Japanese Gastric Cancer Patients Research Articles

Predictive role of preoperative geriatric nutritional risk index for clinical outcomes in surgical gastric cancer patients: A meta-analysis.

The association between the preoperative Geriatric Nutritional Risk Index (GNRI) and postoperative short-term and long-term clinical outcomes remains unclear. The aim of this meta-analysis was to identify the predictive role of the preoperative GNRI for postoperative clinical outcomes of gastric cancer patients based on current evidence. Several databases were searched up to July 28, 2022. The primary and secondary outcomes were long-term survival, including overall survival (OS), cancer-specific survival (CSS) and postoperative complications. Meanwhile, the hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs) were combined to assess the association of preoperative GNRI with postoperative survival and complications separately. The results Eight studies involving 4,189 patients were included, and they were all from Japan. The pooled results demonstrated that a lower preoperative GNRI was significantly related to worse OS (HR = 1.72, 95% CI: 1.18-2.53, P = 0.005) and CSS (HR = 1.67, 95% CI: 1.20-2.32, P = 0.002). Meanwhile, a lower preoperative GNRI was significantly associated with postoperative complications (RR = 1.97, 95% CI: 1.51-2.58, P < 0.001). Further analysis focusing on elderly patients showed similar results. Preoperative GNRI is related to postoperative short-term and long-term clinical outcomes of Japanese gastric cancer patients, and a lower GNRI predicts poorer prognosis.

Risk Factors for Postoperative Liver Enzyme Elevation After Laparoscopic Gastrectomy for Gastric Cancer.

Laparoscopic gastrectomy (LG) is more frequently associated with postoperative liver enzyme elevation (PLEE) than open gastrectomy in phase III clinical trials for Japanese gastric cancer patients. The aim of this study was to determine the risk factors for PLEE after LG for gastric cancer. This study enrolled 153 consecutive patients with gastric cancer who underwent LG. The patient characteristics, the liver retraction method [silicone disc (SD) or Nathanson liver retractor (NLR)], and perioperative outcomes were compared between patients with and without PLEE. PLEE was observed in 26 patients (17%). The patients with PLEE exhibited longer operative times (p=0.005) and more frequent use of the NLR for liver retraction (p=0.022). In the multivariate analysis, liver retraction using the NLR (p=0.003) and aberrant left hepatic artery (ALHA) ligation (p=0.042) were independent risk factors of PLEE. Liver retraction with the SD during LG was shown to be the safer method that is less likely to cause postoperative liver dysfunction. ALHA preservation may contribute to avoiding postoperative liver dysfunction.

Development and validation of a pretreatment nomogram to predict overall survival in gastric cancer.

BackgroundPretreatment clinical staging is essential to select therapy. However, there have been no published pretreatment gastric cancer nomograms constructed using pretreatment clinical prognostic factors, including in nonresection patients. We aimed to develop a new pretreatment gastric cancer nomogram for individualized prediction of overall survival (OS).MethodsThe nomogram was developed using data of 5231 Japanese gastric cancer patients, and it was created with a Cox regression model. Fifteen clinical variables, which were obtained at pretreatment, were collected and registered. Data of two independent cohorts of patients from Seoul St. Mary's Hospital (1001 patients), and the University of Verona (389 patients) formed the external validation cohorts. The model was validated internally and externally using measures of discrimination (Harrell's C‐index), calibration, and decision curve analysis.ResultsThe developed nomogram showed good discrimination, with a C‐index of 0.855; that of the American Joint Committee on Cancer (AJCC) clinical stage was 0.819. In the external validation procedure, the C‐indexes were 0.856 (AJCC, 0.795) in the Seoul St. Mary's cohort and 0.714 (AJCC, 0.648) in the University of Verona cohort. The nomogram performed well in the calibration and decision curve analyses when applied to both the internal and external validation cohorts. A stage‐specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram‐prediction when compared to AJCC.ConclusionThis new pretreatment model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and stratification in clinical trials.

