Search

Background: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma., Patients and Methods: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+)., Results: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843)., Conclusions: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required., Competing Interests: Disclosure DT has received fees from Taiho Pharmaceutical Co., Ltd, Eli Lilly Japan K.K, and Bristol-Myers Squibb Japan. ES has received Honoria from Taiho Pharmaceutical Co., Ltd, Sanofi, Eli Lilly Japan K.K, Takeda Pharmaceutical Co., Ltd, Merck Serono Co., Ltd, Chugai Pharmaceutical Co., Ltd, Daiichi-Sankyo Co., Ltd, and Ono Pharmaceutical Co., Ltd. KY has received lecture fee from Chugai Pharmaceutical Co., Ltd, Merck Biopharma, Bristol-Myers Squibb Japan, Takeda Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Eli Lilly Japan K.K, Ono Pharmaceutical Co., Ltd, Sanofi, and Daiichi-Sankyo Co., Ltd. The Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research has received research funding from Ono Pharmaceutical Co., Ltd, Sanofi, Taiho Pharmaceutical Co., Ltd, Eli Lilly Japan K.K, and Yakult Honsha Co., Ltd. All other authors have declared no conflicts of interest. Data Sharing The data underlying this article will be shared on reasonable request to the corresponding author., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Prognostic factors for the survival of patients with advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy remain controversial. The aim of this study was to identify the clinical factors that predict prognosis in patients with advanced HER2-positive gastric cancer., Methods: We retrospectively reviewed the medical records of HER2-positive gastric cancer patients treated with trastuzumab-based chemotherapy at our institution. Clinical features and laboratory test results that considered prognostic factors were re-examined. Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test and multivariate analysis was performed using Cox's proportional hazard regression model., Results: A total of 133 patients with advanced HER2-positive gastric cancer were enrolled. The median OS in this cohort was 18.7 months. Four prognostic factors: visceral metastasis (lung or liver), levels of hemoglobin (Hb) (< 11.6 g/dl), lactate dehydrogenase (LDH) (> 222 mg/dl), and C-reactive protein (CRP) (> 0.14 mg/dl), were identified as independent prognostic factors. The patients were placed into three groups according to their number of prognostic factors. These included low (0, 1), moderate (2, 3), and high (4) risk factors. The OS was separated into three categories with a median OS of 32.0, 18.7, and 10.1 months, respectively. Compared to the low-risk group, hazard ratios for the moderate- and high-risk groups were 1.75 and 3.49, respectively., Conclusion: Visceral metastasis and abnormal Hb, LDH, and CRP levels were associated with unfavorable OS. These findings may be beneficial for the management of advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Although RAS and PIK3CA mutations have been associated with resistance to anti-EGFR antibody in colorectal cancer or trastuzumab in breast cancer, their implications for trastuzumab resistance in HER2-positive advanced gastric cancer (AGC) remains unclear. We aimed to assess the relationship between trastuzumab efficacy and mutation status in the HER family signaling pathway., Methods: This study retrospectively evaluated patients with HER2-positive AGC who received first-line trastuzumab-containing chemotherapy between March 2011 and November 2015. Multiplex genotyping, including KRAS, NRAS, PIK3CA, and BRAF, was then performed using the Luminex Assay, after which KRAS amplification was measured using quantitative real-time reverse transcription-polymerase chain reaction. Thereafter, the association between genetic alterations and clinical outcomes were evaluated., Results: KRAS mutation (MT) was detected in 6 of 77 patients (7.8%), whereas KRAS amplification was found in 15 of 67 patients (22%). No mutations in NRAS, PIK3CA, or BRAF were identified. The KRAS MT group showed significantly worse response rates (16.7% vs. 66.2%, P = 0.016), progression-free survival [median, 4.8 vs. 11.6 months; hazard ratio (HR), 3.95; 95% CI, 1.60-9.76; P = 0.0029], and overall survival (11.5 vs. 23.6 months; HR, 3.80; 95% CI, 1.56-9.28; P = 0.033) compared to the KRAS wild-type group. KRAS amplification had no effect on clinical outcomes., Conclusion: KRAS mutation was an independent prognostic factor for poor survival and might predict insufficient trastuzumab efficacy, whereas KRAS amplification showed no prognostic significance during trastuzumab treatment. Further investigations are warranted to confirm the predictive value of KRAS status in HER2-positive AGC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear., Methods: We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis., Results: Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9-7.1) in AFPGC and 4.0 months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4-20.8) in