Recurrence prediction using circulating tumor DNA in patients with early-stage non-small cell lung cancer after treatment with curative intent: A retrospective validation study.

Schuurbiers, Milou M. F.; Smith, Christopher G.; Hartemink, Koen J.; Rintoul, Robert C.; Gale, Davina; Monkhorst, Kim; Mandos, Bas L. R.; Paterson, Anna L.; van den Broek, Dan; Rosenfeld, Nitzan; van den Heuvel, Michel M.

Background: Despite treatment with curative intent, many patients with localized non-small cell lung cancer (NSCLC) develop recurrence. The current challenge is to identify high-risk patients to guide adjuvant treatment. Identification of residual disease by detection of circulating tumor DNA (ctDNA) may allow more accurate clinical decision-making, but its reliability in NSCLC is not established. We aimed to build on previous data to validate a tissue-informed personalized ctDNA assay, to predict recurrence in patients with early-stage disease. Methods and findings: Tumor tissue and plasma was collected from patients with stage 0–III NSCLC enrolled to LEMA (Lung cancer Early Molecular Assessment trial, NCT02894853). Serial plasma was collected before and after definitive treatment, with the latter including key timeframes of interest (1–3 days post-treatment, between 14 and 122 days after treatment end, and ≥14 days after treatment end). Somatic mutations identified by tumor exome sequencing were used to design patient-specific assays, to analyze ctDNA. Results were compared and combined with an independent dataset (LUCID; LUng Cancer CIrculating Tumour Dna study, NCT04153526). In LEMA, 130 patients (57% male; median age 66 years (range 44–82); 69% adenocarcinoma, 22% squamous cell carcinoma (SCC); 3%/49%/19%/29% with stage 0/I/II/III) were treated with curative intent. Tumor tissue originated from surgical resection or diagnostic biopsy in 118 and 12 patients respectively. LUCID included 88 patients (51% male; median age 72 years (range 44–88); 63% adenocarcinoma, 31% SCC; 49%/28%/23% with stage I/II/III). Before treatment, ctDNA was detected in 48% LEMA and 51% LUCID patients. Sensitivity, specificity, positive and negative predictive value of ctDNA detection post-treatment (≥1 positive sample ≥14 days after treatment end) to predict recurrence were 61%, 97%, 92% and 84% for LEMA and 64%, 96%, 90% and 83% for LUCID. In the combined cohort, ctDNA detection after treatment was associated with shorter recurrence-free survival (hazard ratio (HR) 11.4 (95% confidence interval (CI) [7.0,18.7]; p < 0.001)) and overall survival (HR 8.1 (95% CI [4.6,14.2]; p < 0.001)), accounting for guarantee-time bias. Of note, a key limitation of this work was the irregular sample collection schedules, during routine follow-up visits, of both studies. Conclusions: ctDNA detection predicted recurrence in independent retrospective cohorts with notable reproducibility, including near-identical detection rates and predictive values, confirming its ability to differentiate patients at high- versus low risk of recurrence. Our results support the potential of tissue-informed ctDNA analysis as a decision-support tool for adjuvant therapy in NSCLC. Author summary: Why was this study done?: Circulating tumor DNA (ctDNA) has emerged as a potentially powerful tool in the treatment of patients with cancer. After curative treatment, there is a risk that patients with early-stage lung cancer are treated sub-optimally; toxic therapy is sometimes administered to patients that don't require additional treatment, while it is withheld from patients that would benefit from further intervention to prevent disease relapse. The authors have previously shown that ctDNA might be able to help healthcare providers decide which patients need additional therapy. Here they aimed to validate and build on this previous data by testing a new, independent group of patients. What did the researchers do and find?: An independent cohort (the Lung cancer Early Molecular Assessment, LEMA, study), comprising ~130 patients with early-stage lung cancer, was tested using the same ctDNA methodology, to determine the reproducibility of the original results. The results were notable in their similarity, showing some of the same associations with similar magnitude. The two datasets were combined to give the authors an even larger dataset to attempt to explore associations between ctDNA and clinical, biological and technical variables. Key findings include that; ctDNA is prognostic (i.e., detection is linked to patient survival) and predictive (i.e., detection indicates which patients' disease are most likely to return). However, ctDNA detection might be influenced by the biology of the patient's tumor. What do these findings mean?: These findings add to mounting data that ctDNA can positively contribute to patient care, by indicating the patients with worse outcomes, and guiding if and when treatment should be administered. Whilst encouraging, more work is needed before ctDNA can be routinely utilized in clinical practice. Fortunately, technological advancements continue to improve the detection and quantification of ctDNA, while large prospective clinical studies will provide stronger evidence for the absolute benefit it offers. A key limitation of this work was the irregular collection of blood samples from patients from both cohorts – ideally samples would be collected according to a regular and extended schedule, over an extended period, e.g., every 3 months over 5 years. Milou MF Schuurbiers, Christopher G Smith and colleagues validate a tissue-based personalized ctDNA assay to predict recurrence in patients with non-small cell lung cancer in a new independent group of patients.

CIRCULATING tumor DNA; NON-small-cell lung carcinoma; SOMATIC mutation; MEDICAL personnel; TECHNOLOGICAL innovations

PLoS Medicine, 2025, Vol 22, Issue 4, p1

1549-1277

Academic Journal

10.1371/journal.pmed.1004574