Management of metastatic esophagogastric junction adenocarcinoma

The prognosis of metastatic disease of esophagogastric junction adenocarcinoma remains poor, despite using a variety of regimens using cytotoxic agents. Recent understanding of molecular characteristic and tumor microenvironment of this cancer is currently instigating new therapeutic options. In this review, we summarized previous evidences of cytotoxic agents widely used worldwide, and updated recent developments of molecular targeted drugs, and immune checkpoint inhibitors.


INTRODUCTION
The esophagogastric junction (EGJ) adenocarcinoma is defined as tumors which have their center within 5 cm proximal or distal to the anatomical esophagogastric junction [1][2][3] .In Western countries, the incidence of EGJ adenocarcinoma has been increasing rapidly over the last few decades, in the background of decreasing rate of Helicobacter pylori infection, and increasing trends of obesity and gastroesophageal reflux disease (GERD).EGJ adenocarcinoma is usually diagnosed with unresectable disease because of difficulty in early detection.Even after curative resection, many cases experience recurrent disease, resulting in lower survival rates of this tumor [4,5] .In spite of multidisciplinary treatments, median overall survival (OS) is around 12 months in advanced EGJ or gastric adenocarcinoma [6,7] .Therefore, the treatment goal for metastatic disease of this tumor should include survival benefit with symptom relief, and systemic chemotherapy is a major treatment option for those cases [8] .Treatments for advanced EGJ adenocarcinoma has been developed as a type of advanced gastric cancer, and many clinical trials were conducted targeting both EGJ and gastric adenocarcinoma.Recent comprehensive molecular analysis for upper GI cancers reveals molecular differences between EGJ and gastric adenocarcinoma [9,10] .Here, we update recent evidences of treatments for advanced EGJ adenocarcinoma, and discuss future perspective.

CYTOTOXIC AGENTS (FOR HER2-NEGATIVE TUMORS)
Fluoropyrimidine (ftorafur, S-1, or capecitabine), platinum (cisplatin, or oxaliplatin), irinotecan, and taxanes (paclitaxel, or docetaxel) are globally used for metastatic disease of EGJ adenocarcinoma.In addition, trastuzumab is a humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor, and approved for tumors with HER2+ [protein overexpression by immunohistochemistry (IHC) or gene amplification by in situ hybridization (FISH)] EGJ adenocarcinoma.Considering chemotherapeutic managements, tumor HER2 status is a valuable information for adding trastuzumab to cytotoxic agents.As a first-line therapy, there is no widely accepted first-line standard regimen for advanced EGJ adenocarcinoma.
In the USA and Europe, fluorouracil and platinum-based agents (CF) or docetaxel, fluorouracil, and cisplatin (DCF) is widely used regimen based on the clinical trial.In 2006, the V-325 study group showed no superiority between DCF and DC (docetaxel and cisplatin) in OS.Median OS was 9.6 months for DCF, and 10.5 months for DC.The incidence of hematologic toxicities was high, but it was comparable between DCF and DC.Grade 3 or 4 neutropenia was the most common in hematologic toxicity; it occurred in 86% in the patients with DCF, and 87% in DC cases, although non-hematologic toxicities of DCF had a higher incidence than that of DC [11] .
In Asia, the recommended first-line treatment is S-1 plus cisplatin (SP) or capecitabine plus cisplatin (XP).In the SPIRITS trial [phase III, including advanced gastric adenocarcinoma (n = 298)], OS was better in patients treated with SP than with S-1 alone.Median OS was 13.0 months [interquartile range (IQR) 7.6-21.9] in those assigned to SP compared with 11.0 months (IQR 5.6-19.8) in those assigned to S-1 alone [hazard ratio (HR) 0.77; 95% CI 0.61-0.98;P = 0.04].Progression-free survival (PFS) was significantly longer in those assigned to SP than S-1 alone [median PFS 6.0 months (3.3-12.9)for SP vs. 4.0 months (2.1-6.8) for S-1 alone; P < 0.0001].The trial showed more grade 3 or 4 adverse events including leucopenia, neutropenia, anemia, nausea, and anorexia, in patients assigned to SP than in patients assigned to S-1 alone [13] .However, the incidence of EGJ cancer remains low in Japan, and this clinical trial included only gastric cancer patients.Therefore, the standard treatment for EGJ cancer has not yet been established in Japan and patients with EGJ cancer are usually treated based on the evidence for gastric cancer.

