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

In operable non-small cell lung cancer (NSCLC), molecular residual disease (MRD) detection via circulating tumor DNA (ctDNA) has emerged as a promising approach to identify individuals at high risk of disease recurrence and potentially guide adjuvant therapy decisions. A recent prospective observational study conducted at Guangdong Provincial People’s Hospital, China, aimed to elucidate the role of MRD detection in patients with operable NSCLC harboring oncogenic fusions, MET exon skipping, or de novo MET amplification following surgical resection and explore the association between postoperative MRD mutations and clinical outcomes.

The study included 49 NSCLC patients who underwent surgery and had next-generation sequencing (NGS)-confirmed oncogenic fusions, MET exon 14 skipping, or de novo MET amplification. After excluding six patients due to lack of perioperative blood samples or loss of follow-up, 43 patients were analyzed. The patients' lung cancer and disease stages were classified according to the World Health Organization criteria and the American Joint Committee on Cancer staging system. Tumor tissues were obtained via biopsy or surgery, and peripheral blood samples were collected before and/or after surgery and during follow-up. The samples were processed to extract tumor DNA, circulating free DNA (cfDNA), and germline genomic DNA from peripheral blood leukocytes (PBLs). Targeted next-generation sequencing was performed to identify tumor somatic variants, and ctDNA-based MRD detection was carried out using a previously reported method.

The primary outcome measure was disease-free survival (DFS), assessed using standard radiological criteria. The study found that MRD detection could predict clinical outcomes in patients with NSCLC, with positive landmark and longitudinal MRD associated with significantly reduced DFS. The detection of MRD mutations in postoperative plasma samples was also found to be associated with patient prognosis, with patients having fusion/MET alterations in longitudinal ctDNA tending to have worse DFS than those with other tissue-derived mutations or ctDNA-private mutations.

The study's results suggest that ctDNA-based MRD detection is a reliable predictor of disease recurrence in operable NSCLC with oncogenic actionable fusion mutations, MET exon skipping, or de novo MET amplification. The positive predictive value (PPV) of MRD detection was 100% and 90.9% at the landmark and longitudinal time points, respectively, indicating a high risk of recurrence for patients with positive MRD. However, the negative predictive value (NPV) was 86.4%, which was lower than previously reported, possibly due to the smaller cohort size and shorter median follow-up time in this study. The longitudinal MRD detection also demonstrated the potential to identify recurrence earlier than imaging modalities, with a median lead time of 4.2 months.

Despite the promising findings, the study has several limitations. The limited sample size, primarily comprising adenocarcinoma patients, and the lack of exploration of the correlation between postoperative MRD status and treatment course may affect the generalizability of the findings. Additionally, the study did not address the potential impact of ctDNA-based MRD detection on treatment decisions or the cost-effectiveness of incorporating this approach into routine clinical practice.

In conclusion, the study provides evidence for the use of ctDNA-based MRD detection in postoperative recurrence risk stratification in operable NSCLC with actionable fusion mutations, MET exon skipping, or de novo MET amplification. The detection of MRD mutations in postoperative plasma samples could inform prognosis and potentially guide adjuvant therapy decisions. However, future studies with larger sample sizes and long-term follow-up are needed to confirm these findings and explore the impact of MRD detection on treatment strategies and patient outcomes.