Metastatic gastric cancer remains a major global health challenge with poor long-term outcomes. Over the past 5 years, the treatment landscape has rapidly evolved with the integration of biomarker-informed strategies that guide the use of immune checkpoint inhibitors and targeted therapies in molecularly defined subgroups, including microsatellite unstable, PD-L1-expressing, HER2-positive and claudin 18.2-positive disease. Standard first-line treatment continues to rely on fluoropyrimidine-platinum chemotherapy backbones, with biomarker-driven agents selectively layered on for improved efficacy. Despite these advances, most patients continue to have disease progression, and durable responses are uncommon. In addition to identifying and validating new targets such as FGFR2b, ongoing efforts are focusing on novel strategies involving established targets, including HER2 and claudin 18.2, using next-generation treatment modalities such as antibody-drug conjugates, bispecific antibodies and cellular therapies. Complementary platforms including circulating tumour DNA and theranostic agents are also being explored to better guide treatment selection, facilitate non-invasive monitoring and enable early response assessments. In this Review, we summarize the current standard of care for patients with metastatic gastric cancer and also highlight emerging approaches aimed at improving the outcomes in these patients.

Abstract Background: Disitamab vedotin (DV) is a human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload via a maleimidocaproyl-valine-citrulline (MC-VC) linker. MMAE is primarily metabolized in vitro by cytochrome P450 3A4 (CYP3A4) and is a substrate of P-glycoprotein (P-gp). A clinical drug-drug interaction (DDI) study previously showed that ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased unconjugated MMAE exposure 1.34-fold following brentuximab vedotin (BV) treatment in patients with CD30+ hematologic malignancies1. Thus, current recommendations for concomitant use of MMAE-conjugated ADCs and a strong CYP3A4 inhibitor are limited to close monitoring for adverse events. However, it’s unclear whether a similar trend of increased exposure holds true for other MMAE-conjugated ADCs. In this study, unconjugated MMAE PK following DV administration was characterized with and without tucatinib, a strong CYP3A4 inhibitor and a known P-gp inhibitor currently approved for previously treated HER2 expressing metastatic breast cancer, to assess the impact of tucatinib-mediated CYP3A4 and P-gp inhibition on unconjugated MMAE PK. Methods: C5731004/SGNDV-004 (NCT06157892) is a phase 1b/2 open-label, multicenter study designed to identify the maximum tolerated dose (MTD) and/or optimal dose of DV when administered in combination with tucatinib in participants with HER2+ (IHC 3+ or IHC 2+/ISH+) and HER2-low (IHC 1+ or IHC 2+/ISH-) expressing locally advanced or metastatic breast cancer (LA/mBC) and locally advanced or metastatic gastric cancer and gastroesophageal junction adenocarcinoma (LA/mGC/GEJC). Participants in the dose escalation phase of SGNDV-004 received DV (1.25 mg/kg or 1.50 mg/kg IV Q2W) starting Cycle 1 Day 1 and tucatinib (TUC, 300 mg PO BID) starting Cycle 1 Day 8. Unconjugated MMAE PK blood samples were collected on Days 1, 2, 3, and 8 in Cycle 1 (DV alone) and Cycle 2 (DV+TUC). Unconjugated MMAE plasma concentrations were analyzed using validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The DDI assessment was made using unconjugated MMAE PK parameters following DV administration including plasma area under the concentration-time curve up to Day 8 (AUC0-168h) and maximal concentrations (Cmax) in Cycle 2 (test) relative to Cycle 1 (reference) and were calculated using PKNCA (R v4.3.1, PKNCA v0.10.2). Results: PK data were available for 6 patients at 1.25 mg/kg and 3 patients at 1.50 mg/kg. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE AUC0-168h values were 232.2 (83%) and 275.7 (101%) ng*hr/mL/(mg/kg), respectively. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE Cmax values were 1.87 (88%) and 2.40 (94%) ng/mL/(mg/kg), respectively. Geometric mean ratios (CI90%) for Cycle 2/Cycle 1 MMAE AUC0-168h and Cmax were 1.18 (1.05-1.35) and 1.28 (1.17-1.40), respectively. Conclusions: Unconjugated MMAE exposure following DV administration of 1.25 mg/kg or 1.5 mg/kg Q2W was increased <1.3-fold in the presence of tucatinib in participants with HER2 expressing LA/mBC or LA/mGC/GEJC, translating to an overall weak DDI impact.

