Abstract
Accurately evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies. Here, using ultradeep targeted next-generation sequencing (NGS), we evaluate the clinical utility of circulating tumor DNA (ctDNA) for dynamic recurrence risk and adjuvant chemotherapy (ACT) benefit prediction in resected non-small cell lung cancer (NSCLC). Both postsurgical and post-ACT ctDNA positivity are significantly associated with worse recurrence-free survival. In stage II-III patients, the postsurgical ctDNA positive group benefit from ACT, while ctDNA negative patients have a low risk of relapse regardless of whether or not ACT is administered. During disease surveillance, ctDNA positivity precedes radiological recurrence by a median of 88 days. Using joint modeling of longitudinal ctDNA analysis and time-to-recurrence, we accurately predict patients’ postsurgical 12-month and 15-month recurrence status. Our findings reveal longitudinal ctDNA analysis as a promising tool to detect MRD in NSCLC, and we show pioneering work of using postsurgical ctDNA status to guide ACT and applying joint modeling to dynamically predict recurrence risk, although the results need to be further confirmed in future studies.
Highlights
Evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies
Discussion circulating tumor DNA (ctDNA) monitoring has emerged as a promising approach for early diagnosis, prognosis prediction, and postsurgical surveillance
Multiple studies have demonstrated that ctDNA positivity after surgical resection was correlated with poor patients outcomes in lung cancer[15,16,28]
Summary
Evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies. Using ultradeep targeted next-generation sequencing (NGS), we evaluate the clinical utility of circulating tumor DNA (ctDNA) for dynamic recurrence risk and adjuvant chemotherapy (ACT) benefit prediction in resected non-small cell lung cancer (NSCLC) Both postsurgical and post-ACT ctDNA positivity are significantly associated with worse recurrence-free survival. Recent studies utilizing personalized mutation detection panels or CAPP-Seq have demonstrated the potential of ctDNA for MRD detection and early detection of recurrence for patients after surgery with or without chemotherapy[15,16] and for patients with long-term responses to PD-L1 blockade[17] Given that these lung cancer studies mainly focused on landmark time points and binary ctDNA detection status, the utility of using serial ctDNA changes during disease surveillance for dynamically predicting patients’ recurrence risk has not been well characterized. Previous studies only focused on the MRD detection after the completion of adjuvant therapy to evaluate its efficacy, whereas whether ctDNA-defined MRD status could guide the administration of ACT in lung cancer patients is still unclear
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