The impact of co-occurring tumor suppressor mutations with mEGFR as early indicators of relapse in lung cancer

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2025-03-14 DOI:10.1016/j.esmoop.2025.104479

S. Hait , V. Noronha , A. Chowdhury , A. Chaudhary , B. Bawaskar , G. Dahimbekar , S. Ahmad , A. Joshi , V. Patil , N. Menon , M. Shah , R. Kaushal , A. Choughule , A. Bharde , J. Khandare , G. Shafi , D. Lakhwani , S. Desai , P. Chandrani , K. Prabhash , A. Dutt

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引用次数: 0

Abstract

Background

Lung adenocarcinoma frequently presents with EGFR mutations, often progressing on EGFR tyrosine kinase inhibitors (TKIs) despite an initial response. Progression is frequently driven by additional genetic changes, including mutations in tumor suppressor genes (TSGs). Understanding the role of these concurrent TSG mutations can help elucidate resistance mechanisms and guide the development of more effective treatment approaches.

Materials and methods

We examined survival outcomes in 483 EGFR-mutant (mEGFR) patients from the GENIE BPC non-small-cell lung cancer (NSCLC) dataset. To understand the mutational landscape and clonal dynamics, whole exome sequencing (WES) was carried out on 48 tumor samples from 16 mEGFR patients at both baseline and post-relapse. A comprehensive gene panel was applied to 200 liquid biopsy samples obtained longitudinally from 25 patients to track clonal evolution.

Results

mEGFR patients with co-occurring TSG mutations exhibited significantly worse outcomes. In the GENIE dataset, overall survival (OS) was shorter [51.11 versus 99.3 months; hazard ratio (HR) 1.8, confidence interval (CI) 1.22-2.75, P = 0.003] and progression-free survival (PFS) was reduced (9.83 versus 11.48 months; HR 1.4, CI 1.03-1.91, P = 0.026). WES analysis revealed 17 TSG mutations that were retained and showed clonal enrichment, particularly in early relapse (progression within 10 months of TKI initiation) or intermediate-stage relapse (relapse occurred between 10 and 20 months), indicated by increased variant allele frequency and their presence was strongly linked to early relapse. Longitudinal clonal studies further confirmed that TSG mutations co-occurring with mEGFR were often truncal, predominantly in early relapsers. Survival analysis using this subset of 17 TSGs showed significantly shorter OS (55.26 versus 99.3 months; HR 1.7, CI 1.12-2.65, P = 0.011) and PFS (9.67 versus 13.12 months; HR 1.5, CI 1.08-2.10, P = 0.013).

Conclusions

A set of 17 co-occurring TSG mutations has been identified as key biomarkers for early relapse in mEGFR lung adenocarcinoma. Longitudinal genomic monitoring, with a focus on clonal evolution, offers valuable insights that can inform personalized treatment strategies and potentially improve patient outcomes.

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来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.