Combination treatment with an anti-programmed cell death-1 (PD-1) antibody, an immune checkpoint inhibitor (ICI), and chemotherapy is the standard treatment for patients with HER2-negative advanced gastric/esophagogastric cancer (AGC). ICI re-administration has been reported to have a clinical benefit for patients with lung cancer or melanoma. However, data on patients with AGC have not yet been collected. We plan to conduct a prospective, multicenter, observational NIVO RETURNS study to evaluate the efficacy and safety of nivolumab monotherapy re-administration in patients with AGC refractory to initial anti-PD-1 or anti-programmed cell death ligand-1 (PD-L1) antibody treatment. Patients who have achieved clinical benefits (complete response, partial response, or stable disease for ≥ 6 months) from prior treatment, including anti-PD-1/PD-L1 therapy, will be included. The primary endpoint will be the objective response rate to nivolumab re-administration. We anticipate that our findings will contribute to the improvement of survival outcomes as later-line treatment for AGC.Clinical trial registration: UMIN000050515, UMIN000051044.

Peritoneal dissemination portends a dismal prognosis in patients with gastric adenocarcinoma in the context of limited effective treatments. The underlying cellular processes that drive gastric peritoneal carcinomatosis remain unclear, limiting the application of novel targeted therapies. In this comprehensive review, we aimed to identify and summarize all existing context-dependent molecular mechanisms that have been implicated in peritoneal dissemination and peritoneal carcinomatosis establishment from primary gastric adenocarcinoma. We applied a multilevel examination including data from in vivo murine models using human gastric cancer cell lines, in vitro technique-based studies, ex vivo models, and genomic/proteomic and molecular profiling analyses to report on various aspects of gastric cancer peritoneal metastasis biology. Mechanisms promoting peritoneal dissemination were grouped into three main functional categories: (1) intrinsic cancer cell biology, (2) cancer cell-peritoneal surface adhesion, and (3) peritoneal tumor microenvironment. We identified significant overlap among the three categories, indicating a complex interplay between multiple molecular mechanisms. By interrupting these pathways, peritoneal-directed therapies have the potential to improve quality and length of life in patients with high-risk primary gastric cancer.

Gastric cancer remains a major health challenge worldwide, with nearly 1 million new cases annually contributing to more than 650 000 deaths. Epidemiologically, gastric cancer shows substantial geographical variation in incidence, with higher rates in Asia, South America, and eastern Europe, and a rapid increase in early-onset cases among people younger than 50 years. Key risk factors for gastric cancer include Helicobacter pylori infection, diet, obesity, smoking, and genetic predisposition. Early detection through comprehensive diagnostic procedures is crucial for optimising treatment outcomes. Standard treatment approaches for locally advanced gastric cancer include surgical resection, particularly D2 lymphadenectomy, complemented by chemotherapy and radiotherapy. There is increasing implementation of minimally invasive surgical techniques for operable disease and integration of immune checkpoint inhibitors and targeted therapies for advanced stages. Emerging therapies, such as novel targeted treatments and next-generation immunotherapies, show promise in improving survival and quality of life. Future directions in the management of gastric cancer focus on precision medicine, continued advancement in immunotherapy, novel early detection methods, and a multidisciplinary approach to care. These strategies aim to enhance the overall effectiveness of treatment and prognosis worldwide.

Trastuzumab deruxtecan (T-DXd) has been approved for a third- or later-line treatment of HER2-positive advanced gastric cancer (AGC) in Japan. However, clinical data on the use of T-DXd in real-world practice remain insufficient. Although early tumor shrinkage (ETS) serves as an early on-treatment indicator of high treatment sensitivity, the use of ETS in predicting T-DXd efficacy remains unclear.

This study aimed to evaluate the clinical efficacy and safety of T-DXd and investigate the clinical utility of ETS as a predictor of long-term efficacy and survival.

Single-center retrospective cohort study.

This study consecutively enrolled patients with HER2-positive AGC who received T-DXd as a third- or later-line treatment between March 2018 and December 2023. Data on patient characteristics, adverse events (AEs), and clinical outcomes were obtained from electronic medical records. Clinical efficacy was assessed using progression-free survival (PFS) and overall survival (OS). In patients with measurable lesions, the overall response rate (ORR), ETS, and depth of response (DpR) were evaluated. Prognostic outcomes were assessed using the log-rank test and the Cox proportional hazards model.

