Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors Journal Article
| Authors: | Di Federico, A.; Hong, L.; Elkrief, A.; Thummalapalli, R.; Cooper, A. J.; Ricciuti, B.; Digumarthy, S.; Alessi, J. V.; Gogia, P.; Pecci, F.; Makarem, M.; Gandhi, M. M.; Garbo, E.; Saini, A.; De Giglio, A.; Favorito, V.; Scalera, S.; Cipriani, L.; Marinelli, D.; Haradon, D.; Nguyen, T.; Haradon, J.; Voligny, E.; Vaz, V.; Gelsomino, F.; Sperandi, F.; Melotti, B.; Ladanyi, M.; Zhang, J.; Gibbons, D. L.; Heymach, J. V.; Nishino, M.; Lindsay, J.; Rodig, S. J.; Pfaff, K.; Sholl, L. M.; Wang, X.; Johnson, B. E.; Jänne, P. A.; Rekhtman, N.; Maugeri-Saccà, M.; Heist, R. S.; Ardizzoni, A.; Awad, M. M.; Arbour, K. C.; Schoenfeld, A. J.; Vokes, N. I.; Luo, J. |
| Article Title: | Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors |
| Abstract: | Background: Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUADMuc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUADMuc by comparing it with LUAD without mucinous histology (LUADnon-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 LUADMuc or LUADnon-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUADMuc and LUADnon-muc. Results: Of 4082 patients with LUAD, 9.9% had LUADMuc. Compared with LUADnon-muc, patients with LUADMuc 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 LUADMuc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUADnon-muc. At stage IV diagnosis, LUADMuc 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 LUADnon-muc, LUADMuc cases showed lower intratumor CD8+, PD-1+, CD8+PD-1+, and FOXP3+ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUADnon-muc (n = 1511), LUADMuc (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 LUADMuc had worse outcomes to chemoimmunotherapy. LUADMuc (n = 18) and LUADnon-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 KRASG12C inhibitors, but LUADMuc had shorter mOS (6.8 versus 10.8 months, P = 0.018). Conclusions: LUADMuc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments. © 2024 European Society for Medical Oncology |
| Keywords: | adult; treatment outcome; aged; survival rate; major clinical study; overall survival; clinical feature; cancer staging; transcription factor foxp3; cd8+ t lymphocyte; cancer immunotherapy; progression free survival; epidermal growth factor receptor; smoking; protein p53; risk factor; histology; lung metastasis; lung adenocarcinoma; immune response; immunotherapy; brain metastasis; genomics; immunophenotyping; clinical effectiveness; k ras protein; b raf kinase; non-small-cell lung cancer; scatter factor receptor; programmed death 1 ligand 1; anaplastic lymphoma kinase; tumor microenvironment; protein kinase lkb1; brg1 protein; chemoimmunotherapy; immune checkpoint inhibitor; human; male; female; article; homeobox protein nkx 2.1; tumor mutational burden; mucinous lung adenocarcinoma; kras inhibitors; lung adenocarcinoma with mucinous |
| Journal Title: | Annals of Oncology |
| Volume: | 36 |
| Issue: | 3 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2025-03-01 |
| Start Page: | 297 |
| End Page: | 308 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2024.11.014 |
| PUBMED: | 39637943 |
| PROVIDER: | scopus |
| PMCID: | PMC11845285 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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