Treatment Sequencing in Metastatic HR+/HER2- Breast Cancer: A Delphi Consensus

Abstract

Background: The treatment landscape in HR+/HER2- metastatic breast cancer (mBC) is continuously evolving, with evidence on new agents and combinations published almost every year. Despite updated therapeutic guidelines, second-line (2L) selection may be challenging due to clinical factors, biomarker status, and available agents. Methods: A two-round Delphi consensus was organized in July 2024, gathering input from 10 experts in research, diagnosis, and treatment of HR+/HER2- mBC on optimal 2L and beyond choice, considering the available biomarkers and results from published clinical trials. Consensus was defined as 70% agreement or disagreement. Results: The experts considered initially a list of 39 statements, structured into the following four sections: biomarker testing; selection of 2L treatment at progression of disease on first line endocrine therapy (ET) + CDK4/6i at ≥6 months after initiation of ET for mBC; selection of 2L treatment at disease progression on ET + CDK4/6i, at <6 months after initiation of ET for mBC, whilst on ET; and selection of post-2L treatment options. After a discussion, the experts decided to remove four statements, refine ten, and include three new ones. The final list consisted of 38 statements, and consensus was achieved in 37. Conclusions: The panel recommends next-generation sequencing as the method of choice for genomic characterization at disease progression on first line. The optimal agent or treatment class is indicated depending on the presence of specific mutations; however, the panel admits that the strategy is different in clinical practice, where novel therapies might not be available or reimbursed.

Keywords: Delphi consensus; HR+/HER2− metastatic breast cancer; second-line therapy; targeted therapy; treatment choice.

Figure 1

Overview of the 2L treatment recommendations in HR+/HER2− mBC based on mutations at disease progression. * SG in monotherapy should be considered for patients with HR+/HER2-0 mBC after at least two lines of ChT, based on the current indication approved in Europe, available at: https://www.ema.europa.eu/en/documents/product-information/trodelvy-epar-product-information_en.pdf (accessed on 8 April 2025). Dotted lines indicate the recommendation based on the DESTINY-Breast06 study [32]. At the time of manuscript development, this was not an approved indication for T-DXd. Abbreviations: 2L, second line; ChT, chemotherapy; mBC, metastatic breast cancer; SG, sacituzumab govitecan; T-DXd, trastuzumab deruxtecan.