Abstract 2181: Genomic correlates of Metastasis in KRAS mutant lung adenocarcinoma
Authors: Boiarsky Daniel , Lydon Christine A. , Chambers Emily , Janne Pasi A. , Awad Mark M. , Van Allen Eliezer M. , Barbie David , Vokes Natalie I. 
Published: June 2022

Background: Lung adenocarcinoma (LUAD) is a disease classified by molecular markers. In KRAS-mutant LUAD, STK11 and KEAP1 mutations are associated with decreased overall survival (OS), but predictors of metastasis have been poorly defined. In this study, we identify clinical and genomic predictors of metastatic KRAS-mutant LUAD.

Methods: Patients with KRAS-mutant LUAD profiled by targeted next generation sequencing (OncoPanel) were included. Stage, histology, recurrence-free and overall survival were assessed. Clinical and genomic features between metastatic vs non-metastatic samples were compared. KRAS-mutant LUAD samples profiled using MSK-IMPACT in the AACR GENIE database were used to validate our findings. Continuous variables were compared using the Mann-Whitney U test and categorical variables were compared using the Fisher’s Exact test. Survival analysis was performed using the Cox Proportional Hazards model. WExT was used to identify co-occurring and mutually exclusive genetic alterations. Benjamini-Hochberg was used to correct for multiple comparisons. P-values &lt; 0.05 and q-values &lt; 0.10 were considered significant.

Results: In the OncoPanel cohort (metastatic n=290; non-metastatic n=324), tumor mutational burden (TMB) (p = .001) and KEAP1 mutations (q = 0.05) were enriched in metastatic samples, while NFKBIA amplifications (q = 0.07) were enriched in non-metastatic samples. KEAP1/STK11 mutations significantly co-occurred (q &lt; 1e-8). Compared to double wild-type samples: KEAP1/STK11 co-mutations were significantly enriched in metastatic samples (n = 72, p = 0.0002, OR 3.4); KEAP1-mutant samples trended towards enrichment in metastatic samples, (n = 21,p = 0.07, OR 2.47); STK11 mutations did not associate with stage (n = 53, p = 0.88, OR = 0.94). In multivariable survival analysis, metastasis (p &lt; 0.005), KEAP1 mutation (p=0.01), and STK11 mutation (p=0.02) were associated with worse OS.

In the MSK-IMPACT validation cohort (metastatic site n=417, primary site n = 781), KEAP1 was the only gene enriched in metastatic samples (q &lt; 0.001) at q &lt; 0.05. Compared to double wild type samples: KEAP/STK11 co-mutations (n=138, p &lt; 0.0001, OR 2.1) and KEAP1 mutations (n=59, p = 0.04, OR 1.77) were enriched in metastatic samples; STK11-mutations did not associate with metastasis (n = 190, p = 0.34, OR 0.83). Other predictors of metastasis included Fraction Genome Altered (FGA) (p &lt; 1e-5), TMB (p &lt; 1e-5), and CDKN2A/B deletions (q &lt; 0.003).

Conclusion: While both KEAP1 and STK11 mutations are associated with decreased OS in KRAS-mutant LUAD, we find in two independent cohorts that only KEAP1 mutations and KEAP1/STK11 co-mutations, but not STK11 mutations, are associated with metastasis. We also found that FGA, TMB, CDKN2A/B deletions are strongly associated with metastasis. Further research is necessary to understand the influence of KEAP1 mutations, independent of and in-conjunction with STK11 mutations, on metastasis.

Citation Format: Daniel Boiarsky, Christine A. Lydon, Emily Chambers, Pasi A. Janne, Mark M. Awad, Eliezer M. Van Allen, David Barbie, Natalie I. Vokes. Genomic correlates of Metastasis in KRAS mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2181.