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.

The Raf murine sarcoma viral oncogene homolog B (BRAF) mutation is detected in 8–12% of metastatic colorectal cancers (mCRCs) and is strongly correlated with poor prognosis. The recent success of the BEACON CRC study and the development of targeted therapy have led to the determination of BRAF-mutated mCRCs as an independent category. For nearly two decades, a growing body of evidence has established the significance of the BRAF mutation in the development of CRC. Herein, we overview both basic and clinical data relevant to BRAF-mutated CRC, mainly focusing on the development of treatment strategies. This review is organized into eight sections, including clinicopathological features, molecular features, prognosis, the predictive value of anti-epidermal growth factor receptor (EGFR) therapy, resistant mechanisms for BRAF-targeting treatment, the heterogeneity of the BRAF mutation, future perspectives, and conclusions. A characterization of the canonical mitogen-activated protein kinase (MAPK) pathway is essential for controlling this malignancy, and the optimal combination of multiple interventions for treatments remains a point of debate.

Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), plus chemotherapy has become a standard treatment for CLDN18.2-positive advanced gastric cancer and is frequently associated with early-onset gastrointestinal (GI) toxicities. While zolbetuximab-induced gastritis has been observed in preclinical studies, it has not been previously reported in patients. We retrospectively analyzed patients with human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive, advanced gastric or gastroesophageal junction cancer who underwent endoscopy during first-line zolbetuximab-containing chemotherapy. Patients who had undergone prior total gastrectomy were excluded. We evaluated associations between gastritis and clinical outcomes including GI toxicities and serum albumin level. Among 58 eligible patients, gastritis was observed in 52 (89.7%) at a median of 7.8 weeks after treatment initiation. Characteristic endoscopic findings included mucosal erythema (100%), white exudate (63.4%), edema (28.8%), and erosions or ulcerations (26.9%). The distribution of gastritis was predominantly diffuse (76.9%) rather than scattered (23.1%), commonly involving multiple gastric regions (90.4%). Patients with diffuse gastritis experienced significantly higher rates of any-grade anorexia compared with those without gastritis (97.5% versus 50.0%, P = 0.005) and more profound serum albumin decline [median decrease -1.2 g/dl, interquartile range (IQR) -1.525 to -0.9 g/dl versus -0.7 g/dl, IQR -0.8 to -0.6 g/dl; P = 0.012]. No patients discontinued treatment due to gastritis. Among 32 patients who underwent follow-up endoscopy during ongoing treatment, improvement was confirmed in 25 patients, and no cases exhibited unresolved gastritis beyond 18 weeks. Early-onset transient gastritis frequently occurred following zolbetuximab-containing therapy and was significantly associated with anorexia and hypoalbuminemia. A deeper understanding of gastritis underlying unique GI toxicities may provide insight into effective management.

Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a “game changer,” the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.

Since bevacizumab was first approved by the U.S. Food and Drug Administration as an anti-angiogenic therapy in 2004, angiogenesis-targeted therapy has been developed for various types of solid tumors. To date, ramucirumab and apatinib are clinically available as treatments for metastatic advanced gastric cancer (AGC). Ramucirumab demonstrated prolonged survival as second-line therapy of metastatic AGC in the RAINBOW and REGARD trials. However, neither ramucirumab extended survival in treatment-naïve patients with AGC in the RAINFALL or RAINSTORM trials nor bevacizumab in the AVAGAST and AVATAR trials. Apatinib demonstrated superior efficacy over the best supportive care in a Chinese phase III trial but not in an international phase III (ANGEL) trial. Currently, combination therapy of ramucirumab with irinotecan or FTD/TPI is being evaluated in the third-line setting, assessing the efficacy of continuous angiogenesis inhibition from second- to third-line therapy. Recently, the role of angiogenesis inhibition via immunomodulators is attractive to clinicians. Emerging results of several early-phase clinical trials indicated the promising antitumor activity of angiogenesis inhibition in combination with immune therapy. This review offers an overview of the history of clinical trials focused on anti-angiogenic for patients with AGC and presents future perspectives in this area.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole‐transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin‐18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD‐L1). Concurrently, WTS was employed as part of the analyses in MONSTAR‐SCREEN‐2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD‐L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC‐positive patients treated with anti‐HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression‐free survival (ERBB2‐high vs. ‐low: median 9.0 vs. 5.6 months, log‐rank p = 0.046). IHC‐based molecular profiling revealed significantly high expression of CLDN18 in RTK‐negative patients, with 78.4% positive for either CLDN18 or PD‐L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC‐negative but WTS‐positive status may benefit from specific biomarker‐targeted therapies.