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Background: Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known., Objective: We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups., Methods: This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein-Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction., Results: Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%)., Conclusions: Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC., Patients and Methods: We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival., Results: A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%)., Conclusions: The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings., Competing Interests: Disclosure YN: research funding to my institution from Chugai, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, Pfizer; Honoraria for lectures, presentations, and speakers bureaus from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, Ono Pharma, Bristol-Myers Squibb; Participation on an Advisory Board of Daiichi Sankyo. YS: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly Japan K.K., MSD K.K., Novartis Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd., Merck Biopharma Japan Co. Ltd., Hisamitsu Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd. TK: honoraria from Bristol Myers-Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, Daiichi-Sankyo. HS: participation on a Data Safety Monitoring Board or Advisory Board of Ono Pharmaceutical Co., Ltd., Zymeworks; Other financial or non-financial interests from Ono Pharmaceutical Co., Ltd., Astellas, Takeda, Amgen, MSD, Daiichi Sankyo. TMi: research funding to my institution from Eli Lilly Japan K.K.; Honoraria for lectures from TAIHO pharmaceutical Co., Ltd, Merck Serono Pharmaceutical, Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Asahi Kasei Pharma Corporation., Otsuka Pharmaceutical Factory, Bristol Myers Squibb, Sanofi, Ono Pharmaceutical Co., Ltd. NI: grants or contracts of my institution from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda, Sanofi, Ohtsuka Pharmaceutical, Eli Lilly Japan; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan, Bristol-Byers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Ono Pharmaceutical Co., Ltd., MSD. TN: payment or honoraria for lectures from Daiichi-Sankyo Pharma, Ono pharma, Bristol Myers Squibb, Eli Lilly, Takeda Pharma, Merck Serono pharma, Chugai pharma, Taiho pharma, Yakulut Honsya; Data Safety Monitoring Board of Janssen Pharmaceutical. YY: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Servier, Yakult, Takeda, Chugai, Daiichi Sankyo, Lily, Teijin, Bayer, Insight SM: grants or contracts from Bayer; Consulting fees from Chugai Pharmaceutical Co., Ltd.; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from TAIHO Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb. MN: payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer Yakuhin, Ltd., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd.; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Hokkaido Association of Supportive Care in Cancer Patients (NPO corporation). KM: research funding to my institution from Chugai, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, Pfizer; Consulting fees from AstraZeneca, Ono Pharmaceutical, Amgen, Astellas; Honoraria for lectures from Ono Pharmaceutical, Taiho, Bristol-Myers Squibb, Eli Lilly, MSD, Daiichi Sankyo; Advisory Board from Ono Pharmaceutical, Amgen, AstraZeneca, Eli Lilly, Takeda. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)-positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy., Methods: The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed., Results: ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log 2 -converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%-90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months)., Conclusion: ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.

Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients., Methods: Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m 2 on days 1 and 15) and FTD/TPI (35 mg/m 2 /dose, twice daily, on days 1-5 and 8-12 [Level A] or on days 1-5 and days 15-19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR)., Results: Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively., Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females, n  = 16 [36.3%]; severe ascites, n  = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo, P  = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11, P  = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.

Patients with advanced or metastatic gastric cancer often suffer from malnutrition, which can have an impact on quality of life, increase the toxicity of chemotherapy and reduce overall survival. Options available to the clinician to manage a patient's nutritional status include screening and assessment of malnutrition at diagnosis, monitoring during the 'cancer journey', early detection of precachexia and the ongoing use of a multidisciplinary team (oncologists, other medical specialists and nutritionists). Because malnutrition is frequently overlooked and under treated in patients with advanced or metastatic gastric cancer, this narrative review focuses on the clinical meaning of nutritional status in gastric cancer and provides general guidance regarding nutritional care management for patients with advanced or metastatic gastric cancer.

Limited data are available regarding the efficacy of nutrition support in advanced gastric cancer (AGC) patients receiving a standard second-line combination chemotherapy. The BALAST study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for patients with AGC treated with ramucirumab plus taxane as second-line treatment. As part of the routine care, patients who are malnourished or at risk of malnutrition will receive nutrition support from dietitians. We will enroll a total of 26 patients to estimate weight control rate at 12 weeks as primary end point. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients receiving second-line chemotherapy.

Nivolumab is an increasingly used standard care treatment for heavily pretreated patients with advanced gastric cancer, with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown the objective response rate to cytotoxic chemotherapy potentially improves after an exposure to immune checkpoint inhibitors. Based on these data, we conducted the multicenter observational REVIVE study to evaluate the efficacy and safety of cytotoxic chemotherapy in nivolumab-refractory or nivolumab-intolerant patients with advanced gastric cancer. Patients who are refractory or intolerant to nivolumab and scheduled to receive irinotecan monotherapy, oxaliplatin combination treatment or oral trifluridine/tipiracil hydrochloride therapy will be included. The primary end point is overall survival of nivolumab-pretreated patients with advanced gastric cancer after the cytotoxic chemotherapy. Clinical trial registration: UMIN000032182 (umin.ac.jp).