A total of 65 patients received T-DXd, with a median age of 66 years (range, 31-82 years); 77% had HER2 immunohistochemistry score of 3+, 71% received T-DXd as a third-line treatment, and 32% required initial dose reduction. At a median follow-up of 33.6 months, the median PFS and OS were 4.5 months and 7.7 months, respectively. Among the 47 patients with measurable lesions, the ORR was 36%. A median DpR of 15.8% was observed, with higher DpR correlating with longer OS. ETS was achieved in 38% of the patients and was an independent predictor of favorable PFS (hazard ratio (HR), 0.21; 95% confidence interval (CI), 0.09-0.49; p < 0.01) and OS (HR, 0.23; 95% CI, 0.10-0.52; p < 0.01). Longer second-line treatment duration was independently associated with improved OS. Overall, grade ⩾ 3 AEs occurred in 37% of the patients. Initial dose reduction reduced AE-induced discontinuation of treatment without compromising efficacy.

T-DXd demonstrated notable efficacy and a manageable safety profile in patients with HER2-positive AGC. Rapid and deep tumor shrinkage may have a significant impact on survival.

Despite advances in systemic therapy, metastatic gastric cancer is associated with a poor prognosis. As peritoneal disease is common, several studies looked at the potential benefits of hyperthermic intraperitoneal chemotherapy (HIPEC) in this context, with encouraging results. However, no Canadian data currently exists on the subject.

This study aims to report characteristics and outcomes of Canadian patients who underwent cytoreductive surgery and HIPEC (CRS-HIPEC) for gastric cancer associated with peritoneal disease or positive peritoneal cytology. This multicenter retrospective study included patients 18 years or older with gastric cancer associated with isolated peritoneal involvement who underwent CRS-HIPEC in five tertiary centers from 2016 to 2022.

CRS-HIPEC was performed on 20 patients aged 34-69 years old, most of whom presented with poorly differentiated (90 %) adenocarcinoma, with synchronous peritoneal disease (95 %). Median PCI was 3 (0-13). The associated 90-day morbidity rate, defined as Clavien-Dindo grade III and above complications, was 10 %. At a mean follow-up of 23.3 months (range 4-48), 25 % of patients remained disease-free, with an estimated median overall survival of 24.2 months.

CRS-HIPEC for gastric cancer can achieve longer term survival in highly selected patients with low-burden peritoneal disease or positive cytology. Ongoing randomized trials will further clarify patients' selection criteria and benefits of this approach.

to analyze the most robust research and recommendations that have informed the potential superiority of treatments with anticancer drugs over any type of supportive care for advanced esophageal cancer (EC).

We conducted a critical historical review. First, we identified randomized clinical trials (RCTs) from a previous scoping review conducted by our research group, ASTAC, updating the search strategy. Second, we searched for the most important and recognized international clinical practice guidelines (CPGs) in advanced EC. Finally, we performed a systematic document analysis to compare whether the recommendations proposed in the CPGs were supported by the previously identified relevant evidence.

We identified and assessed 15 RCTs and 11 CPGs from ESMO (eight), ASCO (two), and NICE (one) published over the last 40 years. There is a clear mismatch between these guidelines' recommendations and the available RCTs regarding the efficacy of anticancer drugs compared to best supportive care (BSC).

There is a lack of consistent evidence to support the treatment of advanced EC patients with anticancer drugs, and a notable mismatch exists between the available evidence and the recommendations made by relevant CPGs. As a result, these guidelines may be biased in favoring the use of anticancer drugs over supportive care and in consequence it is advisable to be very prudent when proposing systemic treatments to patients with advanced EC. Further rigorous and independent research is needed to better evaluate the true benefits of anticancer treatments in advanced EC and to update the CPGs accordingly.

Trifluridine/tipiracil (FTD/TPI) frequently induces chemotherapy-induced nausea and vomiting (CINV). As evidence of factors associated with CINV in oral chemotherapeutic agents is limited, we aimed to assess factors for nausea development in a real-world FTD/TPI-containing treatment for metastatic colorectal cancer (mCRC). Patients with mCRC receiving FTD/TPI with or without bevacizumab (n = 104) were retrospectively evaluated. Nausea occurred in 40.4% of the patients, and the severity was grade 1 for 23.1%, grade 2 for 15.4%, and grade 3 for 1.9%. Multivariable logistic regression analysis suggested that female sex (adjusted odds ratio 2.74, 95% confidence interval 1.02-7.33, p = 0.045) and concomitant bevacizumab (2.68, 1.13-6.37, p = 0.03) were independent risk factors for all-grade nausea during the first cycle as a primary endpoint. Particularly, among patients with FTD/TPI monotherapy, females significantly exhibited nausea compared to males. Our study revealed that concomitant bevacizumab and female sex are independent risk factors for nausea in FTD/TPI-containing treatment for mCRC.

