The exploratory cohort of patients with basal-like tumors will receive paclitaxel plus immune checkpoint inhibitor therapy, based on extensive data demonstrating that the basal tumors exhibit a similar gene expression profile to triple-negative breast cancer and are endocrine resistant.