A better understanding of the prognostic factors associated with OS is useful for making treatment decisions. 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 being stratified 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, and 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 identify, for the first time, prognostic factors associated with the survival of patients with advanced HER2-positive gastric cancer who were treated with trastuzumab-based chemotherapy.
Various prognostic scores or indexes have been suggested for classifying patients with advanced gastric cancer. The most famous 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 cancer, including gastric cancer [21, 4, 22]. For upper gastrointestinal cancer such as locally advanced and metastatic esophagogastric cancer, Chau et al. proposed the use of the RMH index, which was obtained using data from randomised phase III trials in the UK [4] and consists of ECOG PS (≥ 2), liver metastases, peritoneal metastases, and serum ALP (≥ 100 U/L). Likewise, the JCOG index is based on randomised phase III trials conducted in Japan [17] and uses ECOG PS ≥ 1, the number of metastatic sites ≥ 2, no prior gastrectomy, and elevated ALP level as markers of poor prognosis.
Takahari et al. showed how survival curves were clearly separated when patients were stratified by the JCOG prognostic index, as opposed to what was observed when they were stratified by the RMH index [3]. The reasons why these results were inconsistent could be explained by several disparities in the backgrounds, including clinicopathological features, molecular biology, and treatment strategy, between the UK and Japan studies. First, more than half of the patients had either lower oesophageal (27.3%) or gastroesophageal junction cancer (23.0%) in the RMH index sample, whereas these tumour 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, namely Epstein-Barr virus (EBV), microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) type [24]. According to TCGA data, chromosomal unstable tumours are more prevalent in gastroesophageal junction/cardia cancer (65%) than in the gastric body or fundus, suggesting the existence of molecular disparity between the two studies. Third, the majority of patients were treated with an epirubicin, cispaltin, 5-fluorouracil (ECF) regimen in the RMH index study, whereas 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. emphasised 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%) and had a longer median OS (14.1 months) than patients in the USA/Western Europe (37%; median OS: 9.1 months) [7]. These regional differences in gastric cancer may cause inconsistent results between the RMH index and JCOG index, and underscore 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 to those of previous studies [4, 17]. HER2-positive gastric cancer, a specific tumour subtype, is associated with intestinal histology, liver metastasis, and the absence of peritoneal metastasis [27]. Indeed, this cohort demonstrated high incidences of differentiated histology (68%) and visceral metastasis (58%). In addition, according to TCGA, HER2-positive gastric cancer is classified as a chromosomally unstable tumour [24]. Moreover, all patients in our study were treated with trastuzumab-based chemotherapy and their median OS resulted higher (18.8 months) than that obtained in previous studies. Under these circumstances, i.e. advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy, we identified four independent prognostic factors for OS: presence of visceral metastases, and levels of Hb, LDH, and CRP. Visceral metastasis, especially liver metastasis, is a well-known negative prognostic factor in gastrointestinal cancer. Conventionally, tumour burden has been considered one of the reasons why liver metastasis is associated with shorter survival [28]. However, recent data suggest that liver metastasis is associated, not only with aggressive properties such as vascular invasion and angiogenesis, but also with systemic immune tolerance 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 tumour, which can cause bleeding, but also exhaustion due to prolonged illness.
Rapid proliferation and abnormal vasculature induce hypoxia within the tumour [31]. Regardless of the available oxygen level, tumours mainly rely on the anaerobic glycolysis pathway, which is known as the Warburg effect [32]. Under this metabolic pathway, glucose changes to pyruvate and pyruvate is subsequently converted to lactate through catalysis by LDH. As a result, tumour cells take up more glucose and produce more LDH to obtain the energy needed for proliferation. In 18F-FDG-PET, a high maximum standardised uptake value (SUVmax) is known as a negative prognostic factor, and SUVmax and LDH levels are positively correlated; therefore, LDH level could be an indicator of tumour activity [33]. Hypoxia also induces central necrosis in tumours, resulting in cancer-related inflammation and increased CRP levels. Recent data suggest that vascular endothelial growth factor (VEGF) is induced by hypoxia and that VEGF stimulates immunosuppressive cells such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressive cells in the tumour 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-tumour effect under this immunosuppressive microenvironment. Therefore, our prognostic factors may reflect not only the tumour burden but also the tumour 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 because 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 because it was a retrospective study. In previous studies, high ALP level was proposed as an independent risk factor. However, this was not reproduced in the multivariate analysis of this study. The exact reason why high ALP level was not significantly associated with OS in this study is unclear. Considering the distinct molecular profile of the tumours and treatment strategy of patients with HER2-positive gastric cancer, their prognostic factors for survival may differ from those with HER2-negative gastric cancer.
There are several limitations that should be considered in this study. 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 was indicated as a prognostic factor in several reports, was not evaluated. Finally, we do not have any molecular data in terms of 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, this data is valuable and our simple and inexpensive scoring system, using laboratory and imaging tests, will be useful in clinical practice. These factors can be used to help in the decision-making process that involves patients with advanced HER2-positive gastric cancer, based on the estimated prognosis.