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Detection of Low-level EGFR c.2369 C > T (p.Thr790Met) Resistance Mutation in Pre-treatment Non-small Cell Lung Carcinomas Harboring Activating EGFR Mutations and Correlation with Clinical Outcomes

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Pathology & Oncology Research

Abstract

Increasing evidence points to the presence of low-level de novo T790M mutations in patients with non-small cell lung carcinoma (NSCLC) harboring activating EGFR mutations. We utilized digital PCR (dPCR), a highly sensitive gene mutation detection method, to detect pre-treatment T790M mutations in NSCLC tumor samples and correlated the T790M status with clinical features and patient outcomes. DNA extracted from pre-treatment NSCLC tumor tissue with known activating EGFR mutations, diagnosed between October 2010 and May 2017 at PathWest laboratory, was used to perform targeted dPCR for quantitative detection of T790M mutations. T790M was detected in 42 of 109 pre-treatment samples (38.5%). Median variant allele frequency was 0.14% (range 0.02–28.5%). Overall response rate to first generation EGFR tyrosine kinase inhibitors (TKI) was 67% regardless of T790M status. The median progression free survival was 10.7 (IQR 5.6–19.9) versus 6.7 (IQR 3.5–20.8) months in T790M negative and positive patients respectively. T790M positivity correlated with increased rate of early disease progression. It also correlated with increased mortality (HR 3.1 95%CI 1.2–8.1, p = 0.022) in patients who did not respond to TKI treatment. We detected a significant rate of low-level pre-treatment T790M mutations in NSCLC using highly sensitive dPCR. Low-level pre-treatment T790M did not impact treatment response rate or overall survival, but was associated with increased rate of early progression on TKI therapy.

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Author information

Authors and Affiliations

  1. Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia

    Linda Ye & Michael Millward

  2. Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Western Australia, Australia

    Linda Ye & Michael Millward

  3. School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia

    Nima Mesbah Ardakani, Carla Thomas, Connull Leslie & Benhur Amanuel

  4. Department of Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Western Australia, 6009, Australia

    Nima Mesbah Ardakani, Carla Thomas, Connull Leslie & Benhur Amanuel

  5. School of Veterinary and Life Science, Murdoch University, Perth, Western Australia, Australia

    Nima Mesbah Ardakani

  6. Institute for Health Research, The University of Notre Dame Australia, Perth, Western Australia, Australia

    Katrina Spilsbury

  7. School of Medical Science, Edith Cowan University, Joondalup, WA, Australia

    Benhur Amanuel

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  1. Linda Ye
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Contributions

Linda Ye: study design, data collection, data interpretation, writing the manuscript.

Nima Mesbah Ardakani: study design, molecular analysis, data collection, data interpretation, writing the manuscript.

Carla Thomas: molecular analysis, data collection, writing the manuscript.

Katrina Spilsbury: data analysis, writing the manuscript.

Connull Leslie: study design, writing the manuscript.

Benhur Amanuel: study design, molecular analysis, data interpretation, writing the manuscript.

Michael Millward: study design, data interpretation, writing the manuscript.

Corresponding author

Correspondence to Nima Mesbah Ardakani.

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Conflicts of Interest

Michael Millward:

Travel support/conference - AstraZeneca, Bristol-Myers Squibb,

Advisory Board Member - AstraZeneca, Roche, Pfizer, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme

Other authors have no conflict of interest to declare

Ethics Approval

The study was approved by the Sir Charles Gairdner Hospital Executive Committee and Quality Improvement Committee (Approval number 16361).

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Waiver of consent was granted by the Sir Charles Gairdner Hospital Executive Committee and Quality Improvement Committee (Approval number 16361).

Consent for Publication

Consent for publication was granted by the Sir Charles Gairdner Hospital Executive Committee and Quality Improvement Committee (Approval number 16361).

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Ye, L., Mesbah Ardakani, N., Thomas, C. et al. Detection of Low-level EGFR c.2369 C > T (p.Thr790Met) Resistance Mutation in Pre-treatment Non-small Cell Lung Carcinomas Harboring Activating EGFR Mutations and Correlation with Clinical Outcomes. Pathol. Oncol. Res. 26, 2371–2379 (2020). https://doi.org/10.1007/s12253-020-00833-z

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