Distinct genomic and immunophenotypic features of solid-predominant versus nonsolid-predominant stage I lung adenocarcinomas and association with disease recurrence after surgical resection.

8514 Background: Compared to lung adenocarcinomas (LUAD) with nonsolid-predominant histology (lepidic, acinar, papillary, micropapillary), those with predominantly solid features have a higher risk of disease recurrence after surgical resection. However, little is known about the genomic landscape and immunophenotype of solid vs nonsolid stage I LUAD. Methods: We collected clinicopathologic data from patients with resected stage I NSCLC (AJCC 8th Edition), which underwent next-generation sequencing to identify genomic alterations and tumor mutational burden (TMB). A subset of these samples also had multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 to determine differences in tumor immune cells subsets according to histologic subtype. Disease free-survival (DFS) was compared in patients based on their predominant histologic subtype (solid vs nonsolid). Results: Among 658 LUADs, 11.4% (N = 75) had solid-predominant and 88.6% (N = 583) nonsolid-predominant histology. After a median follow-up of 50 months from the time of surgery, 145 patients (22.0%) experienced recurrence. Compared to nonsolid-predominant LUAD, those with solid predominance had a significantly lower prevalence of activating EGFR, BRAFV600E, and METex14 mutations as well as ALK/ RET/ ROS1 rearrangements (9.3% versus 31.6%, P < 0.001), no difference in KRASG12C frequency (24% versus 16.8%, P = 0.14), a higher TMB (median 12.2 versus 7.2 mutations/megabase; P < 0.001), and a shorter median DFS from the time of surgical resection (43.2 months versus not reached, HR: 3.3 [95% CI: 2.2-4.9], P < 0.001). The detrimental effect of solid-predominant LUAD in DFS remained significant after adjusting for other factors such as tumor stage, surgery type, smoking status, and TMB (HR: 2.66 [95% CI: 1.71-4.11], P < 0.001]. Among LUADs profiled by multiplex immunofluorescence, compared to tumors with nonsolid-predominant subtype (N = 197), those with solid predominance (N = 23) had significantly higher numbers of CD8+, FOXP3+, PD-1+ immune cells, and PD-1+ CD8+ T cells, both intratumorally (P < 0.001) and at the tumor-stroma interface (P < 0.001). Solid-predominant subtype was also associated with a higher median PD-L1 expression level on tumor (5% versus 1%; P = 0.01) and immune cells (16% versus 7%, P = 0.02). Conclusions: Among patients with surgically-resected stage I LUAD, solid-predominant histology was associated with distinct genotypic and immunologic characteristics. These findings may aid in identifying patients at greater risk of recurrence after surgery.