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 , J. Luo
{"title":"具有黏液组织学的肺腺癌:临床、基因组学和免疫微环境特征以及基于免疫疗法的治疗和KRASG12C抑制剂的结果","authors":"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 , J. Luo","doi":"10.1016/j.annonc.2024.11.014","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD<sup>Muc</sup>), which is associated with a light/absent smoking history and a high prevalence of <em>KRAS</em> mutations. We sought to characterize LUAD<sup>Muc</sup> by comparing it with LUAD without mucinous histology (LUAD<sup>non-muc</sup>) and determine the relative benefit of current treatments.</div></div><div><h3>Patients and methods</h3><div>Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD<sup>Muc</sup> or LUAD<sup>non-muc</sup> were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD<sup>Muc</sup> and LUAD<sup>non-muc</sup>.</div></div><div><h3>Results</h3><div>Of 4082 patients with LUAD, 9.9% had LUAD<sup>Muc</sup>. Compared with LUAD<sup>non-muc</sup>, patients with LUAD<sup>Muc</sup> had a lighter smoking history (median 15 versus 20 pack-years; <em>P</em> = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, <em>P</em> < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, <em>P</em> < 0.0001). Mutations in <em>KRAS</em>, <em>NKX2-1</em> [thyroid transcription factor 1 (TTF-1)], <em>STK11</em>, <em>SMARCA4</em>, <em>GNAS,</em> and <em>ALK</em> rearrangements were enriched in LUAD<sup>Muc</sup>, while <em>TP53</em>, <em>EGFR</em>, <em>BRAF</em>, and <em>MET</em> mutations were enriched in LUAD<sup>non-muc</sup>. At stage IV diagnosis, LUAD<sup>Muc</sup> was more likely to have contralateral lung metastasis (55.2% versus 36.9%, <em>P</em> < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, <em>P</em> < 0.0001). Compared with LUAD<sup>non-muc</sup>, LUAD<sup>Muc</sup> cases showed lower intratumor CD8<sup>+</sup>, PD-1<sup>+</sup>, CD8<sup>+</sup>PD-1<sup>+</sup>, and FOXP3<sup>+</sup> cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD<sup>non-muc</sup> (<em>n</em> = 1511), LUAD<sup>Muc</sup> (<em>n</em> = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, <em>P</em> < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, <em>P</em> < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, <em>P</em> < 0.0001). Similarly, patients with LUAD<sup>Muc</sup> had worse outcomes to chemoimmunotherapy. LUAD<sup>Muc</sup> (<em>n</em> = 18) and LUAD<sup>non-muc</sup> (<em>n</em> = 150) had similar ORR (16.7% versus 34.9%, <em>P</em> = 0.12) and mPFS (4.6 versus 5.6 months, <em>P</em> = 0.17) to treatment with KRAS<sup>G12C</sup> inhibitors, but LUAD<sup>Muc</sup> had shorter mOS (6.8 versus 10.8 months, <em>P</em> = 0.018).</div></div><div><h3>Conclusions</h3><div>LUAD<sup>Muc</sup> represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"36 3","pages":"Pages 297-308"},"PeriodicalIF":56.7000,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors\",\"authors\":\"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 , J. Luo\",\"doi\":\"10.1016/j.annonc.2024.11.014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD<sup>Muc</sup>), which is associated with a light/absent smoking history and a high prevalence of <em>KRAS</em> mutations. We sought to characterize LUAD<sup>Muc</sup> by comparing it with LUAD without mucinous histology (LUAD<sup>non-muc</sup>) and determine the relative benefit of current treatments.