AFPGC and 9.2 months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS., Conclusion: Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice., Patients and Methods: We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups., Results: In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal., Conclusions: The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer., Experimental Design: We assessed genomic characteristics of FGFR2 -amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2 -amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors., Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%-4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number., Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2 -amplified advanced gastric cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice., Methods: We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model., Results: A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74)., Conclusions: The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Different approaches are used to treat resectable tumours in patients having adenocarcinoma at the oesophagogastrointestinal junction (EGJ) or in the stomach. However, there is limited information about treatment efficacy for patients at metastatic stage. A recent molecular analysis of upper gastrointestinal tract adenocarcinoma revealed that the anatomical location can influence the molecular backgrounds of tumours. This study sought to elucidate whether different therapeutic approaches should be used for EGJ tumours relative to those in the stomach., Methods: This retrospective cohort study was conducted at a single institute in Japan. Patients having metastatic or recurrent adenocarcinoma in the EGJ or stomach who underwent platinum doublet chemotherapy between January 2007 and August 2014 were enrolled. Patients in the EGJ tumour group had tumours having an epicentre within 2 cm proximal or 5 cm distal to the estimated anatomical EGJ and cardia., Results: Among 378 consecutively enrolled patients, 61 were grouped into the EGJ group and the remainder comprised the stomach group. The EGJ group had more men and lower incidence of diffuse type and Borrmann type IV tumours and peritoneum metastasis compared with the stomach group. The median overall survival of patients in the EGJ and stomach groups was similar (17.3 months (95% CI 13.5 to 23.2) vs 14.5 months (95% CI 13.3 to 16.4)). No statistically significant difference was observed in progression-free survival. Although the overall postprogression survival differed significantly between the EGJ and stomach groups (8.2 months (95% CI 5.7 to 12.7) vs 7.1 months (95% CI 6.1 to 7.8)), on grouping patients by histological type, the two groups exhibited similar postprogression survival. Multivariate analysis demonstrated that diffuse-type histology, higher serum CA19-9 levels and neutrophil to lymphocyte ratios were independent poor prognostic factors., Conclusions: Different clinicopathological features of EGJ adenocarcinoma were not associated with clinical outcomes of platinum doublet chemotherapy. Histological subtype rather than anatomical location has more significance for treatment decisions for advanced gastric cancers., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose: In the ATTRACTION-2 trial, nivolumab significantly improved the survival of advanced gastric cancer patients. The pretreatment neutrophil-to-lymphocyte ratio (NLR) is prognostic in patients receiving immune checkpoint inhibitors (ICIs) to treat various cancers. However, a few reports have explored the relationships between NLR changes during ICI treatment and patient survival. Here, we evaluated factors (including NLR changes in patients on nivolumab monotherapy) prognostic for gastric cancer patients., Methods: We retrospectively analyzed 98 gastric cancer patients who received nivolumab (3 mg/kg or 240 mg/body bi-weekly) at our institution between December 2014 and September 2018. We evaluated pretreatment data, and those obtained 30 and 60 days after treatment commenced. We explored the prognostic utility of relative NLR changes in terms of the overall survival (OS) of patients on nivolumab monotherapy., Results: Over a median of 4.9 months of follow-up, 98 gastric cancer patients received a median of four treatment courses. The overall response and disease-control rates were 25% and 52%, respectively. The median OS was 6.4 months (95% confidence interval [CI] 4.6-9.1). On multivariate analysis, factors poorly prognostic in terms of OS were an ECOG performance status of 0-1, a pretreatment NLR > 3, and an NLR difference ≧ 2 over the 60 days before and after nivolumab administration (∆NLR 60 ). Patients with ∆NLR 60 values < 2 survived significantly longer than did those with ∆NLR 60 values ≧ 2 (median OS 9.2 months [95% CI 6.4-11.6] vs. 4.0 months [2.1-4.9]; P = 0.0002)., Conclusions: Nivolumab monotherapy was efficacious in gastric cancer patients. NLR changes during such therapy may be predictive of outcomes.

