Metastatic breast cancer: what still needs to be (re)considered?

#BreastCancer #mBC #2025Guidelines #AGO  


Metastatic breast cancer (mBC) remains one of the leading causes of cancer-related death among women. Despite significant therapeutic advances over the past two decades, it is still considered incurable, with frequent relapses and time-limited responses to treatment. Major challenges in clinical practice include the molecular heterogeneity of tumors, secondary resistance to targeted therapies, the management of complex metastatic sites (bone, brain, visceral), and the lack of unified guidelines for certain rare molecular profiles or patients progressing after CDK4/6 inhibition.  

Furthermore, the integration of biomarkers like circulating tumor DNA (ctDNA) into treatment decisions remains controversial due to the lack of definitive validation. In this evolving context, healthcare professionals are faced with complex, rapidly changing therapeutic choices that require continuously updated practices based on robust data. The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie) group addresses this need with its 2025 update—providing structured, up-to-date clinical recommendations for the diagnosis and treatment of patients with locally advanced or metastatic breast cancer.  

Which treatments are delivering on their promises?  

The AGO update confirms the central role of circulating biomarkers in the diagnostic landscape. Circulating tumor cells (CTCs) retain strong prognostic value in mBC. While ctDNA shows promise in relapse prediction and treatment monitoring, it is not yet included in routine therapeutic decisions due to insufficient supporting data. At the molecular level, ESR1 and PIK3CA mutations offer opportunities for personalized targeted therapy, such as with elacestrant or alpelisib.

For HR+/HER2− tumors, the combination of a CDK4/6 inhibitor and hormone therapy remains the cornerstone of treatment. Ribociclib combined with an aromatase inhibitor is now a preferred first-line option, with an AGO++ recommendation. Upon endocrine resistance, elacestrant (oral SERD) or capivasertib (AKT inhibitor) become relevant second-line strategies.  

In HER2+ breast cancer, trastuzumab deruxtecan (T-DXd) has emerged as the new standard in second-line therapy following initial failure, offering clear clinical benefit. It can be followed by a triplet combination of tucatinib, trastuzumab, and capecitabine, especially in cases with brain metastases. This therapeutic sequence is clearly outlined in the decision algorithm on page 6 of the publication.  

For triple-negative breast cancer (TNBC), patients with PD-L1 positive tumors benefit from first-line immunotherapy combined with chemotherapy (e.g., pembrolizumab or atezolizumab). In cases of progression or failure, two antibody-drug conjugates (ADCs)—sacituzumab govitecan and T-DXd—have shown significant survival benefits and are validated for later lines, as described on page 5.  

Bone metastases are managed with zoledronate or denosumab, optionally combined with targeted radiotherapy. Prophylactic protocols are validated to prevent severe skeletal events.  

In the case of brain metastases, localized approaches such as surgery or stereotactic radiosurgery (SRS) are recommended for patients with fewer than four lesions. For more extensive brain involvement, T-DXd and tucatinib have demonstrated intracranial efficacy and are now part of systemic treatment strategies—marking a major evolution in managing neurologically active disease.    

A compass for the incurable  

While metastatic breast cancer remains incurable, therapeutic progress now allows for more targeted and effective care. Given the increasing complexity of tumor profiles and the continuous emergence of new treatment approaches, clinicians must navigate increasingly nuanced therapeutic decisions.   The 2025 AGO update aims to offer a rigorous framework based on the latest levels of evidence to support clinical decision-making in this ever-evolving setting.

This edition confirms the value of targeted combinations, the relevance of biomarkers in a personalized approach, and the importance of an integrated strategy that includes supportive care and specific metastases. However, some recommendations remain contingent on still incomplete data or inconsistent regulatory approvals, limiting their immediate implementation. Short-term prospects lie in the broader integration of liquid biopsy, the ongoing assessment of digital tools and patient-reported outcomes (PROs), and the development of more individualized approaches based on dynamic tumor biology. Thus, AGO outlines the contours of precision oncology, aimed at improving quality of life and extending survival—even in the metastatic setting. Let me know if you want a version with a more formal, scientific tone for publication or presentation.

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