Abstract Background: Double lung transplantation 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. Among them, 7 patients had tNGS data from 2 or more timepoints and 3 patients had tNGS data from 3 or more timepoints. All patients had common oncogenic genomic clones indicating a truncal mutation. Details are outlined in Table 1. Conclusions: This is the first report showing clonal evolution using tNGS in patients with advanced bilateral lung-limited NSCLC who underwent DLT. All patients harbored common oncogenic driver mutations across all specimens, providing definitive genomic evidence of a monoclonal origin. These findings not only distinguish intrapulmonary metastasis from multiple primary tumors—confirming a Stage IV diagnosis—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. Citation Format: Young Kwang Chae, Sanghwa Kim, Liam Il-Young Chung, Ronald Seungjune Min, Hangyul Lee, Yuchan Kim, Sangmi Yoo, Ruli Gao, Chitaru Kurihara, Ambalavanan Arunachalam, Ankit Bharat. 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 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT251.
Chae et al. (Fri,) studied this question.