Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer
Open accessAbstract
Background Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRAS MUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRAS G12C NSCLC, KRAS G12D NSCLC is associated with low/never-smoking status and is largely uncharacterized.Patients and methods Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype.Results Of 2327 patients with KRAS-mutated (KRAS MUT) NSCLC, 15% (n = 354) harbored KRAS G12D. Compared to KRAS non-G12D NSCLC, KRAS G12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRAS G12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRAS non-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRAS G12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRAS MUT NSCLC who received PD-(L)1-based therapies, KRAS G12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRAS non-G12D.Conclusions KRAS G12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRAS G12D lung cancers will have to take these differences into account.
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The KRASG12D mutation was reported to be more immune suppressive with shorter survival in lung cancer and pancreatic cancer.
“The KRASG12D mutation was reported to be more immune suppressive with shorter survival in lung cancer and pancreatic cancer31,32.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [31]
In NSCLC, KRAS G12D mutation is associated with lower tumour-mutation burden, decreased PDL1 expression, and reduced CD8+ T cell infiltration in the TME.
“In NSCLC, KRAS G12D mutation has been associated with a lower tumour-mutation burden, decreased PDL1 expression, and reduced CD8 + T cell infiltration in the TME [49].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [49]
Compared to non-G12D mutations, KRAS G12D mutations are associated with poorer overall survival with immune checkpoint inhibition (HR 1.45, 95% CI 1.05-1.99; p = 0.02).
“Compared to non-G12D mutations, KRAS G12D mutations are also associated with poorer overall survival with immune checkpoint inhibition (HR 1.45, 95% CI 1.05–1.99; p = 0.02).”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [49]
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- Authors
- Ricciuti, B., Alessi, J. V., Elkrief, A., Wang, X., Cortellini, A., Li, Y. Y., Vaz, V. R., Gupta, H., Pecci, F., Barrichello, A., Lamberti, G., Nguyen, T., Lindsay, J., Sharma, B., Felt, K., Rodig, S. J., Nishino, M., Sholl, L. M., Barbie, D. A., Negrao, M. V., Zhang, J., Cherniack, A. D., Heymach, J. V., Meyerson, M., Ambrogio, C., Jänne, P. A., Arbour, K. C., Pinato, D. J., Skoulidis, F., Schoenfeld, A. J., Awad, M. M., & Luo, J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Hammersmith Hospital (GB)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Turin (IT)
- Corresponding author
- Luo, J.
- ORCID
- Ricciuti, B.
- Alessi, J.V.
- Elkrief, A.
- Wang, X.
- Cortellini, A.
- Li, Y.Y.
- Vaz, V.R.
- Gupta, H.
- Pecci, F.
- Barrichello, A.
- Lamberti, G.
- Nguyen, T.
- Lindsay, J.
- Sharma, B.
- Felt, K.
- Rodig, S.J.
- Nishino, M.
- Sholl, L.M.
- Barbie, D.A.
- Negrao, M.V.
- Zhang, J.
- Cherniack, A.D.
- Heymach, J.V.
- Meyerson, M.
- Ambrogio, C.
- Arbour, K.C.
- Pinato, D.J.
- Skoulidis, F.
- Schoenfeld, A.J.
- Awad, M.M.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2022-10
- Volume
- 33
- Issue
- 10
- Pages
- 1029-1040
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC11006449
- OpenAlex
- W4286435223
- Cited by
- 112
- References
- 26
- Citations by year
- 2026: 28 · 2025: 28 · 2024: 34 · 2023: 19 · 2022: 3
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Society for Immunotherapy of Cancer
- AstraZeneca
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS G12D mutation, non-small cell lung cancer, KRAS mutation, never smokers, PD-L1 expression, tumor mutational burden, tumor-infiltrating T cells, PD-1, PD-L1 inhibitors, immunotherapy response, co-occurring mutations, smoking history, tumor immune microenvironment, multiplex immunofluorescence
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Genomics, Forkhead Transcription Factors, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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