</div></div><div><h3>Patients and methods</h3><div>Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD<sup>Muc</sup> or LUAD<sup>non-muc</sup> were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD<sup>Muc</sup> and LUAD<sup>non-muc</sup>.</div></div><div><h3>Results</h3><div>Of 4082 patients with LUAD, 9.9% had LUAD<sup>Muc</sup>. Compared with LUAD<sup>non-muc</sup>, patients with LUAD<sup>Muc</sup> had a lighter smoking history (median 15 versus 20 pack-years; <em>P</em> = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, <em>P</em> < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, <em>P</em> < 0.0001). Mutations in <em>KRAS</em>, <em>NKX2-1</em> [thyroid transcription factor 1 (TTF-1)], <em>STK11</em>, <em>SMARCA4</em>, <em>GNAS,</em> and <em>ALK</em> rearrangements were enriched in LUAD<sup>Muc</sup>, while <em>TP53</em>, <em>EGFR</em>, <em>BRAF</em>, and <em>MET</em> mutations were enriched in LUAD<sup>non-muc</sup>. At stage IV diagnosis, LUAD<sup>Muc</sup> was more likely to have contralateral lung metastasis (55.2% versus 36.9%, <em>P</em> < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, <em>P</em> < 0.0001). Compared with LUAD<sup>non-muc</sup>, LUAD<sup>Muc</sup> cases showed lower intratumor CD8<sup>+</sup>, PD-1<sup>+</sup>, CD8<sup>+</sup>PD-1<sup>+</sup>, and FOXP3<sup>+</sup> cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD<sup>non-muc</sup> (<em>n</em> = 1511), LUAD<sup>Muc</sup> (<em>n</em> = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, <em>P</em> < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, <em>P</em> < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, <em>P</em> < 0.0001). Similarly, patients with LUAD<sup>Muc</sup> had worse outcomes to chemoimmunotherapy. LUAD<sup>Muc</sup> (<em>n</em> = 18) and LUAD<sup>non-muc</sup> (<em>n</em> = 150) had similar ORR (16.7% versus 34.9%, <em>P</em> = 0.12) and mPFS (4.6 versus 5.6 months, <em>P</em> = 0.17) to treatment with KRAS<sup>G12C</sup> inhibitors, but LUAD<sup>Muc</sup> had shorter mOS (6.8 versus 10.8 months, <em>P</em> = 0.018).</div></div><div><h3>Conclusions</h3><div>LUAD<sup>Muc</sup> represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.</div></div>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\"36 3\",\"pages\":\"Pages 297-308\"},\"PeriodicalIF\":56.7000,\"publicationDate\":\"2024-12-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0923753424049512\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0923753424049512","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:大约10%的肺腺癌(LUAD)具有粘液组织学(LUADMuc),这与轻度/不吸烟史和KRAS突变的高发率有关。我们试图通过将LUADMuc与无粘液组织学的LUAD (LUADnon-muc)进行比较来表征LUADMuc,并确定当前治疗的相对益处。患者和方法:纳入来自5家机构和TCGA胰腺癌图谱中分类为LUADMuc或LUADnon-muc的LUAD患者。比较LUADMuc和LUADnon-muc的临床病理、基因组学、免疫表型、转录特征和治疗结果。结果:4082例LUAD患者中,9.9%为LUADMuc。与LUADnon-muc相比,LUADMuc患者吸烟史较轻(中位数:15 vs 20包年,P=0.008), PD-L1 TPS较低(中位数:0% vs 5%, PMuc),而LUADnon-muc中富集TP53、EGFR、BRAF和MET突变。在IV期诊断时,LUADMuc更容易发生对侧肺转移(55.2% vs 36.9%), Pnon-muc、LUADMuc患者肿瘤内CD8+、PD-1+、CD8+PD-1+和FOXP3+细胞水平较低。在接受ICIs的转移性病例中,与LUADnon-muc (N=1,511)相比,LUADMuc (N=112)的客观缓解率较低(ORR, 8.4% vs 25.9%), PMuc的化疗免疫治疗结果较差。与KRASG12C抑制剂相比,LUADMuc (N=18)和LUADnon-muc (N=150)的ORR (16.7% vs 34.9%, P=0.12)和mPFS (4.6 vs 5.6个月,P=0.17)相似,但LUADMuc的mOS (6.8 vs 10.8个月,P=0.018)较短。结论:LUADMuc代表了一个独特的LUAD亚群,具有独特的临床病理、基因组、免疫表型和转录特征,与基于免疫治疗的标准治疗相比,其预后更差。
Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors
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.
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.