Predicting Recurrence of Stage IA Lung Adenocarcinoma Using Circulating Tumor Cell–Free DNA Whole-Genome Mutational Signatures
Menée à partir du séquençage du génome entier d'échantillons sanguins et d'échantillons tumoraux prélevés sur 42 patients atteints d'un adénocarcinome du poumon de stade IA, cette étude examine la possibilité de détecter l'ADN tumoral circulant et d'utiliser ce dernier pour suivre le niveau de maladie résiduelle et prédire ainsi le risque de récidive
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. Although for stage IA, LUAD surgery is often curative, recurrence rates remain significant. Liquid biopsy enables monitoring residual disease and predicts recurrence; however, utility in stage IA LUAD is not well established. Tumor-informed whole-genome sequencing (WGS) represents a highly sensitive liquid biopsy method for the analysis of circulating tumor cell–free DNA (ctDNA) without designing and maintaining patient-specific probes. This study aimed to determine the prognostic value of genome-wide tumor-informed minimal residual disease monitoring in stage IA non–small-cell lung cancer (NSCLC) using WGS of ctDNA. WGS was performed on 42 patients with stage IA NSCLC. Tumor was sequenced at 40× and germline DNA and plasma derived ctDNA at 20×, and patient-specific mutational signatures were developed from the tumor-normal comparison and applied to ctDNA WGS at each time point using an artificial intelligence–supported pattern recognition algorithm. ctDNA results were compared with clinical recurrence. WGS ctDNA was able to predict recurrence with 0.75 sensitivity and 0.83 specificity, with median 16.7 months lead time compared with clinical or imaging recurrence. ctDNA WGS was able to distinguish between a second primary and recurrence in histologically or clinically challenging cases. Whole-genome sequencing of ctDNA can predict recurrence in the earliest clinical stage of NSCLC, identifying patients who will recur, and providing information to help guide radiological follow-up and adjuvant therapy.
Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer and remains the major cause of cancer-related death.1 Patients with early stage (I to II) are usually treated with resection, with intent to cure, and survival rates are reasonably high. However, even in stage I, the recurrence rate is not negligible, ranging between 5% and 19%, and imaging follow-up remains standard of care. Clinical guidelines recommend adjuvant targeted therapy with osimertinib starting at stage IB NSCLC with sensitizing epidermal growth factor receptor (EGFR) mutations.2,3 Recent studies have shown improved survival with combination of neoadjuvant immunotherapy and chemotherapy in NSCLC stage IB to IIIA.4 The US Food and Drug Administration also approved the use of pembrolizumab after surgery in patients with stage IB to stage III in NSCLC.
Nevertheless, most patients with stage IA are cured by surgery alone, and adjuvant or neoadjuvant therapy in resectable NSCLC comes with adverse effect risks and significant financial costs. Therefore, assessing risk of recurrence after the surgery is critical for the identification of patients who may benefit most from additional therapy. Additionally, continued monitoring for residual disease would allow for earlier detection of recurrences.5 Liquid biopsies have emerged as an important tool for minimally invasive diagnostics, therapy management, and monitoring of patients with solid tumors.6–8
In NSCLC, it was previously demonstrated that circulating tumor cell–free DNA (ctDNA) can be detected in most stage I to III NSCLC.9 Moding et al10 have shown that patients with undetectable ctDNA after initial chemoradiotherapy had a favorable outcome irrespective of further immunotherapy treatment. This and other studies have suggested that ctDNA monitoring can help guide escalation or de-escalation of therapy in patients with solid tumors.11,12
Minimal residual disease (MRD) monitoring is defined as blood-based detection of residual cancer following the initial therapy.13,14 Overall, liquid biopsy approaches for analysis of ctDNA can be divided into targeted panels focusing on a selected number of genes and known mutational hotspots,6,15 or nontargeted exome-wide or genome-wide analysis.14 Furthermore, ctDNA approaches can also be divided into tumor naïve, where only blood is required for ctDNA testing, and tumor informed, where detection sensitivity is enhanced by tumor-derived mutational signature.14,16 The major challenges affecting MRD testing in early-stage NSCLC include a low level of circulating ctDNA fragments, clonal hematopoiesis, low tumor mutational burden, and lack of hotspot mutations in a subset of tumors. It was previously shown that a tumor-informed genome-wide approach enables taking advantage of the full spectrum of tumor mutational signatures and enables ultrasensitive detection and monitoring of solid tumors.14 Whole-genome sequencing (WGS) is a genome-wide approach that represents an accessible method for the analysis of ctDNA without the need of designing and storing patient-specific primer sets. This study sought to determine the prognostic value of genome-wide, tumor-informed MRD monitoring in stage IA NSCLC using WGS of ctDNA.
The Journal of Molecular Diagnostics , article en libre accès, 2026