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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.

Introduction Molecular subtyping of lung adenocarcinoma (AD) and lung squamous cell carcinoma (SCC) reveal biologically diverse tumors that vary in their genomic and clinical attributes. Methods Published immune cell signatures and several lung AD and SCC gene expression data sets, including The Cancer Genome Atlas, were used to examine immune response in relation to AD and SCC expression subtypes. Expression of immune cell populations and other immune related genes, including CD274 molecule gene ( CD274 ) (programmed death ligand 1), was investigated in the tumor microenvironment relative to the expression subtypes of the AD (terminal respiratory unit, proximal proliferative, and proximal inflammatory) and SCC (primitive, classical, secretory, and basal) subtypes. Results Lung AD and SCC expression subtypes demonstrated significant differences in tumor immune landscape. The proximal proliferative subtype of AD demonstrated low immune cell expression among ADs whereas the secretory subtype showed elevated immune cell expression among SCCs. Tumor expression subtype was a better predictor of immune cell expression than CD274 (programmed death ligand 1) in SCC tumors but was a comparable predictor in AD tumors. Nonsilent mutation burden was not correlated with immune cell expression across subtypes; however, major histocompatibility complex class II gene expression was highly correlated with immune cell expression. Increased immune and major histocompatibility complex II gene expression was associated with improved survival in the terminal respiratory unit and proximal inflammatory subtypes of AD and in the primitive subtype of SCC. Conclusions Molecular expression subtypes of lung AD and SCC demonstrate key and reproducible differences in immune host response. Evaluation of tumor expression subtypes as potential biomarkers for immunotherapy should be investigated.

Background: Gene expression-based subtyping in lung adenocarcinoma (AD) and lung squamous cell carcinoma (SQ) classifies AD and SQ tumors into distinct subtypes with variable expression of underlying biology including DNA damage response genes. These subtypes are linked to differences in chemotherapy sensitivity, and may impact response to therapeutics like PARP inhibitors. Methods: Using The Cancer Genome Atlas (TCGA) lung cancer gene expression datasets (AD n=515 and SQ n=501), AD subtypes (Terminal Respiratory Unit (TRU), Proximal Proliferative (PP), and Proximal Inflammatory (PI)) and SQ subtypes (Primitive, Classical, Secretory, and Basal) were defined using gene expression based centroid predictors. Association between AD and SQ expression subtypes and 3 published BRCAness/PARP inhibitor response signatures developed in ovarian and/or breast cancer (Konstantinopoulos et al., PMID 20547991; Daemen et al., PMID 22875744; McGrail et al., PMID 28649435) was examined using linear regression. Association between subtypes and expression of 15 recognized homologous recombination (HR) related genes (ATM, ATR, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCI, FANCD2, MRE11A, RAD51C, RAD51L1, PTEN) was also examined using linear regression, and association tests included adjustment for the 3 BRCAness/PARP inhibitor response signatures and proliferation score. Results: AD and SQ subtypes showed strong association with the 3 BRCAness/PARP inhibitor response signatures (F-test p-values 7.7e-05, 5.9e-13, 9.4e-33 in AD and 1.9e-05, 9.0e-13, 2.7e-19 in SQ). AD and SQ subtypes showed strong association with 15 HR genes (max and median F-test p-values were 8.5e-04 and 7.5e-25 in AD, and 7.3e-04 and 1.4e-12 in SQ). The TRU subtype in AD showed low expression relative to the other AD subtypes for a majority of the HR genes, including BRCA1. In SQ, the same was true for the basal and secretory subtypes. Simultaneous adjustment for the 3 BRCAness/PARP inhibitor response signatures, as well as for proliferation, reduced association strength between subtype and HR gene expression in AD and less so in SQ. In AD, association between subtype and gene expression remained significant for 4 HR genes (using Bonferroni correction for 15 tests), including CHECK2, FANCI, BRIP1, and RAD51L1. In SQ, association between subtype and gene expression remained significant for all HR genes except CHEK1 and FANCA, (median and min Bonferroni-adjusted p-value 2.9e-04 and 2.6e-21). Conclusions: Intrinsic biologic subtypes of lung AD and SQ are associated with published BRCAness/PARP inhibitor response signatures and reveal differential expression of several HR-related genes. Evaluation of these subtypes, particularly in SQ, as potential biomarkers of PARP inhibitor sensitivity should be investigated. Citation Format: Gregory Mayhew, Chuck Perou, D Neil Hayes, Myla Lai-Goldman, Hawazin Faruki. Differences in BRCAness/PARP inhibitor response signatures and homologous recombination gene expression across lung adenocarcinoma and squamous cell carcinoma gene expression subtypes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A037.

Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/ neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/ neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/ neu expression was absent in all but one case. By contrast, HER-2/ neu was expressed in 82% ( P = .008 vs normal) of ducts with flat mucinous hyperplasia, 86% ( P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% ( P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/ neu expression was observed in 69% ( P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/ neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.

3077Background: Gene expression based subtyping in lung Adenocarcinoma (AD) and lung Squamous Cell Carcinoma (SQ) classifies AD and SQ tumors into distinct subtypes with variable biologic and clini...

7576 Background: Recommendations exist to aid the clinically relevant non-small cell lung cancer (NSCLC) classification of squamous (SQ) versus adenocarcinoma (AD), including immunohistochemistry (IHC) for TTF1 and p63. We hypothesize that PCR of RNA gene panels may improve the diagnostic accuracy over IHC. Methods: A multi-institutional cohort of NSCLC patients was abstracted for use of IHC in clinical practice. RNA was isolated from routine paraffin sections and a 54-gene Histology by gene Expression Predictor (HEP) was implemented to distinguish SQ, AD, and other NSCLC variants. IHC for TTF1 and p63 was obtained on a subset of patients in a standardized manner. To compare the reproducibility of PCR diagnostics to morphologic diagnosis, a subset of samples was processed as matched pairs from the same tumor, in blinded manner. Results: 493 clinical samples were analyzed from 419 patients. Pathologists obtained any IHC in 22% of the cases, with TTF1 or p63 in