Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma

Ann Oncol. 2023 Jul;34(7):589-604. doi: 10.1016/j.annonc.2023.04.514. Epub 2023 Apr 29.

Abstract

Background: Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRASMUT) lung adenocarcinoma (LUAD). Less is known about the prognostic role of molecular alterations and their associations with metastatic disease.

Patients and methods: We analyzed clinicogenomic data from 1817 patients with KRASMUT LUAD sequenced at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Patients with metastatic (M1) and nonmetastatic (M0) disease were compared. Transcriptomic data from The Cancer Genome Atlas (TCGA) were investigated to characterize the biology of differential associations with clinical outcomes. Organ-specific metastasis was associated with overall survival (OS).

Results: KEAP1 (DFCI: OR = 2.3, q = 0.04; MSKCC: OR = 2.2, q = 0.00027) and SMARCA4 mutations (DFCI: OR = 2.5, q = 0.06; MSKCC: OR = 2.6, q = 0.0021) were enriched in M1 versus M0 tumors. On integrative modeling, NRF2 activation was the genomic feature most associated with OS. KEAP1 mutations were enriched in M1 versus M0 tumors independent of STK11 status (KEAP1MUT/STK11WT: DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1MUT/STK11MUT: DFCI OR = 2.3, P = 0.0063; MSKCC OR = 2.5, P = 3.6 × 10-05); STK11 mutations without KEAP1 loss were not associated with stage (KEAP1WT/STK11MUT: DFCI OR = 0.97, P = 1.0; MSKCC OR = 1.2, P = 0.33) or outcome. KEAP1/KRAS-mutated tumors with and without STK11 mutations exhibited high functional STK11 loss. The negative effects of KEAP1 were compounded in the presence of bone (HR = 2.3, P = 4.4 × 10-14) and negated in the presence of lymph node metastasis (HR = 1.0, P = 0.91).

Conclusions: Mutations in KEAP1 and SMARCA4, but not STK11, were associated with metastatic disease and poor OS. Functional STK11 loss, however, may contribute to poor outcomes in KEAP1MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients.

Keywords: KEAP1; KRAS; STK11; lung adenocarcinoma; metastatic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / pathology
  • Biomarkers, Tumor / genetics
  • DNA Helicases / genetics
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Lung Neoplasms* / pathology
  • Mutation
  • NF-E2-Related Factor 2 / genetics
  • Nuclear Proteins / genetics
  • Prognosis
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Transcription Factors / genetics

Substances

  • Kelch-Like ECH-Associated Protein 1
  • Proto-Oncogene Proteins p21(ras)
  • NF-E2-Related Factor 2
  • Protein Serine-Threonine Kinases
  • Biomarkers, Tumor
  • SMARCA4 protein, human
  • DNA Helicases
  • Nuclear Proteins
  • Transcription Factors
  • KRAS protein, human