MOLECULARLY TARGETED DRUG
In the first decade of this century, molecularly targeted drugs have been developed for advanced EGJ adenocarcinoma [Table 1].To date, trastuzumab and ramucirumab are the only molecularly targeted drugs with confirmed survival benefit in phase III trials.In this section, we focus on the results of phase III clinical trials.

Trastuzumab (anti-HER2 antibody)
Trastuzumab is a monoclonal antibody targeting HER2.In 2010, ToGA trial [phase III, including EGJ (n = 106) and advanced gastric adenocarcinoma (n = 478)] was to assess the efficacy and safety of trastuzumab plus first-line chemotherapy (XP or FP) of advanced HER2 positive 106 EGJ and 478 gastric adenocarcinoma.HER2 status was tested by IHC and FISH.HER2 positivity was defined as samples with 3+ by IHC, or those with both 2+ IHC and FISH positive.HER2 positivity was frequently observed in tumors located at EGJ, compared to those in stomach (33.2% for EGJ vs. 20.9% for stomach; P < 0.001).Median OS was significantly longer in trastuzumab plus chemotherapy groups than in chemotherapy alone [median 13.8 months (95% CI 12-16) vs. median 11.1 months (95% CI 10-13), HR 0.74; 95% CI 0.60-0.91;P = 0.0046].However, in a subgroup analysis of EGJ adenocarcinoma, there were no survival benefit of trastuzumab (trastuzumab plus chemotherapy groups vs. chemotherapy alone, HR 0.67; 95% CI 0.42-1.08).The most common adverse events in both groups were nausea, vomiting and neutropenia.Rate of overall grade 3-4 adverse events (68% in trastuzumab plus chemotherapy groups vs. 68% in chemotherapy alone) and cardiac adverse events (6% in trastuzumab plus chemotherapy groups vs. 6% in chemotherapy alone) did not differ between the groups [6] .NCCN guideline recommends the addition of trastuzumab to any chemotherapy combination for patients with HER2-positive tumors.

Bevacizumab (anti-VEGF antibody)
Bevacizumab, which is a monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A), inhibiting tumor growth in preclinical studies [15,16] .In AVAGAST trial [phase III, including advanced EGJ (n = 103) and gastric adenocarcinoma (n = 671)], bevacizumab did not confer any survival benefit (median OS 12.1 months in bevacizumab plus XP; vs. median OS 10.1 months in XP alone).In a subgroup analysis of EGJ adenocarcinoma, there was no survival benefit (data not available) [17] .

Cetuximab, or panitumumab (anti-EGFR antibody)
Cetuximab is an EGFR antibody, widely used for patients with KRAS wild-type metastatic colorectal cancer [20,21] , recurrence or metastatic squamous-cell carcinoma of the head and neck [22] , and advanced nonsmall-cell lung cancer [23] .In the EXPAND trial [phase III, including advanced EGJ (n = 144) and gastric adenocarcinoma (n = 747)], the efficacy of adding cetuximab to capecitabine plus cisplatin was examined.However, there was no benefit to adding of cetuximab to chemotherapy compared to chemotherapy alone in the first-line treatment [median PFS 4.4 months in cetuximab plus capecitabine and cisplatin groups (95% CI 4.2-5.5);vs. median PFS 5.6 months in capecitabine and cisplatin alone groups (95% CI 5.1-5.7);HR 1.09; 95% CI 0.92-1.29;P = 0.32].In a subgroup analysis of EGJ adenocarcinoma, there was no benefit to add cetuximab, either [median PFS 5.6 months in cetuximab plus capecitabine and cisplatin groups vs. median PFS 5.6 months in capecitabine and cisplatin alone groups; HR 1.12; 95% CI 0.73-1.71] [24].

