Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis

Kadoaki Ohashi, Kiichiro Ninomiya, Hiroshige Yoshioka, Akihiro Bessho, Takuo Shibayama, Keisuke Aoe, Nobuhisa Ishikawa, Toshiyuki Kozuki, Haruyuki Kawai, Shoichi Kuyama, Seigo Miyoshi, Kazunori Fujitaka, Hideto Obata, Yukari Tsubata, Yoshikazu Awaya, Masaaki Inoue, Koji Inoue, Naokatsu Horita, Hiroyuki Yanai, Katsuyuki HottaKatsuyuki Kiura

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. Materials and Methods: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. Results: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients’ demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076–2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510–20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899–2.298) (pinteraction = 0.015). Conclusion: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.

Original languageEnglish
Pages (from-to)83-89
Number of pages7
JournalLung Cancer
Publication statusPublished - Dec 2020


  • Epidermal growth factor receptor mutations
  • Human epidermal growth factor receptor-2
  • Performance status
  • Time-To-Treatment failure

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research


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