Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors

被引：2

作者：

Di Federico, A. ^{[1
]}

Hong, L. ^{[2
]}

Elkrief, A. ^{[3
]}

Thummalapalli, R. ^{[3
]}

Cooper, A. J. ^{[4
]}

Ricciuti, B. ^{[1
]}

Digumarthy, S. ^{[4
]}

Alessi, J. V. ^{[1
]}

Gogia, P. ^{[3
]}

Pecci, F. ^{[1
]}

Makarem, M. ^{[1
]}

Gandhi, M. M. ^{[1
]}

Garbo, E. ^{[1
]}

Saini, A. ^{[1
]}

De Giglio, A. ^{[5
]}

Favorito, V. ^{[5
]}

Scalera, S. ^{[6
]}

Cipriani, L. ^{[6
]}

Marinelli, D. ^{[7
]}

Haradon, D. ^{[1
]}

Nguyen, T. ^{[1
]}

Haradon, J. ^{[1
]}

Voligny, E. ^{[1
]}

Vaz, V. ^{[1
]}

Gelsomino, F. ^{[5
]}

Sperandi, F. ^{[5
]}

Melotti, B. ^{[5
]}

Ladanyi, M. ^{[8
]}

Zhang, J. ^{[2
]}

Gibbons, D. L. ^{[2
]}

Heymach, J. V. ^{[2
]}

Nishino, M. ^{[9
,10
]}

Lindsay, J. ^{[11
]}

Rodig, S. J. ^{[12
]}

Pfaff, K. ^{[11
]}

Sholl, L. M. ^{[12
]}

Wang, X. ^{[13
]}

Johnson, B. E. ^{[1
,14
,15
]}

Janne, P. A. ^{[1
,14
,15
]}

Rekhtman, N. ^{[8
]}

Maugeri-Sacca, M. ^{[6
]}

Heist, R. S. ^{[4
]}

Ardizzoni, A. ^{[5
]}

Awad, M. M. ^{[1
,14
,15
]}

Arbour, K. C. ^{[3
]}

Schoenfeld, A. J. ^{[3
]}

Vokes, N. I. ^{[2
]}

Luo, J. ^{[1
,14
,15
]}

机构：

[1] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Head & Neck Med Oncol, Houston, TX USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA

[4] Massachusetts Gen Hosp, Boston, MA USA

[5] IRCCS Azienda Osped Univ Bologna, Div Med Oncol, Bologna, Italy

[6] IRCCS Regina Elena Natl Canc Inst, Clin Trial Ctr Biostat & Bioinformat, Rome, Italy

[7] Sapienza Univ Rome, Dept Expt Med, Rome, Italy

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[9] Brigham & Womens Hosp, Dept Radiol, Boston, MA USA

[10] Dana Farber Canc Inst, Dept Imaging, Boston, MA USA

[11] Dana Farber Canc Inst, Ctr Immuno Oncol, Boston, MA USA

[12] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[13] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA

[14] Brigham & Womens Hosp, Dept Med, Boston, MA USA

[15] Harvard Med Sch, Boston, MA USA

来源：

ANNALS OF ONCOLOGY | 2025年 / 36卷 / 03期

关键词：

non-small cell lung cancer; mucinous lung adenocarcinoma; histology; immunotherapy; KRAS inhibitors; genomics; MUTATIONS; KRAS;

D O I：

10.1016/j.annonc.2024.11.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：297 / 308

页数：12