Published online Aug 6, 2019. doi: 10.12998/wjcc.v7.i15.1964
Peer-review started: April 15, 2019
First decision: May 16, 2019
Revised: June 16, 2019
Accepted: June 26, 2019
Article in press: June 27, 2019
Published online: August 6, 2019
Human epidermal growth factor receptor 2 (HER2) was introduced as a predictive biomarker for the treatment of gastric cancer along with trastuzumab, and the strong HER2 intensity of immunohistochemistry (IHC) 3+ was reported as a better prognostic factor for HER2-positive gastric cancer treated with trastuzumab-based chemotherapy. Intratumoral HER2 heterogeneity for HER2-positive gastric cancers was reported to be more frequent than in HER2-positive breast cancers. Although intratumoral HER2 heterogeneity was reported to be one of the poor predictors for the treatment response and poor prognosticator for patients with HER2-positive breast cancer who received trastuzumab-based chemotherapy, the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer treated with trastuzumab has not been well investigated. Furthermore, even the definitions of HER2 heterogeneity for HER2-positive gastric cancer have not been established. In this study, we established the definition of intratumoral HER2 heterogeneity and clarified the clinical significance of HER2 heterogeneity for HER2-positive gastric cancer.
HER2 heterogeneity may be a pivotal predictor for the efficacy of trastuzumab-based chemotherapy. Authors have previously reported that intratumoral HER2 heterogeneity had a negative survival benefit for patients with surgically resected HER2-positive gastric cancer. However, HER2 assessment before treatment is usually based on endoscopic biopsy specimen for metastatic gastric cancer, and the clinical significance of intratumoral HER2 heterogeneity for biopsy specimen is still unknown. If these clinical significances are clarified, HER2 heterogeneity might be introduced to the assessment of HER2 positivity for gastric cancer in the future.
The aim of this study was to clarify the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer treated with trastuzumab-based chemotherapy by evaluation of biopsy specimens.
Patients with HER2-positive metastatic or unresectable adenocarcinoma of the stomach or gastroesophageal junction who received trastuzumab-based chemotherapy as first-line treatment at our hospital were included. The patients were classified into two groups (Homo- and Hetero- group) according to intratumoral HER2 heterogeneity, and their clinicopathological findings, clinical responses, progression-free survival (PFS) and overall survival (OS) were compared. Furthermore, the predictive factor for clinical response and prognostic factor were analyzed using multivariable analyses. Assessment of intratumoral HER2 heterogeneity was conducted on patients who underwent assessment of HER2 positivity from two or more different portions of the same tumor, and three or more biopsy specimens were obtained from each portion. Those patients whose HER2 assessment was performed from only one portion were excluded. We defined intratumoral HER2 homogeneity as every portion of the tumor being HER2-positive by IHC, and any portion of the tumor staining negative for HER2 was defined as intratumoral HER2 heterogeneity.
A total of 776 patients with metastatic or unresectable adenocarcinoma of the stomach or gastroesophageal junction were treated in the study period, and HER2 positivity was observed in 127 patients (16.3%). Intratumoral HER2 heterogeneity was significantly more frequently observed in macroscopically type 3 and type 4 patients than other types, and patients with IHC 2+ than IHC 3+. Tumor shrinkage and clinical responses for the patients with measurable metastatic lesions were evaluated, and overall response rate (complete response and partial response) was considerably better in the Homo group than in the Hetero group. Median survival time in the Hetero group was 12.5 mo, which was considerably worse than that in the Homo group (25.7 mo, HR; 2.430, 95%CI: 1.389-4.273). Median PFS time in the Hetero group was 2.9 mo, which was also significantly worse than that in the Homo group (7.9 mo, HR: 2.000, 95%CI: 1.203-3.333). Multivariate analysis revealed IHC HER2 heterogeneity as one of the independent poor prognostic factors for OS (HR: 3.115, 95%CI: 1.610-6.024) and PFS (HR: 2.123, 95%CI: 1.225-3.676).
In this study, we examined the effect of intratumoral HER2 heterogeneity by IHC for HER2-positive advanced gastric cancer treated with trastuzumab-based chemotherapy on their therapeutic responses and survival. Intratumoral HER2 heterogeneity by IHC evaluated by biopsy specimen before treatment was one of the independent poor predictive factors for tumor shrinkage and a poor prognosticator. Our current study selected patients in whom HER2 positivity could be assessed from more than two different portions of the tumor, and we newly defined HER2 heterogeneity as any of those portions of the tumor that did not show HER2 positivity. We employed the standard criteria of HER2 positivity generally performed in clinical diagnosis, i.e., tumor cell cluster of at least five positive cells with complete basolateral or lateral membranous reactivity. According to our simple definition of intratumoral HER2 heterogeneity, the treatment outcomes were definitively different between the HER2 homogeneity group and heterogeneity group. Assessment of HER2 positivity for endoscopic biopsy specimen in the ToGA trial was established without consideration of intratumor HER2 heterogeneity. Our current study suggests that the combination of heterogeneity and IHC might be beneficial to predict the efficacy of trastuzumab-based chemotherapy.
HER2 heterogeneity is a pivotal predictor for the efficacy of HER2-positive gastric cancers. However, there are still some problems that need to be solved in the future. First, concordance of intratumoral HER2 heterogeneity between endoscopic biopsy specimen and whole tumor tissues has not been investigated in the current study. Secondly, there was no common standard of adequate numbers and portions for the assessment of intratumoral HER2 heterogeneity. Thirdly, this study did not include the intratumoral heterogeneity of HER2 gene amplification. Intratumoral heterogeneity of HER2 gene amplification has been reported to be one of the significant prognostic factors for metastatic or resectable advanced breast cancers. The significance of intratumoral heterogeneity of HER2 gene amplification should also be clarified by further investigations. The survival benefits for anti-HER2 drugs such as lapatinib or pertuzumab in combination with trastuzumab and adjuvant therapy of trastuzumab or trastuzumab beyond progression were demonstrated for breast cancers. However, the efficacy of those anti-HER2 agents had not been proven for gastric cancers, and intratumoral HER2 heterogeneity may be considered as one of the reasons for the difference of these results between breast and gastric cancers. If more detailed clinical significance of intratumoral HER2 heterogeneity is solved in the future, anti-HER2 drugs other than trastuzumab can be adopted, and treatment outcomes of HER2-positive gastric cancers would be improved.