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

IF 56.7 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2024-12-03 DOI:10.1016/j.annonc.2024.11.014

A Di Federico, L Hong, A Elkrief, R Thummalapalli, A J Cooper, B Ricciuti, S Digumarthy, J V Alessi, P Gogia, F Pecci, M Makarem, M M Gandhi, E Garbo, A Saini, A De Giglio, V Favorito, S Scalera, L Cipriani, D Marinelli, D Haradon, T Nguyen, J Haradon, E Voligny, V Vaz, F Gelsomino, F Sperandi, B Melotti, M Ladanyi, J Zhang, D L Gibbons, J V Heymach, M Nishino, J Lindsay, S J Rodig, K Pfaff, L M Sholl, X Wang, B E Johnson, P A Jänne, N Rekhtman, M Maugeri-Saccà, R S Heist, A Ardizzoni, M M Awad, K C Arbour, A J Schoenfeld, N I Vokes, J Luo

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引用次数: 0

Abstract

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.

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来源期刊

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.