Neoadjuvant chemoimmunotherapy requires multidisciplinary interpretation of ctDNA and imaging to manage biomarker discordanceNew Findings Help Interpret Complex Lung Cancer Treatment Results

Neoadjuvant chemoimmunotherapy can produce uneven responses across the primary tumour, regional lymph nodes, and occult systemic disease. Pathology, circulating tumour DNA (ctDNA), and imaging capture different consequences of this response, so their disagreement can contain clinically relevant biological information. This structured narrative review examines same-patient evidence in resectable non-small cell lung cancer and interprets discordance through anatomical compartment, sampling time, and local immune context. Paired tissue studies show distinct primary and nodal immune ecologies and response-associated lymphoid and myeloid programmes. Spatial clonality and unequal shedding shape the circulating signal, while inflammatory and reparative tissue changes can sustain imaging abnormalities after tumour regression. These observations inform four proposed principles for multidisciplinary interpretation. Separate primary and nodal reporting preserves compartment-specific response information. Presurgical ctDNA clearance indicates molecular response, not proof of tissue eradication. Confirmed postoperative molecular conversion provides a rationale for reassessing current disease status. For imaging conflicts that could alter curative-intent management, lesion-level review can identify when tissue confirmation would be feasible and decision-changing. A postoperative pathology–molecular residual disease matrix organises research questions while preserving nodal findings, unresolved lesions, and serial molecular trajectory. The immediate contribution is to identify which additional observation can resolve a consequential conflict; treatment adaptation then requires evidence that acting on the result benefits patients. Biomarker discordance is therefore an interpretive problem with biological content, rather than a reason to let the most favourable test define the entire response.