Although the emergence of immunotherapy has benefited patients with advanced gastric cancer (AGC), the magnitude of the benefit among real-world patients with HER2-negative AGC remains unclear.

The current study aimed to evaluate the treatment features across various immunotherapy approval periods and investigate the utility of immunotherapy for patients with HER2-negative AGC in daily practice.

Retrospective observational study.

We retrospectively evaluated the clinical outcomes of patients with HER2-negative AGC who received first-line platinum-based chemotherapy between 2011 and 2023 across different periods of immunotherapy approval in Japan: Group A (pre-immunotherapy approval): 2011-2017; Group B (approved for third-line treatment or later): 2018-2021; and Group C (approved for first-line treatment): 2022-2023.

A total of 949 patients were enrolled (n = 477, 344, and 128 for Groups A, B, and C, respectively). Patient characteristics were comparable between the three groups, except for the proportion of those aged ⩾75 years (p = 0.002), prior gastrectomy (p = 0.03), and liver metastases (p = 0.0005). The median overall survival (OS) was 16.2, 15.2, and 21.3 months in Groups A, B, and C, respectively, with no significant difference between the groups (log-rank p = 0.50). Patients who received first-line immunotherapy plus chemotherapy (n = 173) showed significantly better OS than did those who did not receive any immunotherapy-containing treatment from 2011 to 2017 (n = 382; hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.61-0.99; p = 0.04). Multivariate analysis showed that the use of first-line immunotherapy was not significantly associated with worse OS, whereas the use of any-line immunotherapy was significantly associated with prognosis (HR, 0.54; 95% CI, 0.47-0.63; p < 0.0001). The proportion of patients receiving any second-line treatment was comparable between the groups: 76%, 80%, and 71%, respectively.

Our study suggests that immunotherapy has a moderate impact on improving the survival of real-world patients with HER2-negative AGC, highlighting the need for appropriate treatment strategies, including efforts to identify biomarkers and the development of other agents.

Gastric cancer (GC) remains one of the most common types of cancer, ranking fifth among cancer-related deaths worldwide. Chemotherapy is an effective treatment for advanced GC. However, the development of chemotherapy resistance, which involves the malfunction of several signaling pathways and is the consequence of numerous variables interacting, seriously affects patient treatment and leads to poor clinical outcomes. Therefore, in order to treat GC, it is imperative to find novel medications that will increase chemotherapy sensitivity and reverse chemotherapy resistance. Traditional Chinese medicine (TCM) has been extensively researched as an adjuvant medication in recent years. It has been shown to have anticancer benefits and to be crucial in enhancing chemotherapy sensitivity and reducing chemotherapy resistance. Given this, the mechanism of treatment resistance in GC is summed up in this work. The theoretical foundation for TCM as a sensitizer in adjuvant treatment of GC is established by introducing the primary signal pathways and possible targets implicated in improving chemotherapy sensitivity and reversing chemotherapy resistance of GC by TCM and active ingredients.

Microsatellite instability-high (MSI-H) gastric cancer (GC) is recognized as a unique subtype of gastric cancer. While patients with advanced MSI-H gastric cancer may respond favorably to a combination of immune checkpoint inhibitors and chemotherapy in first-line treatment, no definitive recommendations exist regarding the optimal regimen for subsequent therapy. Cadonilimab, a PD-1 and CTLA-4 bispecific antibody, has shown encouraging efficacy and safety in the first-line treatment of advanced gastric cancer. However, its utility in the MSI-H gastric cancer subtype following multiple lines of therapy remains uncertain. This case report describes a patient with advanced MSI-H gastric adenocarcinoma that progressed after multiple treatments and achieved notable efficacy with a combination of cadonilimab and apatinib. By examining the current therapeutic landscape for MSI-H gastric cancer, this study explores the potential of combining PD-1/CTLA-4 dual-immunity with anti-vascular therapy as salvage treatment for this gastric cancer subtype. The findings provide valuable reference points for future clinical trials, offering a promising perspective on backline therapeutic strategies for MSI-H gastric cancer and highlighting the potential of integrating bispecific antibodies with anti-vascular therapies.

