Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, <i>MET</i> exon skipping or <i>de novo MET</i> amplification

doi:10.1007/s11684-024-1060-z

2024, Vol. 18

Issue (4) : 735-743 https://doi.org/10.1007/s11684-024-1060-z

Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, MET exon skipping or de novo MET amplification

Rui Fu^1,², Yuanyuan Xiong³, Miao Cai³, Fang Li³, Rongrong Chen³, Yilong Wu^1,², Wenzhao Zhong^1,²(

)

¹. School of Medicine, South China University of Technology, Guangzhou 510006, China
². Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
³. Geneplus-Beijing, Beijing 102206, China

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Abstract

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.

Keywords ctDNA molecular residual disease operable NSCLC gene fusion MET exon skipping MET amplification

Corresponding Author(s): Wenzhao Zhong

Just Accepted Date: 24 April 2024 Online First Date: 24 May 2024 Issue Date: 30 August 2024

Cite this article:

Rui Fu,Yuanyuan Xiong,Miao Cai, et al. Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, MET exon skipping or de novo MET amplification[J]. Front. Med., 2024, 18(4): 735-743.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-024-1060-z
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I4/735

Fig.1 Baseline characteristics of our cohort. Heat map plot based on each patient’s baseline clinical and molecular characteristics. Amp, amplification.

Fig.2 Disease-free survival stratified by postoperative MRD status. (A) Event chart showing clinical characteristics, preoperative and postoperative longitudinal ctDNA status and recurrence status in the overall cohort. Patients were separated by their radiographic outcome. Patients included in the analysis of landmark time points were marked with bold italics, and the landmark time window was marked with cyan. Chemo, chemotherapy; TKI, tyrosine kinase inhibitor; ICI, immune checkpoint inhibitor. (B, C) Kaplan–Meier estimates of disease-free survival in patients stratified by ctDNA status at landmark (B) and longitudinal (C) time points. P value was calculated by the log-rank test and the hazard ratio by the Cox exp(β) method.

Fig.3 MRD is superior to CEA in predicting disease recurrence. (A) Analysis of recurrence time measured by the first ctDNA detection and CT. P value was calculated by the log-rank test and the hazard ratio by the Cox exp(β) method. (B) Example of patient P009 with positive ctDNA and negative CEA before recurrence.

Fig.4 Association of postoperative ctDNA mutation types with patient outcome. (A) Mutational landscape of longitudinal detectable ctDNA in 14 patients with operable NSCLC. (B) Kaplan–Meier estimates of disease-free survival in patients with and without fusion/MET mutations of longitudinal ctDNA. (C) Kaplan–Meier estimates of disease-free survival in patients stratified by whether the longitudinal ctDNA mutations are tissue-derived and fusion/MET mutations. The detectable fusion/MET group comprised patients with at least one fusion/MET mutation detected in at least one postoperative plasma sample. The detectable tissue-derived and undetectable fusion/MET group comprised patients with at least one tissue-derived mutation detected in at least one postoperative plasma sample and no fusion/MET mutation detected in any postoperative samples. P value was calculated by the log-rank test and the hazard ratio by the Cox exp(β) method.

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