Expression and significance of Her2 and Ki-67 in gastric adenocarcinoma without distant metastasis: a cohort study

Abstract

Background: The significance of human epidermal growth factor receptor 2 (Her2) and nucleus-associated antigen Ki-67 expression remains controversial in gastric adenocarcinoma (GaC). The aim of this study was to investigate the expression and clinicopathologic and prognostic significance of Her2 and Ki-67 in resected GaC without distant metastasis.

Methods: Malignant tissues and clinicopathologic data were obtained from 195 patients with resected non-metastatic GaC. Immunohistochemistry staining was performed to examine the expression of Her2 and Ki-67; their association with clinicopathologic factors were investigated using logistic regression, and their association with survival was explored using Kaplan-Meier analysis and Cox proportional hazards regression.

Results: Her2 was majorly expressed in cell membrane and Ki-67 in cell nucleus in non-metastatic GaC. Stronger Her2 expression was significantly associated with better tumor differentiation, neurovascular invasion, less advanced pathological tumor (pT) stage, and more advanced pathological node (pN) stage; while Ki-67 expression was not significantly associated with any investigated clinicopathologic factors. Patients with both negative Her2 and negative Ki-67 expression had poorer tumor differentiation, and more advanced pT and pathological tumor-node-metastasis (pTNM) stages; the association with pT and pTNM stages were further confirmed by multivariable analyses, especially in node-negative disease. Her2 or Ki-67 alone was not significantly associated with pTNM stage. A strongly positive (+++) Her2 expression was associated with poorer survival in multivariable analysis only (P = 0.047); while Ki-67 or combined expression was not significantly associated with prognosis.

Conclusions: In non-metastatic GaC, Her2 expression and combined expression of Her2 and Ki-67 were associated with several clinicopathologic factors including tumor differentiation and stage, and only a +++ Her2 expression was associated with poorer prognosis in multivariable analysis with marginal significance in this study; while Ki-67 alone had both limited clinicopathologic and prognostic values.

Keywords: Cohort study; Gastric adenocarcinoma; Human epidermal growth factor receptor 2 (Her2); Nucleus-associated antigen ki-67.

Fig. 1

Expression of Her2. a pTNM stage I gastric adenocarcinoma; b + from pTNM stage III gastric adenocarcinoma; c ++ from pTNM stage II gastric adenocarcinoma; d +++ from pTNM stage II gastric adenocarcinoma. The positivity degree of Her2 expression follows the National Comprehensive Cancer Network guidelines (https://www.nccn.org): − means “no reactivity or membranous reactivity in < 10% of cancer cells”; + means “faint or barely perceptible membranous reactivity in ≥ 10% of cancer cells; cells are reactive only in part of their membrane”; ++ means “weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10% of cancer cells”; +++ means “strong complete, basolateral, or lateral membranous reactivity in ≥ 10% of cancer cells”. Her2, human epidermal growth factor receptor 2

Fig. 2

Expression of Ki-67. a from pTNM stage I gastric adenocarcinoma; b from pTNM stage II gastric adenocarcinoma; c ++ from pTNM stage I gastric adenocarcinoma; d +++ from pTNM stage III gastric adenocarcinoma. For Ki-67, − means very low proliferation activity with proportion of Ki-67-positive cells < 25%; + means low proliferation activity with proportion of Ki-67-positive cells 25–50%; ++ means moderate proliferation activity with proportion of Ki-67-positive cells 50–75%; +++ means high proliferation activity with proportion of Ki-67-positive cells > 75%

Fig. 3

Kaplan–Meier survival curves according to Ki-67 (a), Her2 (b), and combined expression (c). Prognostic differences across groups were examined using the log-rank test. Her2, human epidermal growth factor receptor 2; H–K−, Her2 negative and Ki-67 negative; H–K+, Her2 negative and Ki-67 positive; H+K−, Her2 positive and Ki-67 negative; H+K+, Her2 positive and Ki-67 positive