Mucinous histology is seen in 10% of patients with lung adenocarcinoma and exhibits distinctive clinical, molecular, and pathological features. In an analysis of patients with lung adenocarcinoma from five institutions and TCGA PanCancer Atlas classified as mucinous or non-mucinous, mucinous cases had a lower cigarette smoking history, PD-L1 expression, and tumour mutation burden (TMB), all of which are features associated with decreased immune checkpoint inhibitors (ICI) efficacy.
The researchers also observed a shorter overall survival (OS) from diagnosis among patients with mucinous histology, regardless of the stage of disease. They observed that patients with early stage of disease (I-III) diagnosed with mucinous histology have a worse prognosis. Additionally, a significant enrichment of KRAS, NKX2-1, GNAS, STK11, and SMARCA4 mutations was observed among cases with mucinous histology. Patients with mucinous histology had poorer outcomes to immunotherapy with or without chemotherapy and KRASG12C inhibitors according to Dr. Jia Luo of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute in Boston, MA, US and colleagues, who published the findings on 2 December 2024 in the Annals of Oncology.
Lung adenocarcinoma with mucinous histology is defined by goblet or columnar cells and abundant intracellular and extracellular mucin. TTF-1 protein staining is frequently faint or negative in lung adenocarcinoma with mucinous histology. Patients with lung adenocarcinoma with mucinous histology more frequently have a never smoking history. Patients with early-stage lung adenocarcinoma with mucinous histology have a tendency to recur with intrapulmonary metastasis rather than distant metastasis. Multiple clonally related spatially separate lung lesions involving one or both lungs are a common radiologic finding. Furthermore, lung adenocarcinomas with mucinous histology more frequently harbour KRAS driver mutation, which is generally associated with a more aggressive form of non-small cell lung cancer, and driver NRG1 fusions.
Adult patients with a histologically or cytologically confirmed diagnosis of lung adenocarcinoma seen at four academic institutions in the US (Dana-Farber/Brigham and Women's Cancer Center, MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital) and at one academic institution in Italy (University of Bologna, IRCCS Policlinico S.Orsola-Malpighi) were included in this study between January 2001 and January 2024. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between the patients with mucinous and non-mucinous histology.
Of 4082 patients with lung adenocarcinoma, 9.9% had tumour with mucinous histology. Compared to lung adenocarcinoma with non-mucinous histology, patients with mucinous histology had a lighter smoking history (median 15 versus 20 pack-years, p = 0.008), lower PD-L1 tumour proportion score (TPS, median 0% versus 5%, p < 0.0001), and lower TMB (median 6.8 versus 8.5 mutations/megabase, p < 0.0001). Mutations in KRAS, NKX2-1 (TTF-1), STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in lung adenocarcinomas with mucinous histology, while TP53, EGFR, BRAF, and MET mutations were enriched in non-mucinous cases.
At stage IV diagnosis, patients with mucinous histology were 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 to non-mucinous, mucinous cases showed lower intratumour CD8positive, PD1positive, CD8positivePD1positive, and FOXP3positive cells.
Among metastatic cases receiving ICIs, compared to 1511 non-mucinous, 112 mucinous cases had 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 mucinous histology had worse outcomes to chemo-immunotherapy. Eighteen patients with mucinous histology and 150 with non-mucinous 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 mucinous had shorter mOS (6.8 versus 10.8 months, p = 0.018).
This is the first study to report worse outcomes with ICI-based therapies in patients with mucinous compared to those with non-mucinous lung adenocarcinomas. This large cohort also found that lung adenocarcinoma with mucinous histology is associated with lower PD-L1 TPS. In addition, the study team observed a significantly lower TMB and intratumoural immune cell density, factors that are all associated with diminished response to ICI therapies, in mucinous compared to non-mucinous cases.
These features are likely all interconnected with each other, as lighter history of tobacco use, lower TMB values, and mutations in genes such as STK11 and KEAP1, which characterise mucinous cases, have been consistently associated with lower tumour immunogenicity in previous studies. This observation further suggests that in addition to lung adenocarcinoma with mucinous histology carrying a worse overall prognosis, it is also less responsive to current ICI-based treatments.
In this cohort, outcomes to KRASG12C inhibitors were similarly worse in patients with mucinous histology, who achieved a statistically significant shorter OS. Although a larger cohort is needed to confirm this observation, it reinforces the notion that lung adenocarcinoma with mucinous histology is a hard-to-treat lung adenocarcinoma subtype.
The authors underlined that physicians and investigators should consider the presence and extent of mucinous histology in lung adenocarcinomas to prognosticate and predict the relative clinical benefit of ICI-based and KRASG12C inhibitor therapies.
Reference
Di Federico A, Hong L, Elkrief A, et al. Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors. Annals Of Oncology; Published online 2 December 2024. DOI: https://doi.org/10.1016/j.annonc.2024.11.014