Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets

Abstract

Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging.

Hierarchical identification of a transcriptional panel for the histological diagnosis of lung neuroendocrine tumors

“…As a result, we additionally collected 10 SCLC frozen biopsy samples from the clinic and verified the accuracy of the NEsubtype-panel, indicating its clinical feasibility. A previous study has published a lung subtype panel, including 57 genes (57-gene), for distinguishing lung cancer subtypes ( Faruki et al, 2016 ). In a word, gene centroid was calculated for each of three subtypes (ADC, SCC, and NE), respectively.…”

“…However, most transcriptional signatures were developed to distinguish between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) belonging to non-NE tumors ( Girard et al, 2016 ; Li et al, 2019 ), and only a few studies focused on lung NE tumors. Faruki et al developed a lung subtyping panel consisting of 57 genes for the diagnosis of ADC, SCC, and NE ( Faruki et al, 2016 ), while it could not determine the NE subtypes. Guo et al constructed a classifier based on transcriptome data to improve the diagnostic accuracy for LCNEC and SCLC ( Guo et al, 2021 ).…”

“…The main treatment for SCLC is combination chemotherapy, typically with etoposide plus either cisplatin or carboplatin (Ramirez et al, 2021), while surgery is only performed on a few early-stage patients; this is different from the treatment modalities of other NE subtypes and non-NE patients (Lindeman et al, 2013). Chemotherapy schedule for LCNEC after surgical resection is typically adopting NSCLC or SCLC chemotherapy regimens, and this has always been controversial (Fasano et al, 2015). As per recent studies, etoposide-cisplatin chemotherapies, that is, "treat as an SCLC," are more effective strategies for LCNEC patients (Fasano et al, 2015;Ramirez et al, 2021).…”

“…Chemotherapy schedule for LCNEC after surgical resection is typically adopting NSCLC or SCLC chemotherapy regimens, and this has always been controversial (Fasano et al, 2015). As per recent studies, etoposide-cisplatin chemotherapies, that is, "treat as an SCLC," are more effective strategies for LCNEC patients (Fasano et al, 2015;Ramirez et al, 2021). For CARCI treatment (an NE subtype with low malignancy), the main therapy is surgical resection (Ramirez et al, 2021).…”

Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Patients With Advanced Non–Squamous Non–Small Cell Lung Cancer

“…22,23 Among these is a 57-gene lung subtyping panel (LSP) of 52 classification genes and 5 housekeeping genes which has demonstrated the ability to reproducibly differentiate squamous, adenocarcinoma, and neuroendocrine lung cancers, including poorly differentiated tumors. [24][25][26] The LSP was used to identify patients with poor prognosis in 3 independent NSCLC cohorts (N>1000) which supports the potential for LSP as a gene expression-based prognostic marker in this population. 25 The use of archived specimens from large prospective clinical trials has been proposed as a means to assess the medical utility of prognostic and predictive biomarkers.…”