Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRAS^G12C inhibitors

Background: Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD^Muc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUAD^Muc by comparing it with LUAD without mucinous histology (LUAD^non-muc) and determine the relative benefit of current treatments. Patients and methods: Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD^Muc or LUAD^non-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD^Muc and LUAD^non-muc. Results: Of 4082 patients with LUAD, 9.9% had LUAD^Muc. Compared with LUAD^non-muc, patients with LUAD^Muc had a lighter smoking history (median 15 versus 20 pack-years; P = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS, NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUAD^Muc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUAD^non-muc. At stage IV diagnosis, LUAD^Muc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUAD^non-muc, LUAD^Muc cases showed lower intratumor CD8⁺, PD-1⁺, CD8⁺PD-1⁺, and FOXP3⁺ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD^non-muc (n = 1511), LUAD^Muc (n = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUAD^Muc had worse outcomes to chemoimmunotherapy. LUAD^Muc (n = 18) and LUAD^non-muc (n = 150) had similar ORR (16.7% versus 34.9%, P = 0.12) and mPFS (4.6 versus 5.6 months, P = 0.17) to treatment with KRAS^G12C inhibitors, but LUAD^Muc had shorter mOS (6.8 versus 10.8 months, P = 0.018). Conclusions: LUAD^Muc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.