Risk factors for cancer-associated thrombosis in advanced cancer patients with chemotherapy or palliative treatment (retrospective study).

819 Background:Cancer-associated thrombosis (CAT) represents the second-leading cause of death in cancer patients and venous thromboembolism (VTE) occurs in about 20% of hospitalized cancer patients. CAT is important for safety cancer treatment.However, the risk factors for CAT in Japanese cancer patients have not been well studied. Methods: We retrospectively examined cases that had received chemotherapy or palliative treatment from April 2017 to February 2018 in our hospital using medical records. Results: Fifty-five cases with 37-94 years (23 males and 32 females) were examined. Primary sites of cancers were as below; pancreatic: n = 14 (25%), colorectal: n = 12 (22%), gastric: n = 7 (13%), breast: n = 4 (7%), lung: n = 3 (5%), esophageal: n = 3 (5%), head and neck: n = 3 (5%), and others: n = 9 (16%).Forty-two patients (76%) were received chemotherapy, and 12 (22%) of them were diagnosed with CAT at the beginning or during the course of chemotherapy (CAT group). The sites of CAT were as follows; lower extremity type venous thrombosis: n = 10, cerebral infarction: n = 3, pulmonary artery thromboembolism: n = 1, portal vein thrombosis: n = 1, subclavian vein thrombosis: n = 1, and others: n = 2. In 12 patients with CAT, primary sites of cancers were as below; pancreatic: n = 6 (45%), gastric cancer: n = 3 (27%), colorectal, esophageal and ovarian cancer: n = 1 (9%), and 8 patients (67%) received anticoagulant therapy, including 7 patients treated with DOACs. 3 patients (38%) discontinued anticoagulant therapy because of gastrointestinal bleeding and 2 patients (25%) had recurrence of VTE during anticoagulant therapy. Overall survival (OS) tended to be shorter in CAT groups than non-CAT group (median OS: 118 days vs 190 days; p = 0.158). Conclusions: As reported in Western countries, the incidence of CAT was about 20%, and higher in Japanese pancreatic and gastric cancer patients. As shorter overall survival in CAT group might be responsible for development of thromboembolism, thromboembolism prophylaxis for high-risk Japanese patients may be recommended. Additionally, the present study showed that recurrence rate of CAT was higher than that of previous clinical trials.

Pertuzumab plus trastuzumab and chemotherapy for Japanese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subgroup analysis of the JACOB trial

BackgroundThe phase III JACOB trial (NCT01774786) compared the efficacy and safety of pertuzumab and trastuzumab plus chemotherapy with placebo and trastuzumab plus chemotherapy in patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric or gastroesophageal junction cancer. We conducted a subgroup analysis in Japanese patients.MethodsPatients were randomized 1:1 to pertuzumab 840 mg or placebo, plus trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) and chemotherapy (cisplatin 80 mg/m2, and capecitabine 1000 mg/m2 twice daily for 28 doses or 5-fluorouracil 800 mg/m2 every 24 h for 120 h), every 3 weeks. Continuation of chemotherapy after 6 cycles was at the discretion of the patient and the treating physician.ResultsA total of 40 Japanese patients were included in each arm. Median overall survival was 22.0 months (95% confidence interval [CI] 13.8–not evaluable) and 15.6 months (95% CI 9.7–19.2) in the pertuzumab and placebo arms, respectively (hazard ratio [HR] 0.64 [95% CI 0.37–1.10]). Median progression-free survival was 12.4 months (95% CI 6.1–14.1) in the pertuzumab arm and 6.3 months (95% CI 4.3–8.1) in the placebo arm (HR 0.50 [95% CI 0.30–0.82]). Grade ≥ 3 adverse events and serious adverse events were more frequent in the pertuzumab arm than the placebo arm.ConclusionsResults from this subgroup analysis of the JACOB trial suggest similar efficacy of pertuzumab in Japanese patients and patients in the overall population, encouraging continued investigation of new agents for gastric cancer in Japanese patients.

