Integrated multi-omic profiling enables recurrence risk stratification beyond pathological stage in resected EGFR-mutant lung adenocarcinoma.

Authors

Stephanie P L Saw, Mengyuan Pang, Jia Chi Yeo, Jacob J S Alvarez, Ngak Leng Sim, Amanda Y Guo, Sinem Kadioglu, Eunice L Y Lau, Yi Ting Lau, Denis Odinokov, Victor Getty, Gillianne G Y Lai, Darren W T Lim, Ravindran Kanesvaran, Mei-Kim Ang, Quan Sing Ng, Wan Ling Tan, Wei Chong Tan, Aaron C Tan, Sophia Y N Wong, Amanda O L Seet, Regina Hoo, Boon-Hean Ong, Tony K H Lim, Anders Jacobsen Skanderup, Daniel S W Tan

Published in

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. Pages 104204. Sep 16, 2026. Epub Sep 16, 2026.

Abstract

Early-stage EGFR-mutant lung adenocarcinoma (LUAD) demonstrates heterogeneous outcomes after curative surgery, yet adjuvant treatment decisions are guided by pathological stage alone. Following the ADAURA trial, adjuvant osimertinib is the standard of care for resected stage IB-IIIA EGFR-mutant LUAD; however, real-world data demonstrate that up to 40% of patients remain disease-free at five years without adjuvant osimertinib, underscoring the need for improved risk stratification.
We performed integrated clinical, genomic and transcriptomic profiling of 400 patients with resected stage IA-IIIA EGFR-mutant LUAD. EGFR-mutant recurrence risk models integrating clinical, genomic and transcriptomic data were developed and validated across one internal and three external cohorts.
Genomic instability, including TP53 co-mutations, copy number alterations and APOBEC-associated mutational signatures, increased with pathological stage. RBM10 co-mutations were enriched in tumours with L858R mutations and correlated with upregulation of WNT signalling and epithelial-mesenchymal transition. Transcriptomic features outperformed clinical or genomic variables alone in predicting recurrence risk, and a multi-omic model demonstrated superior and reproducible performance, achieving a median concordance index of 75.4% across four independent validation cohorts. The multi-omic model stratified recurrence risk within individual pathological stages, including stage I disease, and identified patients most likely to benefit from adjuvant EGFR TKI.
These findings define the molecular heterogeneity of early-stage EGFR-mutant LUAD and support multi-omic risk stratification to inform adjuvant EGFR TKI decisions beyond pathological stage. Prospective validation in larger cohorts will be required to confirm these findings.

PMID:
42749051
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.

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