Background: We recently reported the clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using surgical specimens; patients with homogeneously HER2 positive gastric cancer benefitted more from trastuzumab. However, the majority of patients are diagnosed by endoscopic biopsy, and surgical specimens are not available in these patients. The aim of this study is to verify clinical significance of HER2 heterogeneity on trastuzumab efficacy using biopsy specimens., Methods: Eighty-seven patients, who received trastuzumab-based chemotherapy and whose endoscopic biopsy specimens were available for HER2 assessment, were consecutively enrolled. When all tumor cells in all biopsy specimens overexpressed HER2 protein, it was defined as homogeneously HER2 (homo-HER2) positive group, and the others were defined as heterogeneously HER2 (hetero-HER2) positive group. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were evaluated., Results: Thirty-four patients (39%) were diagnosed as the homo-HER2 group and 53 patients (61%) were the hetero-HER2 group. After the median follow-up period of 17.8 months, the median PFS and OS were 7.6 and 17.8 months, respectively. Significant survival differences were shown between the two groups; the homo-HER2 group showed significantly longer PFS (10.8 vs. 6.1 months, HR 0.469 95% CI 0.29-0.77, p = 0.003) and OS (29.3 vs. 14.4 months, HR 0.352 95% CI 0.20-0.61, p < 0.001). ORR was 68.6% in this cohort. Higher response rate (85.2% vs 58.1%, p = 0.020) and deeper response (- 49.0% vs - 40.0%, p = 0.018) were also found in the homo-HER2 group., Conclusions: Similar to surgical specimens, we verified clinical significance of HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens.

Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease, and diffuse-type histology. Comprehensive molecular analyses of gastric cancers have led to molecular-based classifications and to specific and effective treatment options. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here, we studied 146 gastric cancer patients diagnosed at the age of 40 years or younger at the Cancer Institute Hospital (Tokyo, Japan). Tumor specimens were examined for Helicobacter pylori infection, Epstein-Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications, and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and FISH. Although only a small number of cases were positive for Epstein-Barr virus and microsatellite instability (n = 2 each), we repeatedly found tumors with gene fusion between a tight-junction protein claudin, CLDN18, and a regulator of small G proteins, ARHGAP, in as many as 22 cases (15.1%), and RNA sequencing identified 2 novel types of the fusion. Notably, patients with the CLDN18-ARHGAP fusion revealed associations between aggressive disease and poor prognosis, even when grouped by their clinical stage. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age-onset gastric cancers, and its presence could contribute to their aggressive characteristics., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: There is growing interest in the clinical significance of intratumoral HER2 heterogeneity. Its prognostic and predictive impacts on trastuzumab efficacy were demonstrated in breast cancer. However, its clinical significance in gastric cancer is still unclear., Methods: Twenty-eight HER2-positive gastric cancer patients who had gastrectomy prior to trastuzumab-based chemotherapy were consecutively enrolled. Intratumoral HER heterogeneity was evaluated using whole-tissue sections by immunohistochemistry. When all tumor cells overexpressed HER2 protein, the tumor was defined as homogeneously HER2 (Homo-HER2)-positive group. The others were defined as heterogeneously HER2 (Hetero-HER2)-positive group., Results: There was no significant difference in clinicopathological features between the two groups. The median progression-free survival (PFS) and overall survival (OS) in the Homo-HER2-positive group were significantly longer than those in the Hetero-HER2-positive group (PFS; 20.0 months [95% CI 17.8-22.2] vs. 6.0 months [95% CI 2.3-9.7]; HR 0.11; 95% CI 0.03-0.41; p < 0.001, OS; not reached vs. 14.0 months [95% CI 11.9-16.1]; HR 0.18; 95% CI 0.06-0.61; p = 0.003). In the multivariate analysis, these associations remained significant both in PFS (HR 0.12; 95% CI 0.03-0.46, p = 0.002) and OS (HR 0.21; 95% CI 0.06-0.72, p = 0.013). With respect to response rate, no statistical difference was found between two groups. However, deeper tumor shrinkage was obtained in the Homo-HER2-positive group compared with the Hetero-HER2-positive group (p = 0.046)., Conclusions: Intratumoral HER2 heterogeneity may have robust clinical impact on trastuzumab efficacy in patients with HER2-positive gastric cancer. These findings should be validated by larger independent cohorts and further molecular correlative analyses are warranted.

