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Molecular Diagnostics

The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response

British Journal of Cancer volume 119, pages 1252–1258 (2018)Cite this article

Subjects

Abstract

Background

Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib.

Methods

Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF).

Results

At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act-EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR ≤ 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01).

Conclusion

act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib.

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Acknowledgements

This work was supported in part by research funding granted to Romano Danesi from Fondazione Cassa di Risparmio di Lucca (Lucca, Italy).

Availability of data and materials

Data and results are available at the Unit of Clinical Pharmacology and Pharmacogenetics, University Hospital of Pisa.

Author information

Author notes

  1. These authors contributed equally: Marzia Del Re, Paola Bordi and Eleonora Rofi.

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Marzia Del Re, Eleonora Rofi, Giuliana Restante, Stefania Crucitta, Elena Arrigoni & Romano Danesi

  2. Medical Oncology Unit, University Hospital of Parma, Parma, Italy

    Paola Bordi, Roberta Minari & Marcello Tiseo

  3. Pneumology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy

    Simona Valleggi, Antonio Chella & Iacopo Petrini

  4. Section of Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Riccardo Morganti

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  1. Marzia Del Re
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Contributions

Conception and design: M.D.R., M.T., I.P., and R.D. Development of methodology: M.D.R., E.R., G.R., S.C., and E.A. Clinical protocols/amendments: M.D.R., R.D., and M.T. Acquisition of data: M.D.R., P.B., E.R., G.R., S.C., E.A., and R.M. Analysis and interpretation of data: M.D.R., P.B., E.R., I.P., M.T., R.M., and R.D. Writing, review, and/or revision of the manuscript: all authors. Administrative, technical, or material support: M.D.R., P.B., E.R., and R.D. Study supervision: R.D., M.T., and I.P.

Corresponding author

Correspondence to Iacopo Petrini.

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Competing interests

T.M. received honoraria for participation in advisory boards and speakers’ bureau of Astra-Zeneca. R.D. received a unrestricted research grant from Astra-Zeneca. The other Authors declare no competing interests.

Ethics statement

This work was approved by the Ethics Committee of the Area Vasta Nord Ovest Toscana (Italy) under the reference number 612/2015 and was conducted in accordance with the principles of the Declaration of Helsinki. Patients were instructed about the experimental procedures of the study and enrolled after signature of the informed consent.

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No individual person’s data are reported.

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Del Re, M., Bordi, P., Rofi, E. et al. The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response. Br J Cancer 119, 1252–1258 (2018). https://doi.org/10.1038/s41416-018-0238-z

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