Co-Occurring EGFR S645C and EGFR L858R in a Patient with Lung Adenocarcinoma Induced Primary Resistance to Osimertinib

Abstract

Approximately 10–20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.

Keywords:

• EGFR S645C
• osimertinib
• primary resistance
• NSCLC
• subclone

Abbreviations

TKIs, tyrosine kinase inhibitors; NSCLC, non-small-cell lung cancer; NGS, next-generation sequencing; CT, computed tomography; CEA, carcinoembryonic antigen; AF, allele frequency; PFS, progression-free survival; OS, overall survival; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PD, progressive disease; ctDNA, circulating tumor DNA; eVIP, expression-based variant impact phenotyping; AACR, American Association for Cancer Research; GENIE, Project Genomics Evidence Neoplasia Information Exchange.

Data Sharing Statement

The original contributions presented in this study are included in the article and further inquiries can be directed to the corresponding author.

Ethics Approval and Consent to Participate

The authors declare that written informed consent was obtained from the patient’s and institutional approval for the publication of data and images. The research gene analysis was with ethics approval (HREC ID 4814).

Consent for Publication

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We thank Dr. Ran Ding, Dr. Wanglong Deng and Dr. Dongsheng Chen from Jiangsu Simcere Diagnostics for their assistance with this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Fei Quan, Zhongyu Lu and Duoxia Yang were employed by Jiangsu Simcere Diagnostics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.