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Updated: Oct 18, 2025

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Genetic evolution to tyrosine kinase inhibitory therapy in patients with EGFR-mutated non-small-cell lung cancer

Alex Martinez-Marti1,2,3, Enriqueta Felip1,2,4, Francesco Mattia Mancuso5

  • 1Department of Medical Oncology, Vall d'Hebron University Hospital (VHUH), Barcelona, Spain.

British Journal of Cancer
|October 2, 2021
PubMed
Abstract

Insights

Assessing a single tumor lesion in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can reliably guide treatment decisions. This homogeneity in actionable mutations simplifies therapeutic strategies for metastatic lung cancer.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Research

Background:

  • Tumor heterogeneity complicates effective metastatic cancer treatment, even with identified actionable mutations.
  • Clinicians require clarity on whether single lesion assessment reliably informs therapeutic decisions for non-small cell lung cancer (NSCLC) patients.

Purpose of the Study:

  • To investigate inter-tumor heterogeneity in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations.
  • To determine if a single metastatic lesion biopsy provides sufficient information for guiding EGFR tyrosine kinase inhibitor (TKI) therapy.

Main Methods:

  • Analysis of 22 necropsies from five NSCLC patients with EGFR mutations treated with EGFR TKIs.
  • Next-generation sequencing (NGS) oncopanel and digital droplet PCR (ddPCR) on metastases, longitudinal biopsies, and primary tumors.
  • Whole-exome sequencing for in-depth analysis of clonal and subclonal alterations.

Main Results:

  • Four out of five patients exhibited homogeneity in pathogenic mutations and TKI-resistance mechanisms across metastases.
  • Clonal mutations were homogeneous, while passenger subclonal alterations showed heterogeneity.
  • Resistance mechanisms varied by patient and treatment line; MET amplification was lost upon progression in three patients treated with c-MET inhibitor and TKI combination.

Conclusions:

  • A single metastasis biopsy in EGFR-mutated NSCLC patients can offer a reasonable assessment of actionable alterations under selective TKI pressure.
  • This finding supports the use of single lesion biopsies for therapeutic decision-making in metastatic NSCLC.

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