Epidermal Growth Factor Receptor Kinase Domain Duplication in Lung Adenocarcinoma with Sensitive Response to Afatinib: A Case Report and Literature Review

Abstract

Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare form of EGFR mutation. Unlike the classical mutations such as exon 19 deletion and exon 21 p.L858R point mutation, EGFR-KDD is a special type of large genomic rearrangement (LGR) that results in the duplication of the tyrosine kinase domain at the protein level, leading to the formation of an intramolecular dimer and activation of the EGFR signaling pathway. Case reports and in vitro experiments have shown that EGFR-KDD patients can benefit from EGFR TKI treatment. Similar to classical EGFR mutations, EGFR-KDD inevitably develops resistance during EGFR TKI treatment, leading to disease progression. Due to the rarity of EGFR-KDD, the acquired resistance mechanisms are not yet fully understood, but known mechanisms include EGFR amplification and T790M mutation. In this study, we report a 71-year-old female EGFR-KDD patient who showed a positive response to afatinib treatment initially, but developed resistance upon tumor progression. Subsequent next-generation sequencing (NGS) on the re-biopsy revealed TP53 exon c.688_764 deletion and MET exon 15-20 duplication, suggesting that MET bypass activation might be the acquired resistance mechanisms. Additionally, we conducted a literature review on EGFR-KDD and examined case reports of EGFR-KDD patients treated with EGFR TKIs to summarize the treatment outcomes and resistance mechanisms. We hope to provide more treatment information for patients with rare gene mutations in lung cancer.

Keywords: EGFR kinase domain duplication; acquired resistance; adenocarcinoma of lung; afatinib; targeted therapy; tyrosine kinase inhibitors.

Graphical abstract

Figure 1

Chest CT scans at different time points. (A and B) baseline (3/2023), multiple enlarged mediastinal lymph nodes, with the largest measuring of 44.2*30.8mm; (C and D) after Afatinib treatment (5/2023), multiple enlarged mediastinal lymph nodes, with the largest measuring of 19.8*16.0mm; (E and F) the first time with disease progression (11/2023), multiple enlarged mediastinal lymph nodes, with the largest measuring of 37.4*25.7mm; (G and H) the second time with disease progression (2/2024), fusion of enlarged lymph nodes with maximum diameter of 48.0*27.2mm; a right axillary lymph node with maximum diameter of 25.5*19.4mm; Yellow arrows denote mediastinal lymph node lesions; red arrows indicate the axillary lymph node lesion.