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Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study
Kadoaki Ohashi1, Kiichiro Ninomiya1, Hiroshige Yoshioka2
1Department of Respiratory Medicine, Okayama University Hospital, Japan.
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.
Insights
Human epidermal growth factor receptor-2 (HER2) expression negatively impacts epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment for EGFR-mutated non-small-cell lung cancer (NSCLC). This effect is particularly pronounced in patients with a performance status of 2.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are a standard treatment for EGFR-mutated non-small-cell lung cancer (NSCLC).
- A predictive biomarker for EGFR-TKI efficacy is lacking.
- Human epidermal growth factor receptor-2 (HER2) aberrations are implicated in acquired resistance to EGFR-TKIs, but their direct impact on treatment outcomes requires systematic evaluation.
Purpose of the Study:
- To investigate the impact of HER2 protein expression on the efficacy of EGFR-TKIs in patients with NSCLC harboring EGFR mutations.
- To evaluate HER2 as a potential predictive biomarker for EGFR-TKI treatment response in NSCLC.
Main Methods:
- A post-hoc subgroup analysis of 356 patients with EGFR-mutant NSCLC from a prospective cohort study (HER2-CS study).
- HER2 protein expression was assessed using immunohistochemistry (IHC) with gastric cancer criteria, categorizing patients into HER2-positive (HER2-P, IHC2+/3+) and HER2-negative (HER2-N, IHC0/1+) groups.
- Time-to-treatment failure (TTF) of EGFR-TKI was the primary endpoint, analyzed with respect to HER2 expression levels and patient performance status (PS).
Main Results:
- The HER2-positive group exhibited a significantly shorter TTF compared to the HER2-negative group (HR: 1.657, median 13.3 vs. 19.1 months).
- HER2 expression significantly worsened TTF in patients with a performance status of 2 (HR: 5.497), but not in those with better PS (HR: 1.437).
- An interaction between HER2 expression and performance status on TTF was statistically significant (pinteraction = 0.015).
Conclusions:
- HER2 protein expression in EGFR-mutant NSCLC is associated with a negative impact on EGFR-TKI efficacy.
- The negative effect of HER2 on treatment outcomes is dependent on the patient's performance status.
- HER2 status may serve as a predictive biomarker for EGFR-TKI treatment in specific NSCLC patient subgroups, particularly those with impaired performance status.
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