Exceptional responders in breast cancer

In a presentation at ESMO 2025, Prof Christos Sotiriou, medical oncologist at the Institut Jules Bordet in Brussels, discussed the concept of exceptional responders in metastatic breast cancer. In this, he explored the potential to discontinue therapy or even achieve a cure in this subset of patients. Historically, about 10% of metastatic breast cancer patients exhibit long-lasting responses to treatment. These exceptional responders typically have oligometastatic disease, characterized by a limited number of lesions, often confined to a single organ.

An important initiative by the National Cancer Institute (NCI), launched in 2014, is dedicated to understanding the biology behind these extraordinary responses. Analysis at the genomic level has revealed four mechanisms that may contribute to exceptional responses: defects in DNA repair pathways, reliance on specific oncogenic pathways (e.g., HER2), immune engagement, and favorable genetic prognostic features such as low genomic instability.¹

Notably, patients with HER2-positive and triple-negative breast cancers are more likely to achieve deep complete responses and no-evidence of disease (NED) on imaging. In contrast, complete responses in patients with luminal tumors are rare. Nevertheless, durable stable disease also occurs in a subgroup of these patients. Ongoing studies are evaluating the discontinuation of HER2-targeted treatments after prolonged response, with early data indicating that up to 70% of patients maintain good outcomes while being off therapy.² Similarly, emerging research in triple-negative disease suggests some patients may be cured thanks to robust and sustained immune responses.

In hormone receptor-positive breast cancer, a Dutch trial is currently investigating discontinuation of CDK4/6 inhibition after six months of therapy while continuing endocrine treatment. Early results of this trial suggest that many patients maintain disease control. Of note, this strategy may also help to prevent resistance, as intermittent exposure to CDK4/6 inhibitors may prevent or delay endocrine resistance.³

Despite optimistic trends, robust prospective data are needed before changing clinical practice. Future studies incorporating advanced imaging (e.g., PET, MRI) and liquid biopsies (e.g., circulating tumor DNA) may offer refined tools for identifying patients eligible for treatment discontinuation. If validated, such strategies promise reduced toxicity, improved quality of life, and economic benefits, paving the way for potential cures in metastatic disease.