For patients with ER-positive, HER2-negative advanced or metastatic breast cancer, reassessing tumor biology after progression can reveal changes that influence the next clinical discussion.

Endocrine therapy is central to the management of estrogen receptor-positive, HER2-negative breast cancer. In advanced or metastatic disease, however, tumor biology can evolve over time. One clinically important change is the development of mutations in ESR1, the gene that encodes the estrogen receptor.

These mutations are often acquired during treatment rather than present at the initial diagnosis. Many occur in the ligand-binding domain of the estrogen receptor and can keep receptor signaling active even when estrogen availability is reduced. The result may be diminished sensitivity to an endocrine approach that previously controlled the disease.

That makes the timing of biomarker reassessment important. When disease progresses after endocrine therapy, plasma-based circulating tumor DNA testing can provide a current view of actionable alterations without requiring a new tissue procedure in every case. A negative plasma result may still require clinical judgment about whether tissue testing is appropriate, particularly when tumor DNA shedding is low.

An ESR1 result is one part of a broader treatment assessment. Clinicians also weigh the pace and location of progression, symptoms, prior duration of benefit, previous exposure to targeted therapies, organ function, patient preferences, and other genomic findings. The goal is not simply to identify a mutation, but to place that result in the context of the individual patient’s disease course.

As biomarker-directed options expand, clear communication becomes equally important. Patients should understand why repeat testing may be recommended, what the result can and cannot show, and how it may narrow the range of reasonable next steps. This shared understanding supports more informed decisions after endocrine resistance develops.

At SABCS 2026, ongoing research is expected to further clarify how serial molecular testing, resistance mechanisms, and treatment sequencing can be integrated across ER-positive, HER2-negative advanced breast cancer care.

Key points

  • ESR1 mutations can emerge under the selective pressure of prior endocrine therapy and contribute to treatment resistance.
  • Plasma circulating tumor DNA can help identify an acquired mutation when the disease progresses.
  • Biomarker results should be interpreted with disease burden, symptoms, prior treatment, and the full molecular profile.

This independent editorial article is intended for healthcare professionals and is not a substitute for clinical judgment or current prescribing information.