Background: Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy., Methods: We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR., Results: Eligible patients were sorted into HER2 + (n = 100) and HER2 - (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2 + group and 53.2 and 86.0% in the HER2 - group. Respective median PFS and OS were HER2 + : 7.9 and 20.8 months and HER2 - : 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2 + : 70 and 44% and HER2 - : 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2 + group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2 + group and for PFS in both groups., Conclusion: These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2 + advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

Background: The REGARD trial demonstrated that ramucirumab monotherapy improved both overall survival (OS) and progression-free survival (PFS) compared with best supportive care plus placebo as second-line treatment for patients with advanced gastric cancer. However, the efficacy and safety of ramucirumab monotherapy for previously treated Japanese patients with advanced gastric cancer remains unknown., Methods: Previously treated Japanese patients with advanced gastric cancer who received ramucirumab monotherapy between June 2015 and March 2016 at the Cancer Institute Hospital were enrolled in the study. OS, PFS, best overall response, and safety profiles were retrospectively evaluated., Results: Nineteen patients were enrolled in this study. Ramucirumab monotherapy was generally administered as third-line therapy. After a median follow-up period of 7.4 months, the median PFS was 2.1 months (95% CI 1.0-3.5), and median OS was 12.9 months (95% CI 2.3, not reached). In 13 patients who had measurable lesions on radiologic examination, partial response was observed in one patient (7.7%) and stable disease was observed in five patients (38.5%). A total of 12 patients (63.2%) had adverse events (AEs). Common AEs included hypertension (8 patients, 42.1%), fatigue (6 patients, 31.6%), and bleeding (5 patients, 26.3%). Grade 3 AEs included gastrointestinal bleeding and aspiration pneumonia (1 patient each, 5.3%)., Conclusions: Our data suggest that ramucirumab monotherapy in Japanese patients with previously treated advanced gastric cancer has comparable efficacy and safety profiles as reported in the REGARD trial.

Background: Peritoneal cytology positive for carcinoma cells (CY+) is an independent poor prognostic factor in gastric cancer, and patients with CY+ are diagnosed with stage IV disease. However, there is no standard treatment strategy for CY+ gastric cancer, whereas combination chemotherapy with fluoropyrimidine and platinum has been established as the standard treatment for unresectable advanced gastric cancer or after R2 resection. Herein, we assessed whether adding cisplatin to S-1 (SP) could improve the outcome of CY+ gastric cancer patients, as compared to S-1 monotherapy., Methods: This retrospective study was conducted at a single Japanese institute between June 2005 and March 2014. Patients diagnosed with CY+ advanced gastric cancer and treated with S-1-based therapy were enrolled. Patients with incurable factors other than CY+ were excluded., Results: Forty-four patients were enrolled; 25 and 19 were administered S-1 and SP, respectively. The 2-year survival rates were 52.0% [95% confidence interval (CI), 31.2-69.2%] and 52.6% (28.7-71.9%) in the S-1 and SP groups, respectively. The median overall survival (OS) and progression-free survival (PFS) were 28.2 and 15.6 months in the S-1 group and 24.0 and 18.8 months in the SP group, respectively; they were not significantly different. The relative dose intensities were 0.79 (S-1) in the S-1 group and 0.69 (S-1)/0.70 (cisplatin) in the SP group., Conclusion: Adding cisplatin to long-term S-1 monotherapy did not significantly improve the outcome of CY+ advanced gastric cancer patients.

