Background Adenocarcinoma with mucinous features represents a subtype of lung adenocarcinoma (LUADMuc). Among LUAD, invasive mucinous adenocarcinomas are associated with a higher frequency of KRAS driver mutations but a lighter smoking history.1 Information on the efficacy of immune checkpoint inhibitors (ICI) for patients with LUADMuc remains to be defined.
Methods Clinicopathologic, genomic, and ICI outcomes data were abstracted from patients with LUAD seen at a single academic center. Genomic testing was performed through targeted next-generation sequencing. LUADs with any mucinous component as assessed by a thoracic pathologist (LS) were classified as LUADMuc, and compared with the rest of the cohort (LUADNon-muc). Multiplexed immunofluorescence (mIF) was performed to assess intratumor CD8, PD1, and FOXP3 expression. Multivariable cox-regression models were used to calculate adjusted hazard ratios (aHR).
Results Among 2,417 patients with LUAD, 227 (9.4%) had LUADMuc. No difference in age and sex was observed between patients with LUADMuc vs LUADNon-muc. Compared with LUADNon-muc, patients with LUADMuc had a lower tobacco use history (median pack-years: 20 vs 25, P=0.01), PD-L1 tumor proportion score (median: 0.5% vs 10%, P<0.0001) and tumor mutational burden (median: 6.8 vs 9.1 mut/Mb, P<0.0001). KRAS was the most common driver oncogene in LUADMuc(66.8% vs 40.2% in LUADNon-muc, P<0.001) followed by ALK fusions (3.7% vs 1.1% in LUADNon-muc, P=0.009). Among 1,780 patients with available genomic profiling, mutations in KRAS, STK11, SMARCA4, NKX2.1 and GNAS were enriched in LUADMuc compared with LUADNon-muc (Q<0.05) (figure 1A). Immunophenotyping by mIF (available in 525 [21.7%] patients) showed fewer intratumoral CD8+ cells (P=0.04) and FOXP3+ cells (P=0.009) in LUADMuc vs LUADNon-muc (figure 1B). Among patients with metastatic LUAD who received ICIs, compared with LUADNon-muc (N=848), LUADMuc (N=80) cases had lower objective response rate (ORR) (9% vs 24%, P=0.002), shorter median progression-free survival (mPFS) (2.1 vs 3.5 months, aHR: 0.75, P=0.046) and median overall survival (mOS) (7.2 vs 13.2 months, aHR: 0.70, P=0.02) (figure 2A). Similarly, among patients with LUAD who received chemo-immmunotherapy, compared with LUADNon-muc (N=427), LUADMuc (N=68) achieved lower ORR (21% vs 41%, P=0.001), shorter mPFS (5.0 vs 6.7 months, HR: 0.68, P=0.02) and mOS (10.2 vs 18.5 months, aHR: 0.55, P<0.001) (figure 2B).
Conclusions LUADMuc represents 9% of LUAD. Compared to LUADNon-muc, LUADMuc is characterized by a lighter smoking history, lower PD-L1 expression, tumor mutational burden, and fewer intratumor immune cells; LUADMuc is enriched with KRAS, STK11, SMARCA4, NKX2.1 and GNAS mutations, and demonstrates worse outcomes to ICI-based therapies compared to LUADNon-muc.
Buettner R. Invasive mucinous adenocarcinoma: genetic insights into a lung cancer entity with distinct clinical behavior and genomic features. Mod Pathol. 2022 Feb;35(2):138–139. doi: 10.1038/s41379–021-00945–0. Epub 2021 Nov 19. PMID: 34795416; PMCID: PMC8786656.
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