Patients with unresectable upper gastrointestinal (UGI) cancers have limited treatment options and poor prognosis. Although phase I trials provide access to novel therapies, their benefits in this population are unclear.

We aimed to assess efficacy and survival outcomes of patients with refractory UGI cancers within phase I trials.

We conducted a retrospective pooled analysis of phase I trials enrolling patients with advanced UGI cancers who received at least one dose of the study drug at SCRI UK between 2011 and 2023.

Efficacy and survival outcomes, including objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS), were assessed. Analyses were conducted for the entire cohort and stratified by trial agent class, molecularly matched therapy allocation and receipt of the recommended phase II dose (RP2D). Patients participating in multiple trials were analysed separately for each study.

From 1796 screened patients, 124 with UGI cancers were included in 37 phase I trials. Most were male (75%), with liver or peritoneal metastases (73%), treated with a median of 2 prior therapy lines. Of these, 60% received immunotherapy, 30% small molecules and 10% antibody-drug conjugates. Molecularly matched therapy was given to 22% and 86% received treatment at RP2D. In response-evaluable patients, ORR was 15%, CBR 40%, DCR 86% and median OS was 9.7 months. Treatment at RP2D was significantly associated with higher CBR (odds ratio 4.75, p = 0.04) and prolonged PFS (p = 0.04). Depth of response and treatment at RP2D were independent prognostic factors.

Participation in phase I trials offers benefits in refractory upper gastrointestinal cancers with compelling results in late-line settings and potential early access to new therapies.

This study aims to assess the association between adjuvant radiotherapy and the development of second primary malignancies (SPMs) and identify its determinants in patients who have undergone surgical treatment for gastric cancer.

Retrospective cohort study using the Surveillance, Epidemiology and End Results (SEER) database.

Cohorts (18 registries, 2000-2018, from SEER) were screened for any malignancy that developed after sufficient latency from diagnosis of surgically treated non-metastatic gastric cancer.

24 777 surgically treated gastric cancer cases were included in the cohort. Among them, 6128 patients underwent adjuvant radiotherapy.

The cumulative incidence of SPMs was estimated using Fine and Gray's competing risk model and the radiotherapy-correlated risks were calculated using Poisson regression analysis.

Among patients with sufficient latency, there was no significant association between radiotherapy and the risk of developing second primary solid malignancies (relative risk=1.05, 95% CI 0.83 to 1.33) or haematological malignancies (relative risk=1.17, 95% CI 0.62 to 2.11). Interestingly, radiotherapy was associated with a reduced cumulative incidence of second lung and bronchus cancer compared with no radiotherapy, with a 15-year incidence of 1.4%-3.17% (p<0.05). Radiotherapy was not associated with a significant increase in standardised incidence ratios of SPMs.

Adjuvant radiotherapy was not associated with an increased risk of developing SPMs in surgically treated patients with gastric cancer. Clinical trials are warranted to further verify the findings.

Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS).

A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL).

INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports.

Regorafenib improves survival compared with placebo in refractory AGOC.

Effective later-line chemotherapy treatment options are scarce for patients with metastatic breast cancer (MBC). Trifluridine-tipiracil has shown survival benefit in heavily pre-treated patients with metastatic colorectal and in gastric cancer refractory to a fluoropyrimidine. This study aimed to investigate the efficacy of trifluridine-tipiracil in a Western population of previously treated patients with oestrogen receptor (ER+), HER2- MBC to facilitate further optimization of this treatment strategy.

Adult patients at least 18 years old diagnosed with hormone receptor positive, HER2- receptor negative MBC with a performance status of 0 or 1 who have been treated with capecitabine in the metastatic setting and up to two other lines of chemotherapy, including a taxane, were enrolled in this single-arm, multicentre, phase 2 study in the Netherlands. The participants received trifluridine-tipiracil 35 mg/m2 orally twice a day on days 1-5 and days 8-12 during a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the disease control rate (DCR) at 8 weeks, defined as the percentage of patients that had stable disease, partial response or complete response according to RECIST 1.1, in all patients that received at least one dose of trifluridine-tipiracil and met the key eligibility criteria defined a priori. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life and were performed in all patients that received at least one dose of trifluridine-tipiracil. The primary endpoint was considered met, justifying further research of this treatment regimen, if the lower boundary of the 80% confidence interval (CI) exceeded 30%. The study was registered within ClinicalTrials.gov (NCT04489173) and is closed for inclusion.

