Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung trial explores metastasis-associated alterations and potential prognostic markers.

Abstract

8537 Background: Lung adenocarcinoma (LUAD) molecular heterogeneity influences diagnosis, prognosis, and treatment. Molecular profiling of advanced lesions remains limited compared to early tumors. We analyzed tumors from the SAFIR02-Lung trial to identify molecular alterations associated with advanced LUAD. Methods: We analyzed 366 advanced LUAD tumor samples (250 locoregional [lrmLUAD], 116 distant metastases [dmLUAD]) from metastatic patients in the SAFIR02-Lung trial using targeted sequencing of 45 cancer-related genes and comparative genomic hybridization arrays. Data from The Cancer Genome Atlas (TCGA) and three public datasets—MSK-MET, Jee et al., and the AACR Project GENIE—validated our findings. Results: Advanced tumors exhibited greater chromosomal instability than early-stage lesions, (fraction of genome altered: 28.0% in lrmLUAD, 29.1% in dmLUAD and 7.2% in early-stage LUAD, p < 0.01). Copy-number alterations implicated LAMB3, TNN / KIAA0040 / TNR , KRAS, DAB2, MYC, EPHA3, VIPR2 in tumor progression and AREG, ZNF503, PAX8, MMP13, JAM3, MTURN and CDKN2A in metastasis. CDKN2A homozygous deletions correlated with poor outcomes in early-stage LUAD (hazard ratio = 2.17, 95% CI: 1.43–3.28, p = 0.01). KRAS mutant allele-specific imbalance (MASI), marked by mutant allele amplification, was enriched in advanced samples (8.4% lrmLUAD, 13% dmLUAD, 2.8% early-stage LUAD). Public cohort validation confirmed higher KRAS MASI prevalence in metastatic samples vs. primary tumors (3.17% vs. 1.4%; pooled odds ratio = 2.23, 95% CI: 1.43–3.51, p < 0.01). KRAS MASI tumors were enriched in CDKN2A, MYC, TP53, and NKX2-1 alterations, and displayed less STK11 and KEAP1 variants. Conclusions: Chromosomal instability drives disease progression in LUAD. CDKN2A homozygous deletions are a negative prognostic biomarker in early-stage tumors. Metastasis-associated alterations, including KRAS MASI and CDKN2A deletions, highlight mechanisms of progression and potential prognostic biomarkers, warranting further investigation and therapeutic exploration. Nguyen B, et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 2022;185:563-575.e11. https://doi.org/10.1016/j.cell.2022.01.003 . Jee J, et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat Med 2022;28:2353–63. https://doi.org/10.1038/s41591-022-02047-z . The AACR Project GENIE Consortium, AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discovery 2017;7:818–31. https://doi.org/10.1158/2159-8290.CD-17-0151 .