Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.

UNASSIGNED: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC.
UNASSIGNED: To define potentially cured CRC patients through ctDNA monitoring following surgery.
UNASSIGNED: A prospective, multicenter, observational study.
UNASSIGNED: We enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days.
UNASSIGNED: Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases.
UNASSIGNED: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

OBJECTIVE: Molecular residual disease (MRD) is the main cause of postoperative recurrence of breast cancer. However, the baseline tumor genomic characteristics and therapeutic implications of breast cancer patients with detectable MRD after surgery are still unknown.
METHODS: In this study, we enrolled 80 patients with breast cancer who underwent next-generation sequencing-based genetic testing of 1,021 cancer-related genes performed on baseline tumor and postoperative plasma, among which 18 patients had detectable MRD after surgery.
RESULTS: Baseline clinical characteristics found that patients with higher clinical stages were more likely to have detectable MRD. Analysis of single nucleotide variations and small insertions/deletions in baseline tumors showed that somatic mutations in MAP3K1, ATM, FLT1, GNAS, POLD1, SPEN, and WWP2 were significantly enriched in patients with detectable MRD. Oncogenic signaling pathway analysis revealed that alteration of the Cell cycle pathway was more likely to occur in patients with detectable MRD (p=0.012). Mutational signature analysis showed that defective DNA mismatch repair and activation-induced cytidine deaminase (AID) mediated somatic hypermutation (SHM) were associated with detectable MRD. According to the OncoKB database, 77.8% (14/18) of patients with detectable MRD had U.S. Food and Drug Administration-approved mutational biomarkers and targeted therapy.
CONCLUSIONS: Our study reports genomic characteristics of breast cancer patients with detectable MRD. The cell cycle pathway, defective DNA mismatch repair, and AID-mediated SHM were found to be the possible causes of detectable MRD. We also found the vast majority of patients with detectable MRD have the opportunity to access targeted therapy.

The value of circulating tumor DNA (ctDNA) during chemoradiotherapy (CRT) remains unclear but is critical for detecting molecular residual disease (MRD). In this prospective study, we sequenced 761 blood samples from 139 patients with locally advanced non-small cell lung cancer treated with definitive radiation therapy (RT). ctDNA concentrations showed a significantly declining trend as CRT progressed at on-RT and after-RT time points versus baseline. Thirty-eight (27.3%) patients with early undetectable ctDNA at both on-RT (RT reached 40 Gy) and after-RT time points, indicating early response to CRT, had better survival outcomes for both with or without consolidation immune checkpoint inhibitors. Longitudinal undetectable MRD was found in 20.1% patients. The 2-year cancer-specific progression-free survival of these patients was 88.4%, corresponding to a potentially cured population. Further analysis revealed that pretreatment ctDNA variants serve as an essential MRD informed source. These data provide clinical insights for ctDNA-MRD detection.

[This corrects the article DOI: 10.3389/fonc.2023.1222716.].

Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection.
Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced.
The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression.
Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.