Fifty female patients were enrolled from September 2020 to July 2023, with a median of 3 (IQR, 2-3) previous endocrine therapy lines and 2 (IQR, 2-3) chemotherapy lines for MBC. The DCR rate at 8 weeks was 64.0% (n = 32, 95% CI: 50.1-75.9%; 80% CI: 55.0-72.1%), thereby meeting the primary endpoint of this study. At data cutoff (January 8, 2024), the median follow-up time was 18.2 months (IQR, 13.1-25.1 months). The median PFS was 5.4 months (95% CI: 2.0-7.2 months) and the median OS 14.0 months (95% CI: 8.8-17.8 months). The safety profile of trifluridine-tipiracil aligned with expected toxicities and included leukopenia (n = 36, 69%), neutropenia (n = 43, 83%), and fatigue (n = 43, 83%). The most common grade 3-4 AEs were primarily haematological disorders and included neutropenia (n = 38, 73%), leukopenia (n = 15, 29%) and anaemia (n = 6, 12%). The most common SAEs (any grade) with a possible relationship with trifluridine-tipiracil included anaemia (n = 2) and vomiting (n = 2). No treatment-related deaths occurred. Quality of life scores remained stable throughout the treatment.

Trifluridine-tipiracil demonstrated promising efficacy in heavily pre-treated patients with MBC, despite prior exposure to a fluoropyrimidine. Clinically, this suggests that trifluridine-tipiracil holds potential as a viable oral later-line treatment option with a manageable toxicity profile while maintaining quality of life. Preparations for a phase 3 trial are underway.

Servier, France.

Gastric cancer is the fourth most common malignancy in Korea and remains the fifth and seventh leading cause of cancer death in males and females, respectively. Although the survival rates for gastric cancer have improved, unresectable or metastatic gastric cancer still has an abysmal prognosis, and the five-year survival rate for patients with stage IV gastric cancer is approximately 6.6% in Korea. The treatment of patients with unresectable or metastatic gastric cancer is based on chemotherapy. A combination of fluoropyrimidine and platinum is the most widely used first-line treatment for gastric cancer worldwide. In recent decades, a better understanding of cancer biology has led to targeted therapies becoming the treatment paradigm for many cancers, including gastric cancer. In addition, immunotherapies have also been reported to improve survival in several cancers, particularly in patients with unresectable or metastatic gastric cancer who have failed multiple lines of chemotherapy. This review evaluates landmark studies on chemotherapy for unresectable or metastatic gastric cancer, including targeted therapies and immunotherapies.

Epithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, yet understanding the connections between its molecular subtypes and their therapeutic implications remains incomplete.

We conducted mass spectrometry-based proteomics analyses of 154 EOC tumour samples and 29 normal fallopian tubes, and single-cell RNA sequencing (scRNA-seq) analyses of an additional eight EOC tumours to classify proteomic subtypes and assess their cellular ecosystems and clinical significance. The efficacy of identified therapeutic targets was evaluated in patient-derived xenograft (PDX) and orthotopic mouse models.

We identified four proteomic subtypes with distinct clinical relevance: malignant proliferative (C1), immune infiltrating (C2), Fallopian-like (C3) and differentiated (C4) subtypes. C2 subtype was characterized by lymphocyte infiltration, notably an increased presence of GZMK CD8+ T cells and phagocytosis-like MRC+ macrophages. Additionally, we identified CD40 as a specific prognostic factor for C2 subtype. The interaction between CD40+ phagocytosis-like macrophages and CD40RL+ IL17R CD4+ T cells was correlated with a favourable prognosis. Finally, we established a druggable landscape for non-immune EOC patients and verified a TYMP inhibitor as a promising therapeutic strategy.

Our study refines the current immune subtype for EOC, highlighting CD40 agonists as promising therapies for C2 subtype patients and targeting TYMP for non-immune patients.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC.

A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen.

Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD.

Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.

