The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

Misako Nagasaka, Vijendra Singh, Yasmine Baca, Ammar Sukari, Chul Kim, Hirva Mamdani, Alexander I. Spira, Dipesh Uprety, Gerold Bepler, Edward S. Kim, Luis E. Raez, Sachin Gopalkrishna Pai, Chukwuemeka Ikpeazu, Matthew Oberley, Rebecca Feldman, Joanne Xiu, W. Michael Korn, Antoinette J. Wozniak, Hossein Borghaei, Stephen V. Liu

Research output: Contribution to journalArticlepeer-review


Background: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. Methods: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. Results: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). Conclusion: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Original languageEnglish (US)
Pages (from-to)52-59
Number of pages8
JournalClinical Lung Cancer
Issue number1
StatePublished - Jan 2022
Externally publishedYes


  • ERBB2 mutation
  • Epidermal growth factor receptor mutation
  • HER2 amplification
  • HER2 mutation
  • Next generation sequencing

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research


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