Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study

Abstract

Background: Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC.

Materials and methods: This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression.

Results: HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression.

Conclusions: Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above.

Figure 1

Study design and prognostic value of HER2 expression. (A) Study profile; (B–D) Kaplan–Meier estimates of overall survival according to HER2 expression in patients with stages II and III disease (B), patients with stage II disease (C), and patients with stage III disease (D). HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

Figure 2

Relationship between HER2 status and benefit from adjuvant chemotherapy. (A) Stage II subgroup with low HER2 expression [immunohistochemistry (IHC) scores of 0/1+]; (B) stage III subgroup with low HER2 expression; (C) stage II subgroup with high HER2 expression (IHC scores of 2/3+); (D) stage III subgroup with high HER2 expression; (E) treatment interaction with HER2 expression for 5-year overall survival. HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

Figure 3

Relationship between HER2 status and benefit from adjuvant chemotherapy in the stage II subgroup. (A) Stage II subgroup with a HER2 expression score of 0; (B) stage II subgroup with a HER2 expression score of 1+; (C) stage II subgroup with a HER2 expression score of 2+; (D) stage II subgroup with a HER2 expression score of 3+. HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

Figure 4

Relationship between HER2 expression and benefit from adjuvant chemotherapy in different cohorts. The association between HER2 expression and overall survival was investigated in the internal data set (A) and external data set (B). HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

Figure 5

Relationship between the number of adjuvant chemotherapy drugs and overall survival in the stage II patients, stratified by HER2 expression. (A) Overall survival in stage II patients with a HER2 IHC score of 0; (B) overall survival in stage II patients with a HER2 immunohistochemistry (IHC) score of 1+; (C) overall survival in stage II patients with a HER2 IHC score of 2+; (D) overall survival in stage II patients with a HER2 IHC score of 3+. *Received single-agent chemotherapy versus no adjuvant chemotherapy; ^#Received multiagent chemotherapy versus no adjuvant chemotherapy. HER2, human epidermal growth factor receptor 2; HR, hazard ratio.