Gastric cancer affects over 30,000 Americans annually and has a 5-year survival rate of roughly 40%. Palliative-intent interventions are critical for symptom relief and quality of life, yet access remains inequitable. We examined disparities in receipt of palliative-intent care among disaggregated Hispanic subgroups with gastric cancer. Using the National Cancer Database (2004 to 2021), we identified adults (≥18y) with AJCC stage IV gastric cancer. The primary outcome was receipt of palliative-intent intervention, defined as treatment for symptom alleviation rather than cure. Patients were stratified into Hispanic subgroups (Mexican, Puerto Rican, Cuban, South/Central American, Dominican, Other Hispanic, Not Otherwise Specified [NOS], and Spanish surname only) and compared with non-Hispanic White patients. Multivariable logistic regression adjusted for demographic, socioeconomic, and clinical covariates. Among 73,990 patients (median age 67y), 65.2% were non-Hispanic White. Only 19.3% received palliative-intent treatment. Compared with non-Hispanic White patients, odds of receipt were lower for Mexican (AOR 0.74, 95% CI: 0.64-0.87), Cuban (AOR 0.57, 95% CI: 0.34-0.94), South/Central American (AOR 0.73, 95% CI: 0.61-0.88), and NOS Hispanic (AOR 0.82, 95% CI: 0.75-0.89) patients (all P<0.05). Several Hispanic subgroups experience significantly lower odds of receiving palliative-intent care for metastatic gastric cancer. These inequities likely reflect intersecting socioeconomic, linguistic, and structural barriers. Advancing equity will require culturally responsive communication, improved language access, and systemic reform in end-of-life care delivery.

Lymph node (LN) assessment plays a critical role in cancer staging and prognosis but remains a time-consuming and labor-intensive task in pathology. While artificial intelligence (AI) tools have shown promise in improving diagnostic accuracy, their real-world clinical utility in LN metastasis detection across multiple cancer types remains underexplored. To evaluate the diagnostic performance and efficiency of an AI module in detecting LN metastases from gastric, colorectal, and breast cancers, and to assess its impact on pathologists' workflow. A retrospective study was conducted by using 314 whole slide images from 95 patients who underwent resection for gastric, colorectal, or breast cancer. Three board-certified pathologists reviewed the slides with and without AI assistance. Diagnostic accuracy, review time, and number of mouse clicks required to detect metastases were recorded and compared. AI assistance increased sensitivity-which ranged from 91.8% to 93.9%-to 95.9% for all pathologists, while specificity remained high (97.0%-98.9%). Time to detect LN metastases decreased by up to 78% for some cancer types. The AI-guided click-based review required an average of 1.4 to 5.2 clicks depending on tissue type, with colorectal metastases detected most efficiently. Challenging subtypes, such as breast carcinoma with apocrine differentiation, required more extensive interaction. Micrometastases across all 3 cancer types were successfully identified by the AI. The AI module improved pathologists' sensitivity in detecting LN metastases and significantly reduced review time, particularly for positive nodes. These findings support the integration of AI tools to enhance diagnostic efficiency and accuracy in routine pathology practice.

This study aimed to evaluate the efficacy and safety of apatinib, an oral VEGFR2 tyrosine kinase inhibitor, combined with docetaxel and S-1 (DS) as first-line therapy for metastatic gastric cancer (mGC) patients whose median overall survival (mOS) with chemotherapy typically remains below 12 months. In this prospective, multi-center, single-arm phase II trial (NCT03154983), patients received docetaxel (75 mg/m2, day 1) and S-1 (body surface area-based dosing, days 1-14) every 3 weeks, plus daily apatinib (500 mg), for up to 6 planned cycles. 45 patients were enrolled, with a median follow-up time of 12.4 months. Median progression-free survival (PFS) and overall survival (OS) were 7.6 months (95% CI: 5.8%-9.4%) and 12.4 months (95% CI: 9.3%-15.5%), respectively in the full analysis set. Patients completing ≥4 cycles achieved a better mOS of 14.5 months (95% CI: 12.0%-17.1%). The objective response rate (ORR) and disease control rate (DCR) were 62.2% (95% CI, 46.5%-76.2%) and 82.2% (95% CI, 67.9%-92.0%), respectively, including one complete response (CR). Grade 3-4 treatment-related adverse events occurred in 48.9% of patients, most commonly oral mucositis and neutropenia. These findings support apatinib plus DS as a promising biomarker-independent first-line treatment strategy for mGC.

