4.7 Article

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

Journal

BRITISH JOURNAL OF CANCER
Volume 125, Issue 11, Pages 1561-1569

Publisher

SPRINGERNATURE
DOI: 10.1038/s41416-021-01558-9

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Funding

  1. Spanish Cancer Association (AECC) Scientific Foundation [GCB14-2170]
  2. Spanish Ministries of Health
  3. Fondo de Investigacion Sanitaria-Fondo Europeo de Desarrollo Regional [PI14/01248]
  4. AECC Investigator award from the Spanish Cancer Association (AECC) Scientific Foundation [INVES19056SANS]
  5. Radix fellowship - IdISBa
  6. Janssen

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The study analyzed tumor samples from 5 NSCLC patients, revealing homogeneity in pathogenic mutations and TKI resistance mechanisms in most patients. Despite different resistance mechanisms depending on the patient and treatment line, a single metastasis biopsy from EGFR-mutated NSCLC patients could provide valuable information under selective TKI pressure.
Background Tumour heterogeneity impacts the efficacy of metastatic cancer treatment even if actionable mutations are identified. Clinicians need to understand if assessing one lesion provides reliable information to drive a therapeutic decision in non-small-cell lung cancer (NSCLC) patients. Methods We analysed inter-tumour heterogeneity from five autopsied individuals with NSCLC-harbouring mutations in the epidermal growth factor receptor (EGFR), treated with EGFR tyrosine kinase inhibitors (TKIs). Through a comprehensive next-generation sequencing (NGS) oncopanel, and an EGFR panel for digital droplet PCR (ddPCR), we compared metastases within individuals, longitudinal biopsies from the same lesions and, whenever possible, the primary naive tumour. Results Analysis of 22 necropsies from five patients revealed homogeneity in pathogenic mutations and TKI-resistance mechanisms within each patient in four of them. In-depth analysis by whole-exome sequencing from patient 1 confirmed homogeneity in clonal mutations, but heterogeneity in passenger subclonal alterations. Different resistance mechanisms were detected depending on the patient and line of treatment. Three patients treated with a c-MET inhibitor in combination with TKI lost MET amplification upon progression. Conclusion At a given point and under selective TKI pressure, a single metastasis biopsy in disseminated tumours from EGFR-mutated NSCLC patients could provide a reasonable assessment of actionable alterations useful for therapeutic decisions.

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