Modified neutrophil-platelet score as a promising marker for stratified surgical and oncological outcomes of patients with gastric cancer.

Gastric cancer (GC) is a common malignancy, especially in East Asian countries. There is emerging evidence that circulating neutrophil and platelet levels correlate with cancer progression. We evaluated the short- and long-term outcomes of GC patients systemically, to compare the original neutrophil-platelet score (NPS) and our modified NPS (mNPS). We analyzed the original pre-operative NPS and the mNPS of 621 GC patients. Racial differences between the United Kingdom and East Asian countries accounted for compelling deviation in classification using the original NPS, which could not reliably stratify the prognoses of Japanese GC patients. We developed the mNPS using appropriate cutoff levels for pre-operative neutrophils and platelets, and demonstrated that the pre-operative mNPS was significantly correlated with all of the well-established clinicopathological factors for disease development, including advanced T stage, venous and lymphatic vessel invasion, lymph node/peritoneal /distant metastasis, and tumor-node-metastasis stage. The pre-operative mNPS could stratify prognostication for both overall survival (OS) and disease-free survival (DFS): a high pre-operative mNPS was an independent prognostic factor for the OS and DFS of GC patients and also an independent predictor of post-operative surgical site infection after gastrectomy. Calculating the mNPS could help clinicians to stratify the surgical and oncological risks of patients with GC.

Incidence of cancer-associated thromboembolism in Japanese gastric and colorectal cancer patients receiving chemotherapy: a single-institutional retrospective cohort analysis (Sapporo CAT study)

ObjectiveFew data regarding the incidence of cancer-associated thromboembolism (TE) are available for Asian populations. We investigated the incidence of TE (TEi) and its risk factors among gastric and colorectal cancer...

The validity and safety of 1st-line chemotherapy with capecitabine/oxaliplatin for advanced gastric cancer in Japanese patients over 70 years old

The validity and safety of 1st-line chemotherapy with capecitabine/oxaliplatin for advanced gastric cancer in Japanese patients over 70 years old

Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer.

Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs.Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy.Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance.Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.

Tumor Stage of the Gastric Cancers in the Generation Younger Than 50 Years was More Advanced Compared to the Older Generations in Japan

Introduction: Whereas the populations younger than 40 years old do not ordinarily receive gastric cancer (GC) screening in Japan, there are several cases to suffer GC in the young generation. The present study reviewed retrospectively the chart of all the GC patients in our hospital during the recent 5 years to characterize the GC patients in the generation younger than 50 years old. Methods: All the 345 consecutive GC patients in our hospital from 2010 to 2014 were divided into the 3 age groups: ≤ 50 years old, 51 - 60 years old, and > 60 years old. The patient - and tumor - characteristics including onset age, sex, tumor tissue differentiation, and staging were compared among the groups. Results: The average age of GC onset for the entire cohort was 72.3 years old, and the age was significantly younger in men compared to women (71.4 vs 74.7 years old; P < 0.03). The onset age in the poorlydifferentiated + signet-ring cell GC cases was younger compared to the moderately-differentiated cases (69.6 vs 74.5 years; P = 0.03) and well-differentiated cases (69.6 vs 73.4 years; P < 0.01). The ≤ 50-year-old group was only 4.6% (16/345) of the cohort, and 75% (12/16) of them had poorly-differentiated or signetring cell GC, and the stage of the group was high including more than stage II (75%), and 37.5% (6/16) of stage IV (average stage: 2.5). The percentage of the poorly-differentiated GC + signet-ring cell GC was less in the 51 - 60 years old group (36.4%) and the > 60 years group (30.5%). The tumor staging was less advanced in these groups compared to the groups 50 years old (average stage: 1.8 and 2.0 vs 2.5). The Helicobacter pylori infection rate in the cohort was more than 95% in the present cohort, and 15 out of 16 in the 50 years old group was positive in Helicobacter pylori. Conclusion: GC in the generation younger than 50 years old was relatively uncommon in the present observation, and the staging of the tumor was more advanced compared to the older generations. The advanced stage in the young generation might be due to the GC screening system in Japan, which is focused on the old generation. The eradication therapy of Helicobacter pylori might rescue the onset of GC in Japan, which lead to improve the prognosis in the Japanese GC patients in the near further.