To identify randomised control trials (RCTs) of treatments (recommended by the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines and clinical expertise) for the second- or later-line treatment of advanced/metastatic gastric cancer. To determine the relative efficacy and safety of the treatments. RCTs were identified from a Rapid Literature Review and a published systematic review. Identified RCTs were subject to data-extraction and narrative review. Eligible RCTs were included in evidence networks to determine relative efficacy and safety of the treatments. In total, 44 RCTs (pertaining to eleven treatments), were identified for data-extraction and narrative review; 37 in the second-line setting, five in the second- and later-line setting and two in the third- and later-line setting. Evidence networks were feasible for the second-line treatments only. No statistically significant differences, across treatments, for key efficacy outcomes (overall-survival, progression-free survival), and additional outcome (objective-response rate) were identified. Pembrolizumab was associated with a statistically significant decreased risk of Grade ≥ 3 treatment-related adverse effects versus paclitaxel; no other significant differences, across treatments, were identified for this outcome. The appreciable number of RCTs identified indicates that the treatment landscape here is rapidly evolving. The introduction of novel treatments, in the second-line setting, has not had a statistically significant impact on key efficacy outcomes, and has had little impact on safety outcomes, versus more established treatments. There remains a need for novel treatments that will have a significant benefit on efficacy and safety outcomes.

Prognostic nomogram for patients with HER2-negative metastatic gastric cancer receiving first-line PD-1 blockade

Clinical and Molecular Prognostic Markers of Survival in Metastatic Gastric Cancer: An Institutional Observation Study

This study aimed to characterize the genomic landscape of Korean gastric cancer and evaluate associations among oncogenic alterations, established biomarkers, demographics, and treatment outcomes. A total of 1,283 patients with gastric cancer who underwent tumor-only targeted sequencing as part of practice and received palliative treatment between January 2017 and August 2025 at the Samsung Medical Center were included. Among 1,283 patients (median [IQR] age, 61 [52-68] years; 827 males [64.46%]), TP53 (51.91%), ARID1A (19.02%), ERBB2 (12%), KRAS (10.29%), and PIK3CA (9.12%) were the most frequently altered genes. Epstein-Barr virus-positive tumors exhibited enrichment of BCOR, PIK3CA, and ARID1A alterations and reduced TP53 mutations (false discovery rate [FDR] adjusted P < .01). Human epidermal growth factor receptor 2-positive tumors were characterized by coamplification of ERBB2, CCNE1, and MYC (FDR adjusted P < .001), whereas PD-L1 positivity was associated with KRAS and CDKN2A alterations (FDR-adjusted P < .05). Among patients treated with first-line nivolumab plus chemotherapy (n = 269), those with high tumor mutational burden (TMB; ≥10 mutations per megabase) had improved overall survival (v the low TMB subgroup; hazard ratio [HR], 0.48 [95% CI, 0.25 to 0.93]; P = .03), particularly when combined with PD-L1 positivity (v all other biomarker-defined subgroups; HR, 0.33 [95% CI, 0.14 to 0.76]; P = .006). Moreover, as TMB levels increased, patients derived greater survival benefit from nivolumab plus chemotherapy versus chemotherapy alone, even among those with microsatellite-stable tumors. Across treatment regimens, FGFR2 and MET alterations were linked to poorer outcomes, whereas PIK3CA mutations were observed in patients with longer overall survival after first-line chemotherapy. Our findings provide a comprehensive genomic landscape of Korean gastric cancer and underscore the clinical relevance of integrating genomic and established biomarkers to advance precision oncology.

Surgical management of stage IV gastric adenocarcinoma: A systematic review and expert recommendations from the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) and the Spanish Association of Surgeons (AEC).

Dear Editor, I read the recent article with great interest (title: The Relationship of Sarcopenia With Prognosis in Patients Diagnosed with Metastatıc Gastric Cancer Receiving Palliative Chemotherapy) exploring the relationship between sarcopenia and prognosis in metastatic gastric cancer patients on palliative chemotherapy, which was published in your journal [1]. The findings align with a growing body of literature demonstrating that sarcopenia is a clinically significant prognostic factor, yet several points merit emphasis, clarification, or further exploration to strengthen both the interpretation and implications for clinical practice.

