A enhanced understanding of the prognostic factors associated with OS is useful for preparing a treatment plan. Because HER2 positive gastric cancer has a distinct driver oncogene and a specific treatment regimen, prognostic factors in patients treated with trastuzumab should be investigated separately. In this study, visceral metastasis (lung or liver metastasis), and Hb, LDH, and CRP levels were identified as significant prognostic factors for OS. Moreover, after stratification by risk group (low, moderate, or high), survival curves were clearly separated. The median OS of each group was 32.0, 18.7, and 10.1 months. The HRs of the moderate and high-risk groups, when compared to the low-risk group, were 1.75 (95% CI: 1.05–2.93) and 3.49 (95% CI: 1.81–6.71), respectively. Our data identified for the first time, prognostic factors associated with the survival of patients with advanced HER2-positive gastric cancer. These patients were treated with trastuzumab-based chemotherapy.
Various prognostic scores or indices have been suggested for classifying patients with advanced gastric cancer. The most well-known prognostic score is the GPS, which is based on serum biomarkers such as elevated CRP and hypoalbuminemia [21]. GPS has been validated in several types of cancers, including gastric cancer [21, 4, 22]. For upper gastrointestinal cancers such as locally advanced and metastatic esophagogastric cancer, Chau et al. proposed the use of the RMH index. This index was obtained using data from randomized phase III trials in the UK [4]. It consists of ECOG PS (≥ 2), liver metastases, peritoneal metastases, and serum ALP (≥ 100 U/L). Likewise, the JCOG index is based on randomized phase III trials conducted in Japan [17]. It uses ECOG PS ≥ 1, the number of metastatic sites ≥ 2, no prior gastrectomy, and elevated ALP levels as markers of a poor prognosis.
Takahari et al. showed how survival curves were clearly separated when patients were stratified by the JCOG prognostic index. This was opposed to what was observed when they were stratified by the RMH index [3]. The reasons for these inconsistent results could be explained by several disparities in the backgrounds, including clinicopathological features, molecular biology, and treatment strategies, between the UK and Japan studies. First, more than half of the patients had either lower esophageal (27.3%) or gastroesophageal junction cancer (23.0%) in the RMH index sample. However, these tumor locations were less prevalent (generally less than 10%) in Japan [23]. Second, recent data from The Cancer Genome Atlas (TCGA) demonstrated that gastric cancer consists of four molecular categories: Epstein-Barr virus (EBV), microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) type [24]. According to TCGA data, chromosomal unstable tumors are more prevalent in gastroesophageal junction/cardia cancer (65%) than in the gastric body or fundus. This suggests the existence of molecular disparity between the two studies. Third, the majority of patients were treated with an epirubicin, cisplatin, and 5-fluorouracil (ECF) regimen in the RMH index study. Although, all patients received fluoropyrimidine plus platinum in the JCOG prognostic index study. Finally, post-disease progression treatment is commonly applied in Japan, whereas the proportion of patients receiving post-disease progression treatment is low in Western countries [25]. Takashima et al. emphasized the importance of subsequent treatment to prolong OS by showing a positive correlation between the duration of post-progression survival and the proportion of patients receiving subsequent chemotherapy [26]. Indeed, in the AVAGAST trial, Japanese patients received subsequent chemotherapy with a higher frequency (77%). They had a longer median OS (14.1 months) than patients in the US or Western Europe (37%; median OS: 9.1 months) [7]. These regional differences in the treatment of gastric cancer may cause inconsistent results between the RMH index and JCOG index. This underscores the importance of considering regional differences when identifying prognostic factors.
Notably, this cohort was relatively homogeneous in terms of molecular status and treatment strategy compared with previous studies [4, 17]. HER2-positive gastric cancer, a specific tumor subtype, is associated with intestinal histology, liver metastasis, and the absence of peritoneal metastasis [27]. Indeed, this cohort demonstrated a high incidence of differentiated histology (68%) and visceral metastasis (58%). In addition, according to TCGA, HER2-positive gastric cancer is classified as a chromosomally unstable tumor [24]. Moreover, all patients in our study were treated with trastuzumab-based chemotherapy. Their median OS was higher (18.8 months) than that obtained in previous studies. Under these circumstances, that is advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy, we identified four independent prognostic factors for OS. These include the presence of visceral metastases and levels of Hb, LDH, and CRP. Visceral metastasis, especially liver metastasis, is a well-known negative prognostic factor for gastrointestinal cancer. Conventionally, tumor burden is considered one of the reasons why liver metastasis is associated with a shorter survival [28]. However, recent data suggest that liver metastasis is associated with aggressive properties such as vascular invasion, angiogenesis, systemic immune tolerance. It is also associated with fewer infiltrating CD8+ T-cells at the invasive margin in distant metastasis [29, 30]. Likewise, lower Hb levels could reflect not only the presence of a primary tumor, which can cause bleeding, but also exhaustion due to a prolonged illness.
Rapid proliferation and abnormal vasculature induce hypoxia within tumors [31]. Regardless of the available oxygen level, tumors mainly rely on the anaerobic glycolysis pathway. This is known as the Warburg effect [32]. Under this metabolic pathway, glucose changes to pyruvate, which is subsequently converted to lactate through catalysis by LDH. As a result, tumor cells take up more glucose and produce more LDH to obtain the energy needed for proliferation. In 18F-FDG-PET, a high maximum standardized uptake value (SUVmax) is recognized as a negative prognostic factor. SUVmax and LDH levels are positively correlated. Therefore, LDH levels could be an indicator of tumor activity [33]. Hypoxia also induces central necrosis in tumors. This results in cancer-related inflammation and increased CRP levels. Recent data suggest that vascular endothelial growth factor (VEGF) is induced by hypoxia. VEGF stimulates immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressive cells in the tumor microenvironment [34]. Because one of the mechanisms of action of trastuzumab is antibody-dependent cellular cytotoxicity (ADCC) [35], trastuzumab might not show sufficient efficacy and anti-tumor effects under this immunosuppressive microenvironment. Therefore, our prognostic factors may reflect not only the tumor burden but also the tumor activity and immune status of the host.
In contrast to previous reports, PS was not significantly associated with OS in univariate analysis in our study as all except one of our patients had a PS of 0–1. In addition, there is a limitation in our study when assigning PS between 0 and 1 as it was a retrospective study. In previous studies, a high ALP level has been proposed as an independent risk factor. However, this was not reproduced in the multivariate analysis in this study. The exact reason why high ALP levels were not significantly associated with OS in this study is unclear. Considering the distinct molecular profile of the tumors and treatment strategy of patients with HER2-positive gastric cancer, the prognostic factors for survival may differ from those of patients with HER2-negative gastric cancer.
There are several limitations to this study that should be considered. First, this was a retrospective study conducted at a single institution. Second, the sample size was relatively small and no comorbidity data were available. Third, peritoneal metastasis, which has been indicated as a prognostic factor in several reports, was not evaluated. Finally, we do not have molecular data regarding the immune status and ADCC activity of trastuzumab under hypoxia. These limitations require further clinical validation using a larger prospective independent cohort and molecular correlative analysis. Nevertheless, considering the low incidence of HER2-positive gastric cancer, these data are valuable. Consequently, our simple and inexpensive scoring system, using laboratory and imaging tests, may prove useful in clinical practice. These factors can be used to assist in the treatment decision-making process for patients with advanced HER2-positive gastric cancer as they are based on the estimated prognosis.