NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma.
OBJECTIVE
Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC.


METHODS
Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2(ACT)) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression.


RESULTS
Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway-activated and wild-type (WT) tumors. NRF2(ACT) was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10-randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2(ACT) HR 2.28, P = 0.48; interaction P = 0.15). NRF2(ACT) was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression.


CONCLUSIONS
A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway-activating somatic alterations may have reduced benefit from this therapy.
Departments of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Medicine, University of Toronto, Toronto, Canada.
David W
DW
Cescon
Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Desmond
D
She
Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Shingo
S
Sakashita
Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Chang-Qi
CQ
Zhu
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Melania
M
Pintilie
Departments of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Medicine, University of Toronto, Toronto, Canada.
Frances A
FA
Shepherd
Department of Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. ming.tsao@uhn.ca.
Ming-Sound
MS
Tsao
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D002945:Cisplatin