In recent years, with the rapid development of medical device and biopharmaceutical technologies, the treatment model of gastric cancer surgery has been undergoing tremendous transformations. From the traditional open surgery model to the minimally invasive surgery model supported by devices such as laparoscopes and robots, the "precision minimally invasive" system integrated with 3D/4K high-definition imaging and fluorescent navigation has greatly expanded the capability boundaries of surgeons. Supported by the theory of high-throughput omics-based molecular typing of tumors, the clinical application of novel drugs such as immunotherapeutics and targeted drugs has further reshaped the treatment landscape of gastric cancer. The advancement of conversion therapy has significantly improved the therapeutic efficacy and prognosis of patients with locally advanced or distant metastatic gastric cancer, and the comprehensive treatment model that combines surgery with chemotherapy, radiotherapy, targeted therapy, immunotherapy and other modalities has become a mainstream trend. The role of surgical procedures is being redefined, and the concept of organ and function preservation has gained greater attention on the premise of ensuring oncological efficacy. Against the backdrop of the continuous evolution of gastric cancer diagnosis and treatment models, the establishment and practice of multidisciplinary treatment (MDT) and shared decision-making (SDM) models have become effective guarantees for enhancing the quality of gastric cancer diagnosis and treatment and improving patient prognosis. It is believed that the in-depth integration of cutting-edge technologies such as artificial intelligence with clinical medicine will enable the diagnosis and treatment of gastric cancer to enter the era of precision more rapidly.

Aim of the study – to comprehensively evaluate the impact of postresection syndrome on the tolerability and efficacy of immunotherapy in patients with metastatic gastric cancer and to determine the role of personalized comprehensive rehabilitation in correcting metabolic-nutritional, electrolyte, and psychological impairments in this vulnerable subgroup. Materials and methods. A prospective randomized study (2021–2025) included 168 patients with histologically confirmed stage IV gastric cancer receiving PD-1 inhibitor immunotherapy (pembrolizumab/nivolumab) in the 3rd-4th line. Patients were randomized into an experimental group (n=82): immunotherapy + comprehensive rehabilitation (nutritional support, H 2 /O 2 inhalations, magnetic therapy, psychological correction, electrolyte balance correction); and a control group (n=86): immunotherapy only. Special focus was placed on the subgroup with prior total gastrectomy (n=84). Results. Gastrectomized patients in the experimental group exhibited a pronounced postresection syndrome: baseline PNI 34.66±2.8 (vs. 38.15±3.5 in non-resected, p=0.0047), hypocalcemia (2.05±0.15 mmol/L), hypomagnesemia (0.61±0.09 mmol/L), and chronic pain (78.6 %). After 6 months, the experimental group demonstrated: maximal PNI increase (+21.54 to 56.20, p&lt;0.001), nitrogen balance normalization (+5.2 g/day, p=0.03), Ca² + elevation (to 2.31 mmol/L) and Mg² + recovery (to 0.87 mmol/L) (p&lt;0.05), and significant EORTC QLQ-C 30 improvement (global QoL +15.2 %, physical functioning +14.8 %, pain reduction –55.6 %, p&lt;0.05). Psychological reasons for therapy discontinuation decreased 3.2-fold (OR=0.31). Confirmed progression (iCPD) among patients with unconfirmed progression (iUPD) at week 8 was significantly lower in the experimental group (45.0 % vs. 72.3 %, p=0.05). Conclusions. Patients with a history of gastrectomy constitute a vulnerable subgroup with severe postresection malabsorption, electrolyte deficiency, and nutritional decompensation that impair immunotherapy tolerability and potentially reduce efficacy. Comprehensive rehabilitation integrating metabolic, nutritional, physical, and psychological support effectively restores homeostasis, improves quality of life, and promotes disease stabilization. These findings justify the early integration of personalized rehabilitation programs into clinical standards for this patient category.

Objective. To evaluate the efficacy and safety of different maintenance therapy regimens in patients with HER2-positive metastatic gastric and gastroesophageal junction cancer. Materials and methods. This retrospective analysis included data from 186 patients who received trastuzumab in combination with platinum-fluoropyrimidine chemotherapy. During the maintenance phase, patients were divided into two groups: trastuzumab monotherapy and trastuzumab plus fluoropyrimidines. Results. No significant differences were observed between the groups in overall survival (OS) or progression-free survival (PFS) (OS: 26.0 vs 24.0 months; PFS: 13.5 vs 13.1 months; p&gt;0.05). Combination therapy was associated with a higher incidence of toxicity, including hand–foot syndrome (19.4 % vs 0.8 %) and cardiotoxicity (11.3 % vs 3.2 %). Conclusion. The continuation of fluoropyrimidines during the maintenance phase does not improve treatment efficacy and increases toxicity. The optimal strategy remains prolonged HER2 blockade with trastuzumab.

