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Multicenter Study
. 2025 Mar;36(3):297-308.
doi: 10.1016/j.annonc.2024.11.014. Epub 2024 Dec 3.

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

A Di Federico  1 , L Hong  2 , A Elkrief  3 , R Thummalapalli  3 , A J Cooper  4 , B Ricciuti  1 , S Digumarthy  4 , J V Alessi  1 , P Gogia  3 , F Pecci  1 , M Makarem  1 , M M Gandhi  1 , E Garbo  1 , A Saini  1 , A De Giglio  5 , V Favorito  5 , S Scalera  6 , L Cipriani  6 , D Marinelli  7 , D Haradon  1 , T Nguyen  1 , J Haradon  1 , E Voligny  1 , V Vaz  1 , F Gelsomino  5 , F Sperandi  5 , B Melotti  5 , M Ladanyi  8 , J Zhang  2 , D L Gibbons  2 , J V Heymach  2 , M Nishino  9 , J Lindsay  10 , S J Rodig  11 , K Pfaff  10 , L M Sholl  11 , X Wang  12 , B E Johnson  13 , P A Jänne  13 , N Rekhtman  8 , M Maugeri-Saccà  6 , R S Heist  4 , A Ardizzoni  5 , M M Awad  13 , K C Arbour  3 , A J Schoenfeld  3 , N I Vokes  2 , J Luo  14
Affiliations
Multicenter Study

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

A Di Federico et al. Ann Oncol. 2025 Mar.

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.

Keywords: KRAS inhibitors; genomics; histology; immunotherapy; mucinous lung adenocarcinoma; non-small-cell lung cancer.

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Conflict of interest statement

Disclosure

Alessandro Di Federico: Scientific advisory: Hanson-Wade, Novartis. Honoraria: society for immunotherapy of cancer (SITC). Arielle Elkrief: Advisory Board: Bristol Myers Squibb. Speaker fees: Bristol Myers Squibb, AstraZeneca, Merck. Biagio Ricciuti: Advisory Board: Regeneron, AstraZeneca, AMGEN; Travel support Regeneron, Genentech, Bristol Myers Squibb. Speaker fees: AstraZeneca; Honoraria: Targeted Oncology. Joao V. Alessi: Advisory board: AstraZeneca, Bristol-Myers Squibb; Consultant: MSD, Janssen. Francesco Gelsomino: advisory role from AstraZeneca, Novartis, BMS, Regeneron and Eli-Lilly. Jianjun Zhang: grants from Merck, Novartis, Johnson and Johnson, personal fees from BMS, AZ, Novartis, Johnson and Johnson, GenePlus, Hengrui, Innovent. Don L. Gibbons: advisor/consultant for Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Eli Lilly, Menarini, and Napa Therapeutics and receives research funding from Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, NGM Biopharmaceuticals, Boehringer Ingelheim, and Mirati Therapeutics. John V. Heymach: advisory committees for DAVA Oncology, Regeneron, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, and Chugai Pharmaceuticals; receives research support from Takeda, AstraZeneca, Boehringer-Ingelheim, and Spectrum; and receives royalties and licensing fees from Spectrum Pharmaceuticals. Mizuki Nishino: Consultant: AstraZeneca; Research Grant to the institution from Canon Medical Systems, AstraZeneca, Daiichi Sankyo, and Konica-Minolta. Scott J. Rodig: Leadership: Immunitas; Stock and Other Ownership Interests: Immunitas; Honoraria: Perkin Elmer, Bristol Myers Squibb; Consulting or Advisory Role: Bristol Myers Squibb; Research Funding: Bristol Myers Squibb, Merck, Affimed Therapeutics, Kite, a Gilead company; Patents, Royalties, Other Intellectual Property: Patent pending for use of Anti-galectin1 antibodies for diagnostic use; Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb Kathleen Pfaff: Employment: Dana-Farber Cancer Institute; Patents, Royalties, Other Intellectual Property: receive royalties for patent on a high content screening assay for iPSC-derived motor neuron survival (work done prior to joining DFCI). Lynette M. Sholl: Consulting or Advisory Role: Genentech (Inst), Lilly (Inst), AstraZeneca; Research Funding: Roche/Genentech (Inst), Bristol Myers Squibb (Inst). Bruce E. Johnson: Paid Consultant to Novartis, Checkpoint Therapeutics, Astra Zeneca, Daichi Sankyo, Genentech, Bluedot Bio, G1 Therapeutics, Jazz Pharmaceuticals, Merus, Abdera, Simcere Pharmaceutical Companies. Paid member of a Data Safety Monitoring Board for Revolution Medicines and Merck. Unpaid Member of Steering Committee for Pfizer. Research Support from Cannon Medical Imaging. Supported in part by the Taylor Family Fund for Lung Cancer Research. Pasi A. Janne: consultancy roles for Abbvie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, DualityBio, Eisai, Eli Lilly, Frontier Medicines, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta and Voronoi; stock ownership in Gatekeeper Pharmaceuticals; research funding from AstraZenenca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA Biotechnology, Revolution Medicines and Takeda Oncology; and post-marketing royalties from Dana-Farber Cancer Institute-owned intellectual property relating to EGFR mutations that has been licensed to Lab Corp. Rebecca S. Heist: Consulting honoraria: Astrazeneca, Biohaven, Claim, Daichii Sankyo, Lilly, Merck, Novartis, Regeneron, Sanofi; Research funding (to institution not to self) for clinical trials: Abbvie, Agios, Corvus, Daichii Sankyo, Exelixis, Lilly, Mirati, Mythic, Novartis, Symphogen, Turning Point. Andrea Ardizzoni: research grants from Celgene, BMS, Ipsen, Roche; honoraria for advisory board participation from Bristol Myers Squibb, Merck, ROCHE, AstraZeneca, Eli-Lilly. Mark M. Awad: Consulting or Advisory Role: Merck, Pfizer, Bristol Myers Squibb, Foundation Medicine, Novartis, Gritstone Bio, Mirati Therapeutics, EMD Serono, AstraZeneca, Instil Bio, Regeneron, Janssen, Affini-T Therapeutics; Research Funding: Genentech/Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Amgen (Inst) Travel, Accommodations, Expenses: Bristol Myers Squibb Foundation; Open Payments Link: https://openpaymentsdata.cms.gov/physician/1127368. Kathryn C. Arbour: consultant for AstraZeneca and Sanofi-Genzyme and has received institutional research support from Mirati, Revolution Medicines, and Genentech. Adam J. Schoenfeld: consulting/advising role to J&J, KSQ Therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Prelude Therapeutics, Lyell Immunopharma, Amgen, and Heat Biologics, and research funding to institution from GSK, PACT Pharma, Iovance Biotherapeutics, Achilles Therapeutics, Merck, BMS, Harpoon Therapeutics, and Amgen. Natalie I. Vokes: Consulting: Sanofi, Oncocyte, Lilly, Regeneron, Amgen, Xencor, Astra Zeneca, Tempus, Pfizer, Summit, OncoHost; Speaking fees: Guardant; Travel support Regeneron; Research funding: Circulogene, Mirati; Honoraria: Scienomics, Cancer GRACE, OncLive, OMNI-Oncology. Jia Luo: Jia Luo: honoraria: from Targeted Oncology, Physicians Education Resource, VJ Oncology, Cancer GRACE, Community Cancer Education Inc., advisory board participation: AstraZeneca, Astellas, and Amgen; grants to institution: from Erasca, Genentech, Kronos Bio, Novartis, Revolution Medicines; personal fees: Erasca, Blueprint Medicines, and Daiichi Sankyo. All remaining authors have declared no conflicts of interest.

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