Future prospect of molecularly targeted drugs
Although precision medicine still remains developing for the upper gastrointestinal malignancies, there are some new approaches such as VIKTORY, and PANGEA trials.PANGEA is a phase II trial that gastroesophageal tumors are classified into the following six categories (HER2+, MET+, FGFR2+, VEGFR2+, MSI-H, and EGFR+), and then paired specific targeted therapies (trastuzumab, TBD, anti-EGFR antibody ABT-806, TBD2, ramucirumab, and nivolmab) are assigned according to the biomarkers, along with standard chemotherapy [32] .VIKTORY is a screening trial without drug intervention for metastatic GC patients who failed or progressed on first-line chemotherapy, using cancer panel/nanostring CNV and immunohistochemistry [33] .These efforts may create new algorithms in upper gastrointestinal cancers.

IMMUNOTHERAPY
The most advanced of the emerging development in EGJ and gastric adenocarcinoma is immunotherapy.Programmed death protein 1 (PD1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte protein 4 (CTLA4) are the key drugs to regulate cellular immune functions.Pembrolizumab and nivolumab, which are being developed as anti-PD1 antibodies, have been examined in clinical trials.

Pembrolizumab
Pembrolizumab is a selective, humanized, high-affinity IgG4-κ monoclonal antibody.By binding to PD1, pembrolizumab block the interaction between PD-1 and its ligands.In the USA, pembrolizumab was approved by the FDA for the treatment of melanoma, non-small-cell lung cancer and head and neck cancer.
In a phase Ib trial (KEYNOTE-012), the safety and activity of pembrolizumab was assessed in patients with PD-L1 positive advanced EGJ and gastric adenocarcinoma.The median PFS and the median OS were 1.9 months (95% CI 1.8-3.5)and 11.4 months (95% CI 5.7) respectively [34] .The KEYNOTE-061 is a phase III trial as a second-line therapy for PD-L1-positive patients, comparing pembrolizumab with paclitaxel.The KEYNOTE-062 is phase III trial of pembrolizumab alone or combination with FP or capecitabine vs. FP or capecitabine alone as a first-line therapy for PD-L1-positive patients.Both of these trials are still in progress.

Nivolumab
Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of PD-1.In the ATTRACTION-2 study, which was a randomized phase III trial, investigating the efficacy and safety of nivolumab as a third-line for unresectable advanced and recurrent EGJ and gastric adenocarcinoma regardless of PD-L1 expression.

Future prospect of immunotherapy
Many study reported that PD-L1 expression has been related with poor prognosis and associated with response to immunotherapy [39][40][41][42] .On the other hands, only a few studies reported that PD-L1 blockade was effective without PD-L1 expression [35] .These results indicated that PD-L1 is not yet established as a biomarker for PD-L1 inhibitors.Recent reports suggested that host microbiome and tumor and stromal genomic profiles may be related with response to immune checkpoint blockade [9,10] .The diversity and abundance of specific bacterial species in the oral and fecal microbiome enhanced systemic and antitumor immunity [43,44] .For example, in the patients with advanced tumor who received immunotherapy, the use of antibiotics caused poor prognosis.In addition, oral administration of bacteria improved anti-tumor effect [45] .Some immune checkpoints, such as lymphocyte activation gene 3 protein (LAG3) [46] , T-cell immunoglobulin and mucin domain 3 (TIM3) [47] , T-cell immune-receptor with Ig and ITIM domains (TIGIT) [48] are being currently investigated in clinical trials, in order to develop new drugs in the near future.

CONCLUSION
Global standard treatment for metastatic EGJ and gastric adenocarcinoma is the combination of platinumagents and fluoropyrimidine.The availability of targeted agents such as trastuzumab or ramucirumab, have become a new hope to the patients with this aggressive tumor.Immune checkpoint inhibitors have emerged as a novel therapeutic option.Discovering the best combination of these drugs may lead a dramatic improvement of the prognosis of these aggressive tumors.