Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma

D. Boiarsky; C. A. Lydon; E. S. Chambers; L. M. Sholl; M. Nishino; F. Skoulidis; J. V. Heymach; J. Luo; M. A. Awad; P. A. Janne; E. M. Van Allen; D. A. Barbie; N. I. Vokes

doi:10.1016/j.annonc.2023.04.514

Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma

D. Boiarsky, C. A. Lydon, E. S. Chambers, L. M. Sholl, M. Nishino, F. Skoulidis, J. V. Heymach, J. Luo, M. A. Awad, P. A. Janne, E. M. Van Allen, D. A. Barbie, N. I. Vokes

Thoracic Head & Neck Medical Oncology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRAS^MUT) 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 KRAS^MUT 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 (KEAP1^MUT/STK11^WT: DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1^MUT/STK11^MUT: 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 (KEAP1^WT/STK11^MUT: 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 KEAP1^MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients.

Original language	English (US)
Pages (from-to)	589-604
Number of pages	16
Journal	Annals of Oncology
Volume	34
Issue number	7
DOIs	https://doi.org/10.1016/j.annonc.2023.04.514
State	Published - Jul 2023

Keywords

KEAP1
KRAS
lung adenocarcinoma
metastatic
STK11

ASJC Scopus subject areas

Hematology
Oncology

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10.1016/j.annonc.2023.04.514

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@article{a7619332913146e19a0fe54eb280d339,

title = "Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma",

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, lung adenocarcinoma, metastatic, STK11",

author = "D. Boiarsky and Lydon, {C. A.} and Chambers, {E. S.} and Sholl, {L. M.} and M. Nishino and F. Skoulidis and Heymach, {J. V.} and J. Luo and Awad, {M. A.} and Janne, {P. A.} and {Van Allen}, {E. M.} and Barbie, {D. A.} and Vokes, {N. I.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jul,

doi = "10.1016/j.annonc.2023.04.514",

language = "English (US)",

volume = "34",

pages = "589--604",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "7",

}

TY - JOUR

T1 - Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma

AU - Boiarsky, D.

AU - Lydon, C. A.

AU - Chambers, E. S.

AU - Sholl, L. M.

AU - Nishino, M.

AU - Skoulidis, F.

AU - Heymach, J. V.

AU - Luo, J.

AU - Awad, M. A.

AU - Janne, P. A.

AU - Van Allen, E. M.

AU - Barbie, D. A.

AU - Vokes, N. I.

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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.

KW - KEAP1

KW - KRAS

KW - lung adenocarcinoma

KW - metastatic

KW - STK11

UR - http://www.scopus.com/inward/record.url?scp=85160808041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85160808041&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2023.04.514

DO - 10.1016/j.annonc.2023.04.514

M3 - Article

C2 - 37121400

AN - SCOPUS:85160808041

SN - 0923-7534

VL - 34

SP - 589

EP - 604

JO - Annals of Oncology

JF - Annals of Oncology

IS - 7

ER -

Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma

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