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 (LUAD) have mucinous histology (LUADMuc), which is associated to a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUADMuc by comparing it to LUAD without mucinous histology (LUADnon-muc) and determine the relative benefit of current treatments.

Patients and methods: Patients with LUAD from five institutions and TCGA PanCancer Atlas classified as LUADMuc or LUADnon-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUADMuc and LUADnon-muc.

Results: Of 4,082 patients with LUAD, 9.9% had LUAD^Muc. Compared to LUAD^non-muc, patients with LUAD^Muc had a lighter smoking history (median: 15 vs 20 pack-years, P=0.008), lower PD-L1 TPS (median: 0% vs 5%, P<0.0001), and lower tumor mutation burden (median: 6.8 vs 8.5 mutations/megabase, P<0.0001). Mutations in KRAS, NKX2-1 (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% vs 36.9%, P<0.0001) and less likely to have brain metastases (23.3% vs 41.9%, P<0.0001). Compared to LUAD^non-muc, LUAD^Muc cases showed lower intratumor CD8⁺, PD-1⁺, CD8⁺PD-1⁺, and FOXP3⁺ cells. Among metastatic cases receiving ICIs, compared to LUAD^non-muc (N=1,511), LUAD^Muc (N=112) had lower objective response rate (ORR, 8.4% vs 25.9%, P<0.0001), and shorter median progression-free survival (mPFS, 2.6 vs 3.9 months, P<0.0001) and overall survival (mOS, 9.9 vs 17.2 months, P<0.0001). Similarly, patients with LUAD^Muc had worse outcomes to chemo-immunotherapy. LUAD^Muc (N=18) and LUAD^non-muc (N=150) had similar ORR (16.7% vs 34.9%, P=0.12) and mPFS (4.6 vs 5.6 months, P=0.17) to treatment with KRAS^G12C inhibitors, but LUAD^Muc had shorter mOS (6.8 vs 10.8 months, P=0.018).

Conclusion: LUAD^Muc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.