Background: Diagnostic endoscopy occasionally shows synchronous early gastric cancer (EGC) and esophageal cancer (EC) in the same patient. The treatment plan for these comorbid cancers is unclear because, as EGC is commonly treated surgically, information on post-chemotherapy outcomes for EGC are lacking, although chemotherapy and chemoradiotherapy are important in treating EC. Here, we evaluated whether unresected EGC could be safely observed while synchronous EC is treated with chemotherapy in patients with both cancers., Methods: We enrolled 30 patients with both EGC and EC who were treated with 5-FU plus cisplatin (FP) from January 2006 to September 2013, and who were evaluated with endoscopy before chemotherapy, and approximately every 3 months afterwards., Results: The response rate to FP for EGC was 46.8 %. Notably, five cases (16.7 %) had clinically complete responses with no progressive disease. Progression-free survival was 100 % at 6 months and 96.2 % at 1 year. In univariate analysis, FP was significantly more effective for mixed-type and undifferentiated adenocarcinoma than for differentiated adenocarcinoma., Conclusions: FP was effective for EGC. EGC was stable without progression for more than 6 months while patients underwent FP treatment for EC. We consider observing EGC with no treatment during chemotherapy for EC to be appropriate disease management.

Background: This study was conducted to investigate whether human epidermal growth factor receptor 2 (HER2) status, epidermal growth factor receptor (EGFR) status, and c-MET status are independent prognostic factors for advanced gastric cancer patients who received standard chemotherapy., Method: Unresectable or recurrent gastric or gastroesophageal junction cancer patients with histologically confirmed adenocarcinoma treated with S-1 plus cisplatin as first-line chemotherapy were eligible. Formalin-fixed paraffin-embedded tumor samples were examined for HER2, EGFR, and c-MET status using immunohistochemistry (IHC). Additionally, gene amplification was examined using fluorescent in situ hybridization (FISH) for HER2. Positivity was defined as an IHC score of 3+ or an IHC score of 2+/FISH positive for HER2, and an IHC score of 2+ or 3+ for both EGFR and c-MET., Results: Of the 293 patients from nine institutions, 43 (15%) were HER2 positive, 79 (27%) were EGFR positive, and 120 (41%) were c-MET positive. Ten patients (3%) showed positive co-expression of HER2, EGFR, and c-MET. After a median follow-up time of 58.4 months with 280 deaths, there was no significant difference in overall survival (OS) in terms of HER2 and EGFR status. However, there was a significant difference in OS between c-MET-positive and c-MET-negative patients [median, 11.9 months vs 14.2 months; hazard ratio, 1.31 (95% confidence interval, 1.03-1.67); log-rank P = 0.024]. Multivariate analysis also showed that c-MET positivity was still a prognostic factor for OS [hazard ratio, 1.30 (95% confidence interval, 1.02-1.67); P = 0.037]., Conclusions: The study suggested that c-MET-positive status had poor prognostic value. These data could be used as the basis for future clinical trials for targeting agents for advanced gastric cancer patients.

Unlabelled: The incidence of gastrointestinal bleeding, thromboembolic events and gastrointestinal perforation during chemotherapy with metastatic or unresectable gastric cancer has been unknown. To clarify the incidence of these events, we reviewed the clinical records of our hospital., Patients and Methods: We investigated metastatic or unresectable gastric cancer patients who received chemotherapy during January 2002 to December 2006. Grade≥3 (CTCAE v3.0) adverse events from the first day of chemotherapy to 1 month after the last day of chemotherapy were investigated., Results: A total of 292 patients received chemotherapy. Patient characteristics were as follows: median age 63.5 years (range, 28 to 87); performance status 0/1/2/3: 129/129/31/3; male: female, 206:86, histopathological type intestinal/diffuse/unclassified-adenocarcinoma/others: 91/139/58/4. We found the incidence of Grade≥3 gastrointestinal bleeding in 7 patients (2.4%), thromboembolic events in 5 patients (1.7%) and gastrointestinal perforation in 3 patients (1.0%). Thromboembolic events in patients under 55 years of age were associated with a higher incidence (p=0. 0046)., Conclusion: The incidence was not so high as expected. We should be aware of the frequency of these toxicities in the treatment of gastric cancer.

