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Genetics and Genomics

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

British Journal of Cancer volume 125, pages 1561–1569 (2021)Cite this article

Subjects

Abstract

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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Fig. 1: Tumour evolution and clinical history for each patient.
Fig. 2: Homogeneous driver genomic alterations in necropsies of EGFR-mutated patients.
Fig. 3: Temporal heterogeneity of the disease and selective pressure of the applied therapies.
Fig. 4: Spatial homogeneity reviewed by whole-exome sequencing.

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Data availability

These data will be held at VHIO on secure servers. VHIO is supportive of data sharing and will endeavour to assist in requests for data sharing. All requests for access to the data will be formally requested stating the purpose, analysis and publication plans together with the named collaborators. All requests will be dealt with on a case by case basis in strict observance of applicable laws, rules and regulations.

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Acknowledgements

We would like to thank Dr. Alberto Moldón for helping with manuscript preparation.

Funding

This work was supported by the Spanish Cancer Association (AECC) Scientific Foundation (GCB14-2170) and partially by the Spanish Ministries of Health and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (PI14/01248). MS was supported by an AECC Investigator award from the Spanish Cancer Association (AECC) Scientific Foundation (INVES19056SANS) and is currently supported by a Radix fellowship funded by IdISBa and Janssen.

Author information

Author notes

  1. Miriam Sansó

    Present address: Genomics for Precision Oncology Group, Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases (HUSE), Palma de Mallorca, Spain

  2. These authors contributed equally: Enriqueta Felip, Miriam Sansó.

Authors and Affiliations

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

    Alex Martinez-Marti, Enriqueta Felip, Susana Cedrés, Ana Callejo, Patricia Iranzo, Nuria Pardo & Alejandro Navarro

  2. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Alex Martinez-Marti, Enriqueta Felip, Nely Diaz-Mejia, Susana Cedrés, Ana Callejo, Patricia Iranzo, Nuria Pardo, Josep Maria Miquel & Alejandro Navarro

  3. Autonomous University of Barcelona (UAB), Barcelona, Spain

    Alex Martinez-Marti

  4. University of Vic (UVIC) Central University of Catalonia (UCC), Barcelona, Spain

    Enriqueta Felip

  5. Cancer Genomics Group, VHIO, Barcelona, Spain

    Francesco Mattia Mancuso, Ginevra Caratú, Judit Matito, Ana Vivancos & Miriam Sansó

  6. Molecular Oncology Group, VHIO, Barcelona, Spain

    Paolo Nuciforo

  7. Pathology Department, VHUH, Barcelona, Spain

    Irene Sansano

  8. Balearic Islands Health Research Institute (IdISBa), Palma de Mallorca, Spain

    Miriam Sansó

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Contributions

AMM: conceptualisation, visualisation, methodology, formal analysis, data curation, writing, review and editing. EF: conceptualisation, methodology, formal analysis, supervision, data curation, writing, review, editing and funding acquisition. FMM: bioinformatic analysis and review of the manuscript. GC and JM: performed all DNA extractions, sequencing and ddPCR experiments. PN and IS: performed histopathological analysis and review of the manuscript. NMD, SC, AC, PI, NP and AN: review and editing of the manuscript. JMM: project administration, visualisation and review of the manuscript. AV: conceptualisation, methodology, formal analysis, data curation, review, editing and funding acquisition. MS: conceptualisation, visualisation, methodology, formal analysis, supervision, data curation, writing, review and editing. All authors provided comments on the manuscript and had final approval of the submitted version.

Corresponding author

Correspondence to Miriam Sansó.

Ethics declarations

Ethics approval and consent to participate

Approval to use these tumour specimens was obtained from the institutional review board and performed in accordance with the Declaration of Helsinki. All samples were obtained with the patients’ informed consent.

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No individually identifiable data are presented.

Competing interests

AMM provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, MSD, Pfizer, Boehringer-Ingelheim, AstraZeneca. EF provided consultation, advisory role and/or speaker’s bureau: AbbVie, AstraZeneca, Blueprint medicines, Boehringer-Ingelheim, BMS, Celgene, Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda, Touchtime. PN provided consultation, advisory role and/or speaker’s bureau: Bayer, MSD, Novartis, and Targos. IS provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: Roche, Abbvie, MSD, Pfizer, Takeda, BMS. SC provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, Pfizer, Boehringer-Ingelheim, MSD Oncology, Amphera. AC provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, Pfizer, Boehringer-Ingelheim, MSD Oncology, Kyowa Kirin, Celgene. PI provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, MSD, Boehringer-Ingelheim, MSD Oncology, Rovi, Kyowa Kirin, Grunenthal Pharma S.A. NP provided consultation, attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, Pfizer, Boehringer-Ingelheim. AN provided consultation attended advisory boards and/or speaker’s bureau for the following organisations: BMS, Roche, Pfizer, Boehringer-Ingelheim, Oryzon Genomics. AV has participated in advisory boards for BMS, Guardant Health and Bayer, and has provided consultation for Sysmex. The remaining authors declare no competing interests.

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Martinez-Marti, A., Felip, E., Mancuso, F.M. et al. Genetic evolution to tyrosine kinase inhibitory therapy in patients with EGFR-mutated non-small-cell lung cancer. Br J Cancer 125, 1561–1569 (2021). https://doi.org/10.1038/s41416-021-01558-9

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