NED-oriented oncology in metastatic breast cancer: a hypothesis-driven framework integrating the tumor immune microenvironment, antibody-drug conjugates, and metastasis-directed therapy.

Metastatic breast cancer (MBC) has traditionally been managed as an incurable systemic disease in which the main goals are survival extension, symptom control, and preservation of quality of life. This principle remains appropriate for most patients. However, contemporary systemic therapies, high-resolution imaging, antibody-drug conjugates (ADCs), immune checkpoint inhibition, liquid biopsy, and metastasis-directed therapy (MDT) have made prolonged no evidence of disease (NED) clinically recognizable in selected patients. This Hypothesis and Theory article proposes NED-oriented oncology as a testable framework for carefully selected patients with MBC. The central premise is that complete response and NED should be separated conceptually: complete response is a radiological treatment-response category, whereas NED is a clinical state produced by the integration of systemic disease control, biological remodeling of the tumor immune microenvironment (TIME), and local eradication of all residual visible lesions. We propose a Clinical NED Score to structure candidate selection, a TIME-modifiability layer to estimate biological convertibility, and a five-step algorithm in which systemic therapy is used to generate deep response and immune-ecological remodeling before MDT is considered at maximal response. ADCs are discussed as potential tumor-ecosystem engineering tools because their effects may extend beyond direct cytotoxicity to bystander killing, immunogenic cell death, antigen release, and immune reconfiguration. This framework does not imply that MBC is broadly curable. Rather, it argues that durable NED is a clinically meaningful, prospectively testable state that should be distinguished from transient radiological response and evaluated using endpoints such as NED interval, polymetastatic progression-free survival, systemic therapy switch-free survival, ctDNA-negative duration, and quality-of-life preservation.