Genomic signatures define three subtypes of EGFR-mutant stage II\u2013III non-small-cell lung cancer with distinct adjuvant therapy outcomes

Siyang Liu ,Cheng Huang,Ke-Neng Chen,Shun Xu,Songtao Xu ,Shidong Xu ,Qing Zhou,Ying Cheng,Yucheng Wei ,Xiaofei Li ,Jian Su,Qun Wang,Fan Yang,Weimin Mao ,Jing Yang ,Hong‐Hong Yan ,Hua Bao,Yong‐Yu Liu ,Lunxu Liu ,Buhai Wang ,Wen‐Zhao Zhong ,Xue Wu,Rong Yin,Song Dong,Xiaoling Tong,Yang Shao,Yedan Chen,Shengxiang Ren ,Hu Ma ,Zhidong Liu ,Chun Chen,Xuchao Zhang ,Ping Yu,Lin Wu,Jian Li,Xue‐Ning Yang ,Yi‐Long Wu

doi:10.1038/s41467-021-26806-7

Abstract

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.

Highlights

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected epidermal growth factor receptor (EGFR)-mutant stage II–IIIA non-small cell lung cancer (NSCLC)
Total 171 patients from the ADJUVANT trial with available baseline surgical specimens have been enrolled for genomic profiling (Fig. 1)
We evaluated the predictive power of each mutated gene, and identified the following five predictive markers with significant treatment interactions (Table 1 and Methods): RB1 alterations [interaction hazard ratio 4.07, 95% confidence interval (CI) 1.56–10.58, P = 0.004], NKX21 CN gain [iHR 0.26, P = 0.006], CDK4 CN gain [iHR 0.14, P = 0.024], TP53 exon4/5 missense mutations [iHR 0.33, P = 0.035], and MYC CN gain (iHR 0.10, P = 0.048)

Summary

Introduction

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). As early-stage NSCLC shows a high degree of intratumor heterogeneity with divergent evolutionary lineages[17], the established norm of estimating only a single driver oncogene through randomized trials for adjuvant targeted therapies fails to address the underlying complications of intratumor molecular heterogeneity. In this regard, the development of next-generation sequencing (NGS)

Methods

Results

Conclusion