Clinical, pathologic, and genomic hallmarks of KRAS-amplified non-small cell lung cancer.
Authors: Ricciuti Biagio , Alessi Joao Victor Machado , Wang Xinan , Lamberti Giuseppe , Pecci Federica , Di Federico Alessandro , Gandhi Malini Marion , Sholl Lynette M. , Ambrogio Chiara , Awad Mark M. 
Published: June 2023

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Background: KRAS-mutant non-small cell lung cancers (NSCLCs) have unique clinicopathologic and genomic features, and novel therapies are in development to target many KRAS-mutant tumor types. Whether KRAS amplification also defines a unique, potentially targetable, molecular subset of NSCLC is currently unknown. Methods: Clinicopathologic and genomic data were abstracted from multiple independent cohorts of pts whose cancers underwent tumor genomic profiling at the Dana-Farber Cancer Institute (Cohort 1), AACR Project GENIE v.13, The Cancer Genome Atlas (TCGA), and 212 other studies (Cohort 2). Patient (pt) outcomes were examined according to KRAS amplification status ( KRAS amplified vs KRAS non-amplified). Whole transcriptome sequencing and quantitative proteomics data from TCGA and the Cancer Cell Line Encyclopedia (CCLE) were used to correlate KRAS amplification with KRAS RNA levels and protein expression. Results: Among 15,341 pts with NSCLC, KRAS amplification was identified in 355 (2.3%) cases (median number of copies [range]: 11 [7-87]); the prevalence was similar in adenocarcinomas and squamous cell carcinomas. Compared to KRAS non-amplified cases, pts with KRAS-amplified NSCLC were more likely to be men (52.4% vs 45.6%, p = 0.01), have a history of smoking (82.1% vs 64.2%, p < 0.01), and higher median pack-years (35 vs 23.5, p < 0.01). However, median age was similar between the two groups (66 vs 66, p = 0.88). KRAS amplification was also associated with higher aneuploidy (median fraction of genome altered 30.4% vs 14.3%, p < 0.01), tumor mutational burden (p < 0.01 across different platforms), and increased median PD-L1 expression (20% vs 5%, p = 0.01). Of the 355 NSCLC samples with KRAS amplification, 152 (43%) had no concurrent oncogene driver mutations. In unbiased mutation enrichment analyses, KRAS-amplified tumors were enriched in concurrent mutations in KRAS, PALB2, POLE, and SLC34A2 (q < 0.1), while KRAS non-amplified tumors were enriched for oncogenic EGFR mutations (q < 0.1). Transcriptomic and proteomic profiling from the TCGA and CCLE cohorts demonstrated that KRAS amplification was associated with significantly increased KRAS mRNA (p < 0.01) and protein expression (p < 0.01), compared to KRAS non-amplified samples. In pts with available clinical outcomes data in the combined cohort (N = 9,335), the median overall survival (OS) from the date of diagnosis was significantly shorter in KRAS-amplified vs KRAS non-amplified cases (adjusted HR: 1.40, p < 0.01). KRAS amplification was confirmed to confer significantly worse survival outcomes in pts with both KRAS wild-type (N = 6,695, adjusted HR 1.37, p = 0.02) and KRAS-mutant (N = 2,640, adjusted HR 1.34, p = 0.02) NSCLC. These results were independently replicated in Cohort 1 and Cohort 2. Conclusions: KRAS amplification defines a novel molecular subset of NSCLC characterized by distinct clinicopathologic and genomic features and worse survival.