Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer

Abstract

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC.

Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.

Figure 1.

Flow diagram of patient inclusion in subanalyses with clinical questions answered by each analysis denoted.

Figure 2.

Study schematic and baseline characteristics. A, Study flowchart. Patients with stage I to III NSCLC (tumor diameter ≥2 cm) treated with definitive surgery were enrolled. Peripheral blood samples were collected before surgery and every 3 to 6 months after surgery. B, Heat map plot based on baseline characteristics and preoperative ctDNA tests of each patient. C, Multivariate logistic regression model for preoperative ctDNA detection. Pathologic type (adenocarcinoma) and SUVmax were independently associated with preoperative ctDNA detection. D, Detection rate of preoperative ctDNA in patients with different pathologic types. E, Detection rate of preoperative ctDNA in patients with different groups of SUVmax subgroup. F, Schematic diagram of residual blood sample collection from resected lung lobe. G, Comparison between two peripheral blood samples and residual blood ctDNA analysis of additional 11 patients with stage I NSCLC. AD, adenocarcinoma; Chemo, chemotherapy; SCC, squamous cell carcinoma; TKI, tyrosine kinase inhibitor; TMB, tumor mutation burden.

Figure 3.

MRD monitoring after surgery. A, The NPV and PPV of undetectable and detectable MRD at landmark and longitudinal time points, respectively. B, NPV and PPV of undetectable and detectable MRD at longitudinal time points across different stages. C, Kaplan–Meier analysis of DFS stratified by landmark MRD status: detectable (n = 21) versus undetectable (n = 224). D, Kaplan–Meier analysis of DFS stratified by longitudinal MRD status: detectable (n = 46) versus undetectable (n = 190). E, Kaplan–Meier analysis of DFS stratified by longitudinal MRD status across different stages. F, Kaplan–Meier analysis of time to MRD detection and time to imaging recurrence from the end of treatment for all patients. G, Flowchart of occurrence time of MRD or recurrent events in stage II/III patients; the peak timeframe of detectable MRD occurrence was 12 to 18 months after surgery. H, Estimated hazard rate curves for event occurrences in stage II/III patients with landmark-undetectable MRD (n = 85, events were defined as detectable MRD or disease recurrence).

Figure 4.

Sensitivity analysis and treatment history of 47 patients with recurrence. A, Sensitivity analysis of MRD detection at landmark, longitudinal, and surveillance time points. B, Treatment and MRD test history of all 47 patients with recurrence. Chemo, chemotherapy; TKI, tyrosine kinase inhibitor.

Figure 5.

MRD predictive value on adjuvant therapy. A, Heat map plot based on baseline characteristics of patients with detectable MRD at preadjuvant and landmark time points (n = 23). B, Kaplan–Meier analysis of DFS stratified by adjuvant therapy for patients with detectable MRD at preadjuvant and landmark time points: with adjuvant therapy (n = 10) versus without (n = 13). C, Kaplan–Meier analysis of DFS stratified by adjuvant therapy for patients with undetectable MRD at preadjuvant and landmark time points: with adjuvant therapy (n = 45) versus without (n = 182). D, Heat map plot based on baseline characteristics of patients with undetectable MRD at preadjuvant and landmark time points after propensity score matching (PSM). E, After PSM, Kaplan–Meier analysis of DFS stratified by adjuvant therapy for patients with undetectable MRD at preadjuvant and landmark time points: with adjuvant therapy (n = 22) versus without (n = 22). F, Dynamic changes of ctDNA frequency before and after adjuvant therapy for patients with detectable MRD (n = 10), and the DFS of these patients. The arrow represents five of them who still maintained disease-free status. AD, adenocarcinoma; Chemo, chemotherapy; SCC, squamous cell carcinoma; TKI, tyrosine kinase inhibitor.