Gastric cancer is one of the most common cancers in both Korea and worldwide. Since 2004, the Korean Practice Guidelines for Gastric Cancer have been regularly updated, with the 4th edition published in 2022. The 4th edition was the result of a collaborative work by an interdisciplinary team, including experts in gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology, and guideline development methodology. The current guideline is the 5th version, an updated version of the 4th edition. In this guideline, 6 key questions (KQs) were updated or proposed after a collaborative review by the working group, and 7 statements were developed, or revised, or discussed based on a systematic review using the MEDLINE, Embase, Cochrane Library, and KoreaMed database. Over the past 2 years, there have been significant changes in systemic treatment, leading to major updates and revisions focused on this area. Additionally, minor modifications have been made in other sections, incorporating recent research findings. The level of evidence and grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation system. Key factors for recommendation included the level of evidence, benefit, harm, and clinical applicability. The working group reviewed and discussed the recommendations to reach a consensus. The structure of this guideline remains similar to the 2022 version. Earlier sections cover general considerations, such as screening, diagnosis, and staging of endoscopy, pathology, radiology, and nuclear medicine. In the latter sections, statements are provided for each KQ based on clinical evidence, with flowcharts supporting these statements through meta-analysis and references. This multidisciplinary, evidence-based gastric cancer guideline aims to support clinicians in providing optimal care for gastric cancer patients.

Differences in demographics, medical expertise, and patient healthcare resources across countries have led to significant variations in guidelines. In light of these differences, in this review, we aimed to explore and compare the most recent updates to gastric cancer treatment from five guidelines that are available in English. These English-version guidelines, which have been recently published and updated for journal publication, include those published in South Korea in 2024, Japan in 2021, China in 2023, the United States in 2024, and Europe in 2024. The South Korean and Japanese guidelines provide a higher proportion of content to endoscopic and surgical treatments, reflecting their focus on minimally invasive techniques, function-preserving surgeries, and systemic therapy. The Chinese guidelines provide recommendations addressing not only surgical approaches but also perioperative chemotherapy and palliative systemic therapy. Meanwhile, in the United States and European guidelines, a higher proportion of the content is dedicated to perioperative and palliative systemic therapy, aligning with their approaches to advanced-stage disease management. All guidelines address surgical and systemic chemotherapy treatments; however, the proportion and emphasis of content vary based on the patient distribution and treatment approaches specific to each country. With emerging research findings on gastric cancer treatment worldwide, the national guidelines are being progressively revised and updated. Understanding the commonalities and differences among national guidelines, along with the underlying evidence, can provide valuable insights into the treatment of gastric cancer.

Breast cancer is a heterogeneous disease that is ranked as one of the most common cancers worldwide. Currently, although there are existing molecules such as progesterone receptor and estrogen receptor for breast cancer treatment, discovering more effective drug targets is still in urgent need. In this study, we have obtained six sequencing datasets of breast cancer from GEO database and identified a set of differentially expressed molecules, including 67 miRNAs and 133 genes. Function enrichment analysis by miRPathDB database indicated that targets of 11 miRNAs could be enriched in breast cancer pathway with a p-value ≤ .05. A special miRNA-gene interaction network was constructed for analysis of the progression of breast cancer. We then ranked the importance of each molecule (i.e. miRNA and gene) by their node centrality indexes in the network and selected the top 10% of molecules. The statistical analysis of these molecules showed three miRNAs (hsa-miR-1275, hsa-miR-2392, hsa-miR-3141) have significant effects on the prognosis and survival of patients. By searching for potential drugs in Drugbank database, we have identified four candidates (phenethyl isothiocyanate, amuvatinib, theophylline, trifluridine) for targeting these genes. In conclusion, we believe that these drugs and their analogs could be used in the targeted therapy of breast cancer in the future.