The efficacy of locoregional therapy with intraperitoneal (IP) drug delivery plus systemic chemotherapy for peritoneal carcinomatosis is understudied. We investigated progression-free survival (PFS) and overall survival (OS) in patients with peritoneal carcinomatosis from gastric, appendiceal, or small bowel adenocarcinoma who received intravenous (IV) and IP paclitaxel plus capecitabine or nilotinib. Two separate single-institution phase II clinical trials evaluating IP and IV paclitaxel therapy plus capecitabine or nilotinib for peritoneal carcinomatosis were analyzed. Enrolled patients with peritoneal-only metastatic gastric cancer received IP and IV paclitaxel plus capecitabine. Participants with peritoneal carcinomatosis from appendiceal, gastric, or small bowel adenocarcinoma received IP and IV paclitaxel plus nilotinib. Twelve patients with a median age of 46 years (range 38-64) received bidirectional paclitaxel plus capecitabine. Median overall PFS and OS was 5.3 months (95% confidence interval [CI] 1.5-13.3) and 12.5 months (95% CI 4.7-14.7), respectively. Seven patients with peritoneal carcinomatosis from appendiceal, gastric, or small bowel adenocarcinoma with a median age 59 years (range 46-69) received bidirectional paclitaxel plus nilotinib. Median PFS and OS was 3.6 months (range 2.6-6.6) and 8.3 months (range 2.8-10.2), respectively, for those receiving bidirectional paclitaxel plus nilotinib. Adverse events (AEs) were common; grade 3-5 AEs occurred in 90.1% (10/11) of participants receiving IP/IV paclitaxel plus capecitabine and 100% (7/7) of patients receiving IP/IV paclitaxel plus nilotinib. There was no extra-peritoneal disease progression, suggesting tumor confinement among all participants. Bidirectional paclitaxel-based chemotherapy plus capecitabine may delay progression of gastric adenocarcinoma with peritoneal-only metastasis. Bidirectional paclitaxel-based chemotherapy plus nilotinib was associated with mostly stable peritoneal disease in this small, heterogenous cohort. Bidirectional paclitaxel combinations are feasible and may have a role in therapy for disease stabilization in individuals with peritoneal carcinomatosis.

329 Background: Five-year survival of patients with metastatic gastric cancer (mGC) is poor. Tumor characteristics, timing of diagnosis, and treatment patterns differ between patients from Eastern and Western regions. Therefore, we aimed to evaluate treatment patterns and outcomes of patients with mGC in South Korea. Methods: This retrospective study aimed to analyze electronic medical records. Treatment patterns were evaluated in 2,229 patients, and clinical outcomes were assessed in 2,083 patients. Results: The median age of the included patients was 60 (range, 18–92) years (62.8%, male; 95.5% had ECOG of 0–1). Among tested patients, HER2-positivity, MSI-H/dMMR, and PD-L1 22C3 Combine Positive Score ≥1 rates were 16.0%, 4.7%, and 49.1%, respectively. Of the 2,353 patients, 94.7%, 68.0%, and 52.9% received first-line (1L), second-line (2L), third-line (3L) therapy, respectively. Platinum doublets were used for 1L (61.3%); paclitaxel plus ramucirumab, 2L (50.6%); and irinotecan-based therapy, 3L (51.1%). The median overall survival (OS) was 3.8 and 16.3 months in the untreated and treated patients, respectively. Overall, HER2-positive patients treated with HER-2 targeted agent had a longer OS (19.1 months), and those treated with combined HER2-targeted plus immune checkpoint inhibitor (ICI) therapy (23.1 months) had the longest OS. In HER2-negative patients, OS was 15.7 months with chemotherapy, and 17.6 months with combined chemotherapy plus ICI. No survival differences were found between patients treated with oxaliplatin and cisplatin in 1L, irinotecan and taxane in 2L/3L, and across 2L to 3L sequences. Conclusions: Our findings support the benefits of multiline personalized treatments in mGC.

