EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes

Abstract

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS.ConclusionsEGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI

“…The morphology is one prognostic factor in the current study. Although EGFR mutation has been reported in non-adenocarcinoma lung cancer, particularly in squamous cell carcinoma (SCC), the PFS of EGFR-TKIs for EGFR mutated lung SCC was shorter than the patients with EGFR mutated adenocarcinoma [ 34 ]. Mutations in other genes have been reported as the potential understanding mechanisms of resistance to EGFR-TKI in lung SCC [ 34 ].…”

Small Molecule Compounds of Natural Origin Target Cellular Receptors to Inhibit Cancer Development and Progression

“…The ERBB receptors can activate a variety of signaling pathways regulating cell proliferation, invasion, angiogenesis, apoptosis and differentiation [ 95 , 96 , 97 ]. EGFR mutations are frequently observed in lung cancers and related to shorter progression-free survival [ 98 ]. The HER2/neu gene is amplified and overexpressed in 25–30% of human breast and ovarian cancers and associated with poor prognoses of the patients [ 99 ].…”

Histologic Transformation in EGFR-Mutant Lung Adenocarcinomas: Mechanisms and Therapeutic Implications

“…Although multiple case reports have suggested resistance to EGFR TKIs after developing SCC transformation, few case reports have suggested durable responses to TKIs, highlighting that SCC transformation may not always contribute to EGFR TKI resistance [14,67]. Patients with de-novo EGFR-mutated SCC tend to have a shorter PFS than their adenocarcinoma counterparts [68]. However, the biology of SCC transformation remains poorly defined, and it is not uncommon for NSCLCs to have coexistent adenocarcinoma and squamous cell carcinoma components [69].…”

“…Higher frequencies of mutations in neurofibromatosis (NF1), ataxia telangiectasia and Rad3 related (ATR), and breast cancer (BRCA1) genes have been reported in EGFR-mutant SCCs compared to EGFR-mutant adenocarcinomas [68]. However, despite comprehensive genomic analyses, no consistent molecular signature has been identified in SCC transformation; considerable genomic complexity is seen in these patients with mutations in phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathways, chromosome 31 amplification, and FGF amplification [66].…”