In addition to blood test data, inflammation-based prognostic markers have been used to predict the prognosis of various types of cancer. However, several of these previous studies may be outdated, as they were conducted prior to the widespread adoption of immune checkpoint inhibitors, leading to limited reports on their efficacy. The present study aimed to assess the accuracy of different inflammation-based prognostic markers in patients with advanced or recurrent gastric cancer undergoing nivolumab monotherapy as salvage-line chemotherapy. In a retrospective cohort study across Japan, a total of 159 patients with advanced or recurrent gastric cancer who were treated with nivolumab between September 2017 and March 2020 were selected. Blood test data were collected within 14 days of the start of chemotherapy and 17 inflammation-based prognostic markers were evaluated. Cox regression analysis was performed using all patient background factors. Subsequently, model selection was performed using backward elimination based on the Akaike information criterion (AIC) to obtain effective background factors which could be assessed for their impact on patient survival. For each marker, the magnitude of the impact on the survival rate, after adjusting for the background factors, was assessed using concordance and AIC analyses. A total of 159 patients (female, 30.2%; median age, 70 years) were included in the present study. Most patients received platinum, fluoropyrimidine and taxane treatment, with a median of three prior lines of systemic therapy. With a median follow-up of 3.3 months (95% CI, 2.5-3.8), median overall survival and time to treatment failure were 3.8 months (95% CI, 3.3-4.5) and 1.8 months (95% CI, 1.8-2.3), respectively. Amongst the 17 markers analyzed, the modified Glasgow prognostic score (mGPS) was classed as the most useful factor that affected the survival rate of patients. Real-world data showed that mGPS, an inflammation-based prognostic marker, had the strongest correlation with prognosis in patients with advanced or recurrent gastric cancer receiving nivolumab monotherapy. The present study was registered as a clinical trial with the UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr/index.htm) under the trial registration number UMIN000050590 on 15th March 2023.

The aim of this study was to evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) for heavily pretreated metastatic gastric cancer from the perspective of the Chinese healthcare system.

Based on the overall survival and progression-free survival (PFS) data from the Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS) trial (NCT02500043), a three-state Markov model (PFS, progressed disease and death) was constructed to analyse the cost-effectiveness of FTD/TPI compared with the placebo in heavily pretreated metastatic gastric cancer. Cost and utility were from pricing records and the literature. The model was simulated for 5 years with monthly cycles. Costs and health outcomes were discounted by 5%. We then conducted sensitivity analyses to evaluate the robustness of the parameters. The model results were from the Chinese healthcare system.

The output results were the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER).

According to the model results, FTD/TPI generated an additional cost of US$26 855.66 and 0.88 QALYs compared with the placebo. ICER of FTD/TPI compared with the placebo was US$30 494.89 per QALY. Sensitivity analyses revealed that the utility value of the PFS stage and FTD/TPI adverse event costs were the main influencing parameters, and the results were stable. At a threshold of three times per capita gross domestic product of China (US$35 559.34 in 2022), the probability of FTD/TPI being cost-effective compared with placebo was 99.2%.

From the perspective of the Chinese healthcare system, FTD/TPI is a more cost-effective option compared with the placebo for the treatment of heavily pretreated metastatic gastric cancer in patients who have received at least two prior advanced treatment regimens.

The Chinese population registered in the Chinese Clinical Trial Registry (ChiCTR2400080940) and clinical trial (NCT05029102).

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.

This review highlights advances and recent changes in the treatment paradigm for advanced esophageal adenocarcinoma (EAC) and gastroesophageal junction adenocarcinoma (GEJAC).

Chemotherapy remains the backbone of treatment for advanced EAC/GEJAC. New targets/agents include immunotherapy, HER-2, claudin18.2, and FGFR2b, with various mechanisms (CAR-T, bispecific mAB, ADCs) altering the treatment landscape against these targets. The approaches to these targets may act together, in sequence, and even synergistically to improve outcomes. Herein, we review the state of the field, including highlighting ongoing clinical trials and additional emerging agents and approaches.

With relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX.

A systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX.

The base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable.

This NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles.

Recent advances in the development of biomarker-directed therapy and immunotherapy, for advanced and metastatic gastric cancers, have the potential to improve survival and quality of life. Much attention has been directed towards second- and later-line treatments, and the landscape here is evolving rapidly. However, uncertainty in relative effectiveness, high costs and uncertainty in cost effectiveness represent challenges for decision makers.

To identify economic evaluations for the second-line or later-line treatment of advanced and metastatic gastric cancer. Also, to assess key criteria (including model assumptions, inputs and outcomes), reporting completeness and methodological quality to inform future cost-effectiveness evaluations.

A systematic literature search (from database inception to 5 March 2023) of EconLit via EBSCOhost, Cochrane Library (restricted to National Health Service [NHS] Economic Evaluation Database and Health Technology Assessment [HTA] Database), Embase, MEDLINE and of grey literature was conducted. This aimed to identify systemic treatments that align with National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) Clinical Practice Guidelines. Data were collected on key criteria and on reporting completeness and methodological quality. A narrative synthesis focussed on cost-effectiveness and cost-of-illness studies. Outcomes of interest included total and incremental costs and outcomes (life-years and quality-adjusted life-years), ratios of incremental costs per unit outcome and other summary cost and outcome measures. Also, for cost-effectiveness studies, reporting completeness and the methodological quality were assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and the Philips Checklist, respectively.

