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

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. We analysed inter-...

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Bibliographic Details
Published in:British journal of cancer 2021-11, Vol.125 (11), p.1561-1569
Main Authors: Martinez-Marti, Alex, Felip, Enriqueta, Mancuso, Francesco Mattia, Caratú, Ginevra, Matito, Judit, Nuciforo, Paolo, Sansano, Irene, Diaz-Mejia, Nely, Cedrés, Susana, Callejo, Ana, Iranzo, Patricia, Pardo, Nuria, Miquel, Josep Maria, Navarro, Alejandro, Vivancos, Ana, Sansó, Miriam
Format: Article
Language:English
Subjects:
Biopsy
c-Met protein
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - enzymology
Carcinoma, Non-Small-Cell Lung - genetics
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - genetics
Evolution & development
Evolution, Molecular
High-Throughput Nucleotide Sequencing
Humans
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
Metastases
Mutation
Next-generation sequencing
Non-small cell lung carcinoma
Patients
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Small cell lung carcinoma
Tumors
Tyrosine kinase inhibitors
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Summary: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. 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. 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. 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.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-021-01558-9