The purpose of this study was to quantify circulating tumor cells (CTCs) in advanced gastric cancer (AGC) patients, and to demonstrate the role of CTCs in cancer therapy. This study investigates the hypothesis that CTCs can predict clinical outcomes in patients with AGC. From November 2007 to June 2009, 52 patients with AGC were enrolled into a prospective study. The chemotherapy regimen was an S-1-based regimen (S-1 with or without cisplatin) or paclitaxel. CTCs of whole blood at baseline, 2 weeks, and 4 weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics. Patients with > or =4 CTCs at 2-week points and 4-week points had a shorter median progression-free survival (PFS) (1.4, 1.4 months, respectively) than those with the median PFS of <4 CTCs (4.9, 5.0 months, respectively) (log-rank test; P < 0.001, P < 0.001, respectively). Patients with > or =4 CTCs at 2-week points and 4-week points had shorter median overall survival (OS) (3.5, 4.0 months, respectively) than those with the median PFS of <4 CTCs (11.7, 11.4 months, respectively) (log-rank test; P < 0.001, P = 0.001, respectively). In conclusion, this study demonstrates that CTC measurement may be useful as a surrogate marker for determining response to S-1-based or paclitaxel regimens in AGC.

Because of the complex nature of the diverse histologic grade in gastric carcinomas a useful biomarker should be provided to scale the aggressiveness of the disease and to determine surgical strategy, especially for advanced carcinomas. Our previous study of MUC1 in gallbladder carcinoma using mAb MY.1E12 has revealed the stromal localization of MUC1 adjacent to the carcinoma was correlated with poor prognosis. In gastric carcinoma the biological significance of the localization of MUC1 recognized by mAb MY.1E12 has not been fully investigated. We performed immunohistochemical analysis to determine the correlations with the localization of mAb MY.1E12-reactive-MUC1 (MY.1E12-MUC1) and clinicopathological findings. A total of 91 consecutive patients with stage II, IIIA or IIIB gastric carcinoma after curative resection were reviewed retrospectively. The localization of MY.1E12-MUC1 was classified as negative, apical, cytoplasmic or stromal type based on the predominant subcellular localization. Immunostaining of MY.1E12-MUC1 was recognized in 84% of the 55 cases of differentiated-type carcinoma and in 53% of the 36 cases of undifferentiated-type carcinoma (P<0.01). In differentiated-type carcinoma, the proportion of stromal-type dominant localization of MY.1E12-MUC1 was increased at the deepest invading sites. Postsurgical liver metastasis was seen in 11 (30%) of 37 cases showing stromal or cytoplasmic-type localization-dominant group and in 1 (6%) of 18 cases showing apical-type localization-dominant group or negative staining group (P<0.05). The postsurgical survival was significantly poorer in the former group than in the latter (P=0.004). In differentiated-type gastric carcinoma, the presence of the cytoplasmic- or stromal-type localization of MY.1E12-MUC1 at the deepest invading sites correlates with aggressiveness of the disease, such as the tendency to form liver metastasis. This phenotype may serve as a unique biological feature associated with the malignant behavior of differentiated-type gastric carcinomas.

Background: many reconstruction procedures have been developed in efforts to resolve patients' complaints after total gastrectomy. however, there have been few reports of longterm comparisons between reconstruction procedures, especially with regard to the prevention of duodenal food passage. this study was undertaken to compare the longterm subjective and functional results among roux-en-y esophagojejunostomy (r-y), r-y with pouch (p-y), and jejunal interposition with pouch (p-i) after total gastrectomy., Methods: consecutive patients requiring curative total gastrectomy were enrolled in this prospective study by the envelope method., Results: hospital stay was longer following a p-i than an r-y or a p-y. over 50% of r-y patients complained of heartburn, and 20% of r-y patients showed dumping syndrome throughout the postoperative period, with this rate being significantly different from rates in the other two groups. p-y patients complained of early satiety in the late postoperative period, while p-i patients complained of early satiety in the early postoperative period. the nutritional index in p-i patients was higher than those in patients with the other two procedures. gastrointestinal and hepatobiliary dual scintigraphy (ghds) showed that the rate of bile reflux with an r-y was relatively high after surgery. food reflux with a p-y was increased (9.4% to 11.1%), but with a p-i food reflux was decreased at 3 years after surgery (13.3% to 9.9%). patients with a p-y had a faster recovery of body, weight in the early postoperative period; however, at 5 years after operation, body weight recovery with a p-i was greatest., Conclusion: reconstruction should be performed with pouch formation after total gastrectomy with curative intent.