Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients

Shoko Nakasone,Ayako Suzuki,Hitomi Okazaki,Keiichi Onodera,Junko Zenkoh,Genichiro Ishii,Yutaka Suzuki,Masahiro Tsuboi,Katsuya Tsuchihara

doi:10.1016/j.lungcan.2021.06.011

Abstract

ObjectivesMicrotubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy. Materials and methodsWe explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine. ResultsWe identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance. ConclusionWe demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse.

Highlights

Early-stage non-small cell lung cancer (NSCLC), including lung adenocarcinoma, is best managed by surgical resection with curative intent
Vinorelbine is the most frequently used drug for adjuvant therapy of lung adenocarcinoma, and we examined transcriptome features associated with the Microtubule inhibitors (MTIs) sensitivity of each cell type
We propose a module-based stratification of lung adenocarci nomas to predict the efficacy of MTI-based adjuvant chemotherapy

Summary

Introduction

Early-stage non-small cell lung cancer (NSCLC), including lung adenocarcinoma, is best managed by surgical resection with curative intent. The LACE trial and other meta-analyses have shown that the combination of adjuvant chemotherapy based on cisplatin with other cytotoxic drugs improves overall survival by 5% for stage II-IIIA NSCLC patients who underwent resection [1,2,3,4,5,6,7]. New cytotoxic drugs, such as docetaxel and pemetrexed, have not been validated in such analyses, and there have been few randomized controlled trials of direct comparison of vinorelbine with new cytotoxic drugs in adjuvant therapy. A phase III randomized controlled study evaluating the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant therapy failed to show the superiority of the former for patients with resected non squamous NSCLC [13]. Vinorelbine plus cisplatin remains the standard adjuvant chemotherapy for patients with resected lung adenocarcinoma

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