Molecular Residual Disease in Non-Small Cell Lung Cancer: Technology or Patient Outcomes?

Molecular residual disease (MRD) testing approaches with plasma next-generation sequencing (NGS) testing to identify circulating tumor DNA (ctDNA) in resectable-stage non-small cell lung cancer (NSCLC) are evolving. The MRD concept is to better guide perioperative systemic treatment and identify recurrent NSCLC before symptomatic radiographic recurrences. Multiple tumor-informed assays are available with technology driving lower levels of ctDNA detection. However, it remains unclear that individual patients derive survival outcome benefit from MRD testing. NSCLC tumor biology of spatial heterogeneity, early parallel metastases, and recurrence clonal evolution can impact tumor-informed approaches irrespective of specific assay level of ctDNA detection. Clinical decision making guided by tumor-informed MRD testing to date have been limited by recurrence risks of up to 20% when landmark MRD-negative, improved outcomes benefit of adjuvant treatment even when landmark MRD-negative, and lead times with longitudinal MRD-positive conversion of several months or longer before overt radiographic recurrences with no proven strategy of survival benefit with intervening treatment. Cautionary tumor biology and clinical issues remain in the clinical utility of tumor-informed MRD testing in resected NSCLC. These need to be clarified with certainty before MRD testing should step beyond a technology-driven prognostic recurrence risk indicator before becoming an absolute clinical guide to meaningfully impact individual patient management and outcomes.