A Novel Oncogenic Driver in a Lung Adenocarcinoma Patient Harboring an EGFR-KDD and Response to Afatinib

Abstract

Introduction: Oncogenic mutations in the epidermal growth factor receptor (EGFR) occur frequently in patients with lung cancer. These mutations may serve as critical predictive biomarkers in patients with non-small cell lung cancer (NSCLC). Among them, EGFR exon 18-25 kinase domain duplication (EGFR-KDD) mutations have been identified as a novel EGFR gene subtype in NSCLC. Case Presentation: We reported a rare case of a 59-year-old male diagnosed with adenocarcinoma. A biopsy revealed an EGFR-KDD identified by the next generation sequencing (NGS). Effective treatment outcome has been observed after administration with afatinib. Conclusion: This case highlights that comprehensive NGS technique is valuable in detecting novel genetic mutations in tumors.

Lung Adenocarcinoma Patient Harboring EGFR-KDD Achieve Durable Response to Afatinib: A Case Report and Literature Review

“…Preclinical data demonstrate that EGFR -KDD confers constitutive activity to the EGFR tyrosine kinase and sensitivity to EGFR-TKIs including erlotinib, afatinib, and osimertinib ( 8 ). Several instances of clinical evidence have revealed the efficacies of EGFR-TKIs in advanced LUAD but yielded variable antitumor responses ( 8 – 11 ). The first case of EGFR -KDD in LUAD is reported by Gallant et al where a 33-year-old male smoker diagnosed with stage IV LUAD did not carry any common EGFR mutations but achieved PR after being treated with afatinib ( 8 ).…”

“…The first case of EGFR -KDD in LUAD is reported by Gallant et al where a 33-year-old male smoker diagnosed with stage IV LUAD did not carry any common EGFR mutations but achieved PR after being treated with afatinib ( 8 ). Stable disease (SD) response to afatinib was observed in a 59-year-old patient with LUAD ( 11 ). Furthermore, studies have also documented that patients with EGFR -KDD-positive LUAD showed response to first-generation EGFR-TKI icotinib and third-generation EGFR-TKI osimertinib ( 9 , 10 ).…”

Durable response to EGFR tyrosine kinase inhibitors in a patient with non–small cell lung cancer harboring an EGFR kinase domain duplication

“…NGS of a tumor specimen obtained after erlotinib therapy did not reveal a potential resistance mechanism, including the EGFR T790M mutation. The limited data available for the treatment of NSCLC patients with EGFR‐KDD has shown that it is sensitive to several EGFR‐TKIs 3–11 . Preclinical studies showed that afatinib inhibited the growth of cells expressing an EGFR‐KDD form of the receptor and that cetuximab further enhanced the activity of afatinib 6,11 .…”

“…Given that most conventional sequencing platforms or PCR‐based methods do not routinely detect EGFR alterations affecting introns, such screening procedures may miss some patients who would benefit from targeted therapy. We reviewed 19 EGFR‐KDD patients from seven studies and the case reported here ( n = 20 in total) in order to investigate who should further be examined for EGFR‐KDD 3–7,9,10 . Patient ages ranged from 33–87 (median, 59.5), and 12/21 (57.1%) patients were male.…”

“…Tyrosine kinase inhibitors (TKIs) are established as standard therapy for non–small cell lung cancer (NSCLC) with sensitizing mutations of the epidermal growth factor receptor (EGFR) 1,2 . EGFR kinase domain duplication (EGFR‐KDD) is the result of rare genomic alterations that activate EGFR signaling and confer sensitivity to EGFR‐TKIs 3–11 . Most instances of EGFR‐KDD are the result of duplication of exons 18 to 25 of EGFR , although rare cases due to duplication of exons 17 to 25 or exons 14 to 26 have been described 4 .…”