Distinct clinical and genomic landscape of bilateral parenchymal non–small cell lung cancer (NSCLC) using the AACR GENIE BPC database.

e20558 Background: NSCLC with bilateral lung involvement is currently staged as IV (M1a). However, patients with lung-only metastasis without lymph node (LN) involvement often exhibit atypical clinical courses. We aimed to characterize the survival and genomic signatures of this "Bilateral Parenchymal (BP)" subgroup compared to stage III and other stage IV NSCLC. Methods: From the AACR GENIE Biopharma Collaborative (BPC) cohort (N = 1,846), we analyzed a selected group of 1,156 patients with stage III or IV disease. Patients were categorized into: BP (n = 62; bilateral parenchymal only, no LN/distant metastatis), stage III (n = 388), and other stage IV (n = 706). Overall survival (OS) was estimated via the Kaplan-Meier method. Genomic alterations, including non-synonymous somatic mutations and copy number alterations, were compared across cohorts using Fisher’s Exact test with Benjamini-Hochberg correction for multiple testing. Results: The BP group was predominantly comprised of adenocarcinoma (93.5%) with a median age of 65.7 years. The median OS for the BP group was 30.7 months (95% CI, 22.4–38.9), which was significantly superior to other stage IV (21.6 months; 95% CI, 19.3–24.1; HR, 0.66; 95% CI, 0.47–0.91; p = 0.012) and comparable to stage III (33.6 months; 95% CI, 28.5–39.4; HR, 1.39; 95% CI, 0.98–1.97; p = 0.064). Genomically, the BP group exhibited a significantly lower prevalence of TP53 mutations (40.3%) compared to other stage IV (59.0%; p = 0.005) and stage III (55.7%). Notably, GNAS mutations were highly enriched in the BP group (10.5%) compared to stage III (1.7%) and other stage IV (1.6%) (p < 0.001). Other enriched alterations in the BP group included NEGR1 (7.1%, p = 0.016) and ASXL2 (7.4%, p = 0.024). Conclusions: NSCLC with bilateral parenchymal involvement without LN involvement represents a unique clinical entity with a survival profile more aligned with stage III than metastatic disease. This improved prognosis is associated with a distinct genomic landscape featuring lower TP53 and higher GNAS mutation, a molecular signature frequently associated with mucinous histology. It also provides a biological rationale for exploring aggressive local therapies, such as bilateral lung transplantation.