In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients

BackgroundFibroblast growth factor receptor (FGFR2) has been proposed as a target in gastric cancer. However, appropriate methods to select patients for anti-FGFR2 therapies have not yet been established.MethodsWe used in situ techniques to investigate FGFR2 mRNA expression and gene amplification in a large cohort of 1036 Japanese gastric cancer patients. FGFR2 mRNA expression was determined by RNAscope. FGFR2 gene amplification was determined by dual-color in situ hybridization (DISH).ResultsWe successfully analyzed 578 and 718 samples by DISH and RNAscope, respectively; 2% (12/578) showed strong FGFR2 gene amplification (FGFR2:CEN10 >10); moderate FGFR2 gene amplification (FGFR2:CEN10 <10; ≥2) was detected in 8% (47/578); and high FGFR2 mRNA expression of score 4 (>10 dots/cell and >10% of positive cells with dot clusters under a 20× objective) was seen in 4% (29/718). For 468 samples, both mRNA and DISH data were available. FGFR2 mRNA expression levels were associated with gene amplification; FGFR2 mRNA levels were highest in the highly amplified samples (n = 12). All highly amplified samples showed very strong FGFR2 mRNA expression (dense clusters of the signal visible under a 1× objective). Patients with very strong FGFR2 mRNA expression showed more homogeneous FGFR2 mRNA expression compared to patients with lower FGFGR2 mRNA expression. Gastric cancer patients with tumors that had an FGFR2 mRNA expression score of 4 had shorter RFS compared with score 0–3 patients.ConclusionRNAscope and DISH are suitable methods to evaluate FGFR2 status in gastric cancer. Formalin-fixed paraffin-embedded (FFPE) tissue slides allowed evaluation of the intratumor heterogeneity of these FGFR2 biomarkers.

High Prevalence of Claudin 18.2 Expression in Japanese Patients with Gastric Cancer.

e15584 Background: Expression of the gastric mucosal tight junction protein, Claudin-18.2 (CLDN18.2), is altered in gastric cancer (GC). In a phase 2 clinical trial (NCT01630083; FAST), a monoclonal antibody against CLDN18.2 (IMAB362) significantly increased overall survival in European patients with CLDN18.2-positive (CLDN18.2+) gastric and gastroesophageal junction adenocarcinomas when added to an EOX chemotherapy regimen. As the GC occurrence is high in Japan, this study evaluated the prevalence of CLDN18.2 expression in Japanese patients with GC. Methods: CLDN18.2 expression was assessed in primary GC tumors and corresponding lymph node metastases (LNM) by cell membrane staining intensity using a validated, semi-quantitative, immunohistochemical assay for CLDN18.2 expression. Samples showing any positivity for specific staining with at least 1+ intensity were defined as CLDN18.2+. Correlation between percentage of CLDN18.2+cells in primary tumors and corresponding LNM was determined with Spearman’s rank correlation. Results: A total of 263 samples, including tissues from 134 primary GC tumor/LNM matched pairs, 128 primary GC tumors only, and 1 LNM only were collected at Kurume University Medical Center, Japan, between 2000 and 2012. Overall, CLDN18.2 was detected in 87% (n = 228/262) of all primary tumors and 80% (n = 108/135) of LNM. Strong CLDN18.2 expression (≥2+ membrane staining intensity in ≥40% of tumor cells; eligibility criterion in FAST) was observed in 52% (n = 135/262) of primary tumors and 45% (n = 61/135) of LNM. Individual tumor samples consisted of a mixture of tumor cells expressing CLDN18.2 at different staining intensities; samples with a high fraction of CLDN18.2 reactivity had a large proportion of tumor cells staining with 3+ intensity (Spearman r = .8413, P&lt; .0001). In matched pairs, 72% of samples were CLDN18.2+ (n = 96/134) and 9% were CLDN18.2– (n = 12/134). The fraction of CLDN18.2+ tumor cells at any staining intensity strongly correlated in matched paired samples (Spearman r = .6942; P&lt; .0001). Conclusions: CLDN18.2 expression is highly prevalent in Japanese GC patients, making it a targetable alteration and supporting development of IMAB362 as a therapeutic agent for this patient population.

Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.

A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.

Mo1693 - Screening for H. Pylori Infection by Using Barium Radiography is Useful for the Detection of Gastric Cancer in Japanese Patients

Mo1693 - Screening for H. Pylori Infection by Using Barium Radiography is Useful for the Detection of Gastric Cancer in Japanese Patients

Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study.

AIMTo evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.METHODSWe performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks.RESULTSThree patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.CONCLUSIONmDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.

ISY-9-6 - Current status and future perspective of perioperative chemotherapy for localized gastric cancer

Establishment of perioperative chemotherapy is imperative to improve the surgical outcome of localized gastric cancer. There are the large disparities between Japan/Korea and Western countries in perioperative treatment of localized gastric cancer. The main reason for this difference is due to different prognosis of the patients. The better prognosis is considered due to early diagnosis based on the national screening program. Because of the status, development of adjuvant treatment after curative resection was the focus in Japan. In perioperative strategies, 5 years survival of western population is 20-40%, and that of Japan and Korea is around 70%. The standard treatment is also different. In Japan and Korea, D2 resection followed by adjuvant chemotherapy is the standard. At the same time postoperative chemo-radiotherapy is standard in US, and perioperative chemotherapy is standard in EU. In Japan, our standard strategy is D2 resection followed by oral S-1 for 1 year. Capecitabine plus oxaliplatin (cape-Ox) showed 6 months survival after D2 resection in the CLASSIC trial in Korea, Taiwan, and China. A phase 2 study in Japan on the same regimen is also available. Use of cape-Ox in the practice is under discussion based on the data. On the other hand, high intensity of post-operative chemotherapy is considered not feasible based results from perioperative chemotherapy trials in western countries. Considering the current status, we will discuss the future strategies of perioperative treatment of Japanese gastric cancer patients.

Abstract 1843: Identification of peritoneal dissemination-related genes in gastric cancer