Neoadjuvant chemotherapy(NAC)is a promising approach for the improvement of gastric cancer treatment outcome. S-1 plus cisplatin(SP)or S-1 plus oxaliplatin (SOX)is generallythe first choice of NAC regimen. We experienced that NAC with ramucirumab(RAM)plus paclitaxel(PTX)was effective in locallyadvanced gastric cancer, but that with SOX was ineffective. A 68-year-old man developed locallyadvanced gastric cancer and received NAC with SOX, which was stopped because of tumor enlargement. The patient was then given NAC with RAM plus PTX, which was effective and enabled radical excision. Anti-angiogenic agents maycause wound healing complications, which mayincrease the risk of leakage. However, he was discharged without postoperative complications. Therefore, RAM plus PTX can be a promising NAC regimen for locallyadvanced gastric cancer.

Objectives: This study aimed to evaluate whether a decrease of computed tomography (CT) value for tumors serves as a predictive marker in patients with advanced gastric cancer (aGC) who have undergone chemotherapy with vascular epithelial growth factor receptor 2 inhibitor (ramucirumab)., Method: We retrospectively analyzed 44 patients with aGC who received taxane alone (TAX arm; n = 33), ramucirumab alone, or ramucirumab in combination with taxane (RAM arm; n = 11) as second-line or later chemotherapy between July 2010 and October 2016. In all patients, tumor size and tumor CT value were evaluated at two timepoints: pretreatment and first evaluation. We calculated the change of the tumors' CT value. The associations of these factors with tumor response, progression-free survival (PFS), and overall survival were investigated., Results: Ten (90.9%) of 11 patients in the RAM arm and 18 (54.5%) of 33 patients in the TAX arm showed decreased CT values. The rate of CT value change in the RAM arm (median -32.80%, range -53.63 to 6.84%) was higher than that in the TAX arm (median -0.44%, range -37.47 to 40.64%; p = 0.0005). When using the median value of CT value change as a cut-off, PFS was significantly longer in patients with a high rate of CT value change (decrease ≥32.80%) than in those with a low rate (decrease <32.80%) in the RAM arm (median 292 and 112 days; p = 0.045), while no significant difference of this kind was found in the TAX arm (median 91 and 125 days; p = 0.45)., Conclusions: Patients with aGC treated with ramucirumab experienced a significant decrease of CT value of tumors and had an association between the rate of CT value change and PFS. Our study suggests that CT value changes of tumors may be a predictor for the efficacy of ramucirumab in aGC., (© 2019 S. Karger AG, Basel.)

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided., Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis., Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies., Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1‑mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors., (©2014 American Association for Cancer Research.)

Background: Gastric carcinoma occurs at a high rate in alcoholic Japanese men. Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/2*2) and macrocytosis (mean corpuscular volume [MCV] > or = 106 fl) enhance the risk for esophageal carcinoma, which frequently occurs with gastric carcinoma in this population. Whether alcoholism affects Helicobacter pylori-induced chronic atrophic gastritis (CAG) is unknown., Methods: This study of Japanese alcoholic men with (n = 45) and without (n = 281) gastric carcinoma included assessment of H. pylori IgG antibody, serum pepsinogen-confirmed CAG, MCV, and ALDH2 genotype., Results: The gastric carcinoma cases had a significantly higher age-adjusted prevalence of H. pylori-positivity (78%vs 57%), CAG (78%vs 42%), ALDH2*1/2*2 (36%vs 14%), MCV > or =106 fl (38%vs 20%), and concurrent esophageal/oropharyngolaryngeal carcinoma (18%vs 5%) than controls. Among gastric cancer-free controls, the prevalence of CAG was higher than generally reported in Japan, regardless of H. pylori status (H. pylori-positive, 56%vs 35-36% for Japanese general population; H. pylori-negative, 8%vs 1-3%). Alcoholism may accelerate the progression of CAG. Each of these factors increased the risk of gastric carcinoma (OR(s) = 3.7 for H. pylori-positive, 2.7 for non-severe CAG, 8.7 for severe CAG, 3.5 for ALDH2*1/2*2, 2.5 for MCV > or =106 fl, and 3.7 for concurrent carcinoma). A multivariate analysis showed that CAG and ALDH2*1/2*2 were independently related to the risk of gastric carcinoma. Combinations of CAG and ALDH2*1/2*2 showed greater risks of gastric carcinoma (OR(s) = 4.0 for non-severe CAG alone, 17.6 for severe CAG alone, 9.7 for ALDH2*1/2*2 alone, 17.1 for non-severe CAG plus ALDH2*1/2*2, and 39.2 for severe CAG plus ALDH2*1/2*2)., Conclusions: Combining blood tests for H. pylori, CAG, MCV and ALDH2 genotype could offer a new means of predicting risk of gastric carcinoma in Japanese alcoholic men.