Dai-Shinozaki Ayuka, Sakakibara-Konishi Jun, Hatanaka Kanako C, Wakabayashi Kento, Shinagawa Naofumi, Matsuno Yoshihiro, Hatanaka Yutaka, Konno Satoshi
Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University Hospital, Sapporo, Japan.
Department of Internal Medicine, Division of Respiratory Medicine and Neurology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Respir Med Case Rep. 2025 Jul 1;57:102249. doi: 10.1016/j.rmcr.2025.102249. eCollection 2025.
Afatinib, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), irreversibly inhibits the pan-human epidermal growth factor receptor (HER) family. It is effective in patients with lung cancer with various mutations; however, its efficacy in overcoming resistance following first-line EGFR-TKI treatment remains unclear. Here, we report the case of a 68-year-old woman with lung adenocarcinoma (pStage IA, pT1bN0M0) who underwent surgical resection in March 2012 following several previous lung cancer resections. In November 2012, postoperative recurrence with pleural dissemination led to the detection of the L858R mutation in the malignant pleural effusion specimen using peptide nucleic acid-locked nucleic acid polymerase chain reaction clamping (PNA-LNA PCR clamp). The patient was treated with gefitinib for 8 years, after disease progression with multiple lung metastases. The metastatic lesions harbored compound S768I and L858R mutations, as identified using the Oncomine Dx Target Test Multi-CDx System (ODxTT). Treatment with afatinib resulted in rapid metastatic lesion regression. Reanalysis of the previously resected surgical specimens confirmed the presence of the S768I and L858R compound mutations in all samples, which suggests that S768I was not an acquired resistance mutation. Furthermore, immunohistochemical analysis revealed an increase in HER2 and HER3 protein expression in the gefitinib-resistant specimens. These findings suggest that HER2 and HER3 upregulation may contribute to gefitinib resistance, and that afatinib may effectively target these resistance mechanisms.
阿法替尼是第二代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），可不可逆地抑制全人类表皮生长因子受体（HER）家族。它对具有各种突变的肺癌患者有效；然而，其在克服一线EGFR-TKI治疗后的耐药性方面的疗效仍不清楚。在此，我们报告一例68岁女性肺腺癌患者（pStage IA，pT1bN0M0），该患者在先前多次肺癌切除术后于2012年3月接受了手术切除。2012年11月，术后复发并伴有胸膜播散，通过肽核酸-锁核酸聚合酶链反应钳夹（PNA-LNA PCR钳夹）在恶性胸腔积液标本中检测到L858R突变。该患者在疾病进展出现多处肺转移后接受吉非替尼治疗8年。使用Oncomine Dx Target Test Multi-CDx System（ODxTT）鉴定发现，转移病灶存在复合S768I和L858R突变。阿法替尼治疗导致转移病灶迅速消退。对先前切除的手术标本进行重新分析，证实所有样本中均存在S768I和L858R复合突变，这表明S768I不是获得性耐药突变。此外，免疫组织化学分析显示，吉非替尼耐药标本中HER2和HER3蛋白表达增加。这些发现表明，HER2和HER3上调可能导致吉非替尼耐药，而阿法替尼可能有效靶向这些耐药机制。