A total of 19 eligible economic evaluations were identified (cost-effectiveness studies [n = 15] and cost-of-illness studies [n = 4]). There was a general lack of consistency in the methodological approaches taken across studies. In the main, the cost-effectiveness studies indicated that the intervention under consideration was more effective and more costly than the comparator(s). However, most interventions were not cost effective. No studies were fully compliant with reporting-completeness and methodological-quality requirements. Given the lack of consistency in the approaches taken across cost-of-illness studies, outcomes could not be directly compared.

To our knowledge, this is the first published systematic literature review that has qualitatively synthesised economic evaluations for advanced and metastatic gastric cancer. There were differences in the approaches taken across the cost-effectiveness studies and the cost-of-illness studies. The conclusions of most of the cost-effectiveness studies were consistent despite identified differences in approaches. In the main, the interventions under consideration were not cost effective, presenting challenges to sustainability and affordability. We highlight a requirement for cost-effectiveness evaluations and for second-line or later-line treatments of advanced and metastatic gastric cancer that consider all relevant comparators and that are compliant with reporting-completeness and methodological-quality requirements. By addressing the methodological gaps identified here, future healthcare decision-making, within the context of this rapidly changing treatment landscape, would be better informed.

CRD42023405951.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic. Gastric cancer (GC) poses a great threat to people's health, which is a high-risk factor for COVID-19. Previous studies have found some associations between GC and COVID-19, whereas the underlying molecular mechanisms are not well understood.

We employed bioinformatics and systems biology to explore these links between GC and COVID-19. Gene expression profiles of COVID-19 (GSE196822) and GC (GSE179252) were obtained from the Gene Expression Omnibus (GEO) database. After identifying the shared differentially expressed genes (DEGs) for GC and COVID-19, functional annotation, protein-protein interaction (PPI) network, hub genes, transcriptional regulatory networks and candidate drugs were analyzed.

We identified 209 shared DEGs between COVID-19 and GC. Functional analyses highlighted immune-related pathways as key players in both diseases. Ten hub genes (CDK1, KIF20A, TPX2, UBE2C, HJURP, CENPA, PLK1, MKI67, IFI6, IFIT2) were identified. The transcription factor/gene and miRNA/gene interaction networks identified 38 transcription factors (TFs) and 234 miRNAs. More importantly, we identified ten potential therapeutic agents, including ciclopirox, resveratrol, etoposide, methotrexate, trifluridine, enterolactone, troglitazone, calcitriol, dasatinib and deferoxamine, some of which have been reported to improve and treat GC and COVID-19.

This research offer valuable insights into the molecular interplay between COVID-19 and GC, potentially guiding future therapeutic strategies.

Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab.

This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test.

The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p < 0.0001 and PFS, p < 0.0001; PLR: OS, p = 0.0289 and PFS, p = 0.0302; and NLR: OS, p = 0.0077 and PFS, p = 0.0044).

Measurement of the changes in CAR, PLR, and NLR could provide a simple, prompt, noninvasive method to evaluate response to nivolumab monotherapy.

This study is registered with number K2023006.

After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer.

Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor that can prevent tumor progression and induce apoptosis. Maximum tolerated dose (MTD), safety, and antitumor activity of Minnelide alone and its combination with paclitaxel were evaluated in this open-label, single-center, dose-escalation phase I study (NCT05566834) in patients who were previously treated for advanced gastric cancer (AGC). Minnelide was administered orally using a 3 + 3 dose-escalation design as monotherapy (Regimen A), and in combination with paclitaxel (Regimen B & C). Our results show that no patients experienced dose limiting toxicity (DLT) in the combination group (Regimen B& C) while 2 patients experienced DLT from the Regimen A group (n = 11) (Minnelide 1.5 mg). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4 %) and abdominal pain (11.1 %). In Regimen C, 71.5 % achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on these encouraging results, a phase II study is being initiated to test the effectiveness of the combination regimen in patients with advanced gastric cancer.

Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile.

The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab.

This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5.

PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).