434 Background: In the phase 3 DESTINY-Gastric04 study (NCT04704934), T-DXd significantly improved overall survival versus ramucirumab + paclitaxel as second-line treatment in patients (pts) with HER2-positive (HER2+) metastatic gastric cancer. Accurate determination of HER2+ status is crucial to reliably identify pts likely to benefit from T-DXd. Methods: In DESTINY-Gastric04, biopsies were obtained from pts after progression following prior trastuzumab-based therapy. HER2 status was determined by central testing using immunohistochemistry (IHC; Agilent HercepTest) and in situ hybridization (ISH; Agilent IQ-FISH) from first tissue screening in 2021 until a protocol amendment in 2023, and by central or local testing thereafter. We analyzed HER2 status based on central testing and evaluated concordance between local and central HER2 testing. HER2+ was defined as IHC 3+ or IHC 2+/ISH+. Results: Of 1088 pts who underwent tissue screening, 638 pts underwent main screening, and 494 pts were randomly assigned to the treatment arms. Of 833 pre-randomized subjects with central HER2 testing results, 68% were HER2+ with consistent rates in primary and metastatic tissue specimens (Table) and across laboratory locations. Retrospective central HER2 testing was done for 122 of 133 pts who were randomized in DESTINY-Gastric04 based on HER2+ status by local test. In these pts, positive percentage agreement (PPA) was ~80% regardless of biopsy site (Table). PPA was higher for specimens that were IHC 3+ vs IHC 2+/ISH+ by local test (91% [95% CI, 84%-96%] vs 43% [95% CI, 25%-63%]). Concordance between local and central HER2 status varied across assay types. Conclusions: Results support the use of existing HER2 assays to select pts with gastric cancer for second-line treatment when needed and suggest that both primary and metastatic tissue specimens may be suitable for HER2 testing. Clinical trial information: NCT04704934 . All cases Primary tissue Metastatic tissue Cases with central testing results n = 833 n = 550 n = 283 HER2+, n (%) 564 (68) 366 (67) 198 (70) IHC 3+ 488 (59) 323 (59) 165 (58) IHC 2+/ISH+ 76 (9) 43 (8) 33 (12) Cases with local and central testing results (retrospective) n = 122 n = 82 n = 40 PPA (95% CI), % 80 (71-86) 79 (69-87) 80 (64-91)

Leptomeningeal carcinomatosis (LMC) from gastric cancer is rare but carries a poor prognosis, and its risk factors and clinical presentation remain unclear. Among 3850 patients treated with palliative chemotherapy, those with pathologically or cytologically confirmed LMC were included. Responsiveness to intrathecal methotrexate (IT-MTX) was defined as a malignant cell count < 1/μL on ≥ 2 consecutive cerebrospinal fluid analyses. Survival outcomes were compared across subgroups with different clinical presentations. During a median follow-up of 13.7months, LMC was diagnosed in 0.8% (32/3850) of patients. At the time of LMC diagnosis, 27 patients were undergoing palliative systemic chemotherapy, 4 were diagnosed with recurrence following curative surgery, and 1 was diagnosed with the initial presentation of metastatic gastric cancer. Multivariate logistic regression analysis revealed that signet ring cell carcinoma (SRC) and/or poorly differentiated adenocarcinoma (PD) was the most relevant risk factor for LMC (adjusted odds ratio 4.78; p = 0.036). Thirty patients received IT-MTX, with responders (n = 23) showing longer overall survival (OS) than non-responders (n = 7) (p = 0.004). Among the 29 patients with available data on extracranial disease control, those with controlled extracranial disease at LMC diagnosis (n = 19) demonstrated significantly better OS following IT-MTX than those with progressive extracranial disease (n = 10) (p = 0.023). SRC and/or PD is a key risk factor for LMC, which often arises despite controlled extracranial disease, necessitating early evaluation for neurologic symptoms. Survival outcomes depend on IT-MTX response and the status of extracranial disease.

Background:Metastatic gastric cancer (GC) is biologically heterogeneous; however, current staging classifies all metastatic cases as stage IV without reflecting this variability. Circulating tumor DNA (ctDNA)-derived biomarkers, including maximum somatic allele frequency (MSAF), may serve as surrogates for tumor burden and underlying tumor biology.Objectives:This study aimed to evaluate the prognostic significance of baseline MSAF in patients with metastatic GC receiving first-line palliative chemo or chemoimmunotherapy.Design:This was a retrospective, single-center cohort study of consecutively tested patients.Methods:We analyzed 108 patients with pathologically confirmed metastatic gastric adenocarcinoma who underwent baseline ctDNA next-generation sequencing prior to first-line systemic therapy between December 2022 and April 2024. MSAF was defined as the highest variant allele frequency detected in ctDNA and evaluated as both a continuous and categorical variable. Patients were stratified into MSAF-high and MSAF-low groups using the cohort mean (12.31%) as the cutoff. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier estimation and Cox proportional hazards regression analyses.Results