Abstract INTRODUCTION: Peritoneal dissemination (PD) is highly frequent and incurable metastasis in gastric cancer (GC). The mechanism causing PD is still poorly understood. In this study, we aimed to identify the genes responsible for PD using several large-scale public microarray databases. MATERIALS AND METHODS: First, we identified the candidate genes, which satisfied the all-4 outlines using microarray data as follow: 1) overexpressed in GC cell lines with high potential of PD; 2) overexpressed in GC patients with PD in Singapore from Duke-NUS Graduate Medical School; 3) overexpressed in tumor tissues in GC from TCGA database; 4) poor prognostic factor in GC from TCGA database. Next, we measured the expression of candidate genes by Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and performed clinicopathological studies of the expression in 146 Japanese GC patients who underwent surgery in our hospital. Finally, we performed gene set enrichment analysis (GSEA) with TCGA database to elucidate the correlation between candidate genes and gene sets that are associated with tumorigenesis or tumor progression in GC. Then, we examined the correlation between the candidate genes and one of the gene sets that were identified through GSEA by qRT-PCR in 5 GC cell lines (MKN7, KATO3, AGS, HSC39, 39As). RESULTS: 1. We identified Arl4c (ADP-ribosylation factor-like 4c) as a PD candidate gene by above our screening system. 2. The expression of Arl4c was significantly higher in tumor tissues than in corresponding normal tissues in Japanese GC patients (p&amp;lt;0.0002). In clinicopathological analysis, the high expression group of Arl4c was significantly associated with depth of invasion (p&amp;lt;0.01) and PD (p&amp;lt;0.05). Multivariate analysis indicated that high expression of Arl4c was an independent prognostic factor (hazard ratio 2.20; 95% CI 1.06-4.97; p&amp;lt; 0.03) among all clinicalpathological factors in GC. 3. GSEA revealed that the expression of Arl4c positively correlated with epithelial-mesenchymal transformation (EMT) gene set. In the 5 GC cell lines, the expression of Arl4c negatively correlated with the expression of cdh1, which was well known as a down-regulated gene in EMT. CONCLUSION: Arl4c is a member of the ADP-ribosylation factor family of GTP-binding proteins and plays a role in cholesterol transport. Recent study revealed that Arl4c regulates YAP/TAZ pathway that is well known to induce EMT and promotes tumorigenesis in lung or colorectal cancer. Our results suggest that Arl4c should be involved in PD via EMT induced by the YAP/TAZ pathway, resulting in a poor prognostic marker in GC. Arl4c may be a novel biomarker and a therapeutic target for PD in GC. Citation Format: Qingjiang Hu, Shiya Kidogami, Sho Nambara, Hisateru Komatsu, Kuniaki Sato, Yushi Ogawa, Tomoko Saito, Shotaro Sakimura, Hidenari Hirata, Ryutaro Uchi, Naoki Hayashi, Tomohiro Iguchi, Takaaki Masda, Shuhei Ito, Hidetoshi Eguchi, Yoshihiko Maehara, Koshi Mimori. Identification of peritoneal dissemination-related genes in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1843.

Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study

BackgroundAdjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer.MethodsPatients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1–14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate.ResultsOne hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9–72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4–78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77–91 %). No new safety signals were identified.ConclusionsThe feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

Gene expression profiling of Japanese gastric cancer patinets using Asian Cancer Research Group classification.

72 Background: Gastric cancer is well known as having heterogeneous features. Recently, the Asian Cancer Research Group (AGRG) had proposed a new classification scheme based on the gene expression profile of the tumor. However, the genomi/expression profiling of gastric cancer in Japanese patients is still unknown. We started a comprehensive molecular profiling study that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from 2014. We already had evaluated more than 1,500 samples from various type of cancer. Among them, 104 gastric cancer patients were analyzed. Methods: Fresh surgically resected tumor/normal samples and peripheral blood were obtained and whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies) were performed. Patients were grouped based on the gene expression profile according to AGRG classification, and clinicopathological features were compared among the group. Results: Patients were classified into MSI in 14, MSS/EMT in 15, MSS/TP53+ in 38 and MSS/TP53- in 37, respectively. There was no significant difference of sex among the group. Age was significantly younger in MSS/EMT and MSS/TP53-. In MSI, tumor tended to be located at antrum, and differentiated type tumor was predominant. In MSS/EMT, advanced T stage (T4) and undifferentiated type of tumor was predominant. In MSS/TP53+, relatively less advanced stage and localized macroscopic type tumor was predominant. In MSS/TP53-, relatively advanced stage and invasive macroscopic type tumor was predominant. Although the follow-up period is insufficient, relapse-free survival was the worst in MSS/EMT and no patient recurred in MSI. Conclusions: Classification of gene expression profiling based on ACRG was possible in Japanese gastric cancer. Distribution and tumor characteristics were almost identical to ACRG cohort. Gene -expression profiling may be comprehensively used for tumor classification and further clinical trials of molecular targeting agents.

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.

BackgroundVariability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.MethodsWe previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.ResultsWe identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10−8 by Fisher’s exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.ConclusionsThese results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1721-z) contains supplementary material, which is available to authorized users.