Real-world use and prognostic performance of a 14-gene molecular risk assay in stage IA–IIA non-small cell lung cancer.

Abstract

e20031 Background: Despite early diagnosis, stage IA-IIA non-small cell lung cancer (NSCLC) carries a high risk of relapse and mortality. The AIM-HIGH randomized trial demonstrated that a validated 14-gene molecular expression assay identified molecularly high-risk patients who benefited from adjuvant cisplatin-based chemotherapy. We evaluated the real-world applicability of these findings. Methods: This retrospective cohort study included 233 patients with resected stage IA–IIA NSCLC at Mount Sinai Medical Center from 2021 to 2024 who were stratified by genetic risk (GR) using a 14-gene molecular assay and by clinical risk using National Comprehensive Cancer Network (NCCN) clinicopathologic risk (CPR) features. Disease-Free Survival (DFS) rates were analyzed using Kaplan–Meier estimates with log-rank testing, and multivariable Cox regression. Associations were evaluated using chi-square or Fisher’s exact tests. Analyses were conducted using R. Results: The cohort was 50.2% female, 91% white, 79.4% Hispanic. Adjuvant chemotherapy was given to 5/118, 12/64, and 9/51 patients in the low-, intermediate-, and high-GR groups, respectively. Relapse rates by GR were 9.3%, 20.35%, and 21.6% for low, intermediate, and high risk, respectively, while relapse rates by CPR were 14.47%, 18.5% for low and high risk, respectively. Median DFS was not reached. At 36 months, DFS rates by GR were 84.3%, 66.2%, and 71.4% for low, intermediate, and high risk, respectively (p = 0.045), and 36-month DFS by CPR was 77.6% and 76.1% for low and high risk, respectively (p = 0.43). Adjuvant chemotherapy was not associated with improved DFS. For postoperative circulating tumor DNA (ctDNA), 36-month DFS rates were 20.0% in positive and 86.1% in negative patients (p < 0.0001). On multivariable Cox regression, ctDNA positivity (HR 4.20, 95% CI 1.27-13.85; p = 0.019), high genetic risk (HR 2.16, 95% CI 1.09-4.26; p = 0.027), positive surgical margins (HR 4.61, 95% CI 1.24-17.17; p = 0.023), and PD-L1 expression (HR 2.58, 95% CI 1.16-5.74; p = 0.020) were independently associated with DFS. Conclusions: The 14-gene assay demonstrated superior prognostic stratification for relapse in resected IA–IIA NSCLC compared with traditional CPR features, in our primarly Hispanic cohort. Intermediate and high GR groups showed lower 36-month DFS, with the high-risk group also showing lower 12-month DFS, suggesting higher early relapse risk. Despite evidence supporting molecularly guided adjuvant chemotherapy, fewer than 19% of patients in intermediate- and high-GR groups received adjuvant treatment in our cohort, reflecting a gap of care that may contribute to higher recurrence. High GR, postoperative ctDNA positivity, PD-L1 expression, and positive surgical margins were independently associated with worse DFS and should be considered in postoperative risk assessment to guide individualized adjuvant treatment decisions.