Genomic clonality analysis of patients with metastatic lung-limited non–small cell lung carcinoma (NSCLC) who underwent double lung transplantation (DLT) across timepoints and tumor region.

8658 Background: Double lung transplantation (DLT) registry aimed for lung-limited malignancies (DREAM) study (NCT05671887) cohort A evaluates DLT as a therapeutic strategy for patients with advanced bilateral lung-limited NSCLC. This is the first translational report of the genomic clonality analysis of the DREAM study across timepoints and tumor regions. Methods: Patients with advanced bilateral lung-limited NSCLC who underwent DLT at Northwestern Memorial Hospital between September 2021 and December 2025 were included in the DREAM study cohort A. Patients with extrapulmonary disease were excluded. The primary indications for DLT were disease refractory to systemic therapies, with or without respiratory failure. Tissue next generation sequencing (tNGS) data was collected from diagnosis, bilateral explant and recurrence samples. Commercial tNGS panels utilized include Altera, Caris, Foundation Medicine, Tempus xT, and PGDx. Truncal genetic mutations were identified from genes that were common to all tNGS panels. Results: Among 18 patients enrolled in DREAM study cohort A, 11 patients with bilateral tissue NGS were analyzed. The median age was 55.5 years (range 37-74), 9 (81%) were female, and 5 (45%) had a history of smoking. 6 patients (54%) had invasive mucinous adenocarcinoma histology. All 11 patients harbored common gene mutations in bilateral tumors and had common oncogenic genomic clones indicating a truncal mutation. Details are outlined in Table 1. Conclusions: All patients harbored common oncogenic driver mutations across all available specimens, providing definitive genomic evidence of a monoclonal origin. These findings not only distinguish intrapulmonary metastasis from multiple primary tumors but also support a common ancestral tumor clone that has progressed over time and space. Further characterization of tumor evolution in advanced bilateral lung-limited NSCLC is warranted. Clinical trial information: NCT05671887 . Case Tissue NGS by timepoints and region (Dx/Explant/Recur) Shared variants 1 RML / Bilateral Exp / RUL *PIK3CA E110del, *SETD2 D2112fs, GRM3 R331C 2 LUL / Bilateral Exp / Pelvic bone *EGFR G719A 3 LLL / Bilateral Exp / T9 vertebra *KRAS G12D 4 Bilateral Exp / Pelvic bone *ETV6 splice, KMT2D L1443Q 5 Bilateral Exp *KRAS G12V, STK11 (*A200fs, *314fs) 6 LUL / Bilateral Exp *BAP1 Q595*, *GNAS R201C 7 Bilateral Exp *EGFR Ex19del 8 Bilateral Exp / LLL *KRAS G12V 9 Bilateral Exp EGFR (*Ex19del, C797S), LRP1B R531H, PTPRT I320N, SF3B1 A368V Additional Cases: Case 10 (Bilateral Exp): *KRAS G12C, *ARID1A Q507*, *ATM c.1A>T, *ATRX W1572*, *STK11 W332*, CHD2, MALT1, PHLPP1, PTPRT, RICTOR, SEMA3C, TAF1 (W457L, D169Y). Case 11 (RLL, Bilateral Exp): *MET Ex14 skip, *TP53 V143M, ERBB3, NF2. Asterisk (*) indicates oncogenic/likely oncogenic variants defined by OncoKB . Abbrev: Dx, diagnosis; Exp, explant; Recur, recurrence.