UNASSIGNED: The primary objective of this study is to thoroughly investigate the intricate correlation between postoperative molecular residual disease (MRD) status in individuals diagnosed with stage I-IIIA non-small cell lung cancer (NSCLC) and clinicopathological features, gene mutations, the tumour immune microenvironment and treatment effects.
UNASSIGNED: The retrospective collection and analysis were carried out on the clinical data of ninety individuals diagnosed with stage I-IIIA NSCLC who underwent radical resection of lung cancer at our medical facility between January 2021 and March 2022. The comprehensive investigation encompassed an evaluation of multiple aspects including the MRD status, demographic information, clinicopathological characteristics, results from genetic testing, the tumor immune microenvironment, and treatment effects.
UNASSIGNED: No significant associations were observed between postoperative MRD status and variables such as gender, age, smoking history, pathological type, and gene mutations. However, a statistically significant correlation was found between MRD positivity and T (tumor diameter > 3 cm) as well as N (lymph node metastasis) stages (p values of 0.004 and 0.003, respectively). It was observed that higher proportions of micropapillary and solid pathological subtypes within lung adenocarcinoma were associated with increased rates of MRD-positivity after surgery (p = 0.007;0.005). MRD positivity demonstrated a correlation with the presence of vascular invasion (p = 0.0002). For the expression of programmed cell death ligand 1 (PD-L1), tumour positive score (TPS) ≥ 1% and combined positive score (CPS) ≥ 5 were correlated with postoperative MRD status (p value distribution was 0.0391 and 0.0153). In terms of ctDNA elimination, among patients identified as having postoperative MRD and lacking gene mutations, postoperative adjuvant targeted therapy demonstrated superiority over chemotherapy (p = 0.027).
UNASSIGNED: Postoperative ctDNA-MRD status in NSCLC patients exhibits correlations with the size of the primary tumor, lymph node metastasis, pathological subtype of lung adenocarcinoma, presence of vascular invasion, as well as TPS and CPS values for PD-L1 expression; in postoperative patients with MRD, the effectiveness of adjuvant EGFR-TKI targeted therapy exceeds that of chemotherapy, as evidenced by the elimination of ctDNA.

There is still a substantial need of more treatment options for patients with limited-stage small cell lung cancer (LS-SCLC). The standard therapy for LS-SCLC is platinum-based doublet chemotherapy administered concurrently with thoracic radiotherapy (cCRT). In China, sequential chemoradiotherapy (sCRT) is also a common practice. However, the disease inevitably progresses in most patients despite the curative intent and initial response.
Sugemalimab is an anti-programmed death ligand-1 (PD-L1) antibody that improved clinical outcomes for patients with stage III non-small cell lung cancer after cCRT or sCRT. The SUPPASS study is a phase II/III, randomized, double-blind, placebo-controlled, multicenter study (NCT05623267) that aims to investigate the efficacy and tolerability of sugemalimab as consolidation therapy in patients with LS-SCLC who have no progression following cCRT or sCRT. Approximately 346 patients will be randomized in a 1:1 ratio to receive sugemalimab 1200 mg or placebo every 3 weeks for up to 12 months. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall survival (OS), landmark PFS rate, landmark OS rate, objective response rate and safety. Longitudinal molecular residual disease (MRD) testing will be performed as preplanned exploratory analysis.
Study results will help demonstrate the efficacy and tolerability of anti-PD-L1 antibody consolidation therapy in LS-SCLC patients who have not progressed following cCRT or sCRT, and help determine the clinical implications of MRD in LS-SCLC.

Circulating tumor DNA (ctDNA) has potential as a promising biomarker for molecular residual disease (MRD) detection in lung cancer. As the next-generation sequencing standardized panel for ctDNA detection emerges, its clinical utility needs to be validated. We prospectively recruited 184 resectable lung cancer patients from four medical centers. Serial postoperative ctDNAs were analyzed by a standardized panel. A total of 427 postoperative plasma samples from 177 eligible patients were enrolled. ctDNA positivity after surgery was an independent predictor for disease recurrence and preceded radiological recurrence by a median of 6.6 months (range, 0.7-27.0 months). ctDNA-positive or -negative patients with tumors of any stage had similar disease-free survival (DFS). Patients who received targeted therapy had significantly improved DFS than those not receiving adjuvant therapy or receiving chemotherapy, regardless of baseline/preadjuvant ctDNA status. According to whether the ctDNA variants were detected in its matched tissue, they were classified into tissue derived and non-tissue derived. Patients with detectable postoperative ctDNA with tissue-derived mutations had comparable DFS with those with non-tissue-derived mutations. Collectively, we demonstrated that postoperative ctDNA has the potential to stratify prognosis and optimize tumor stage in resectable lung cancer. ctDNA variants not identified in tissue samples should be considered in MRD test.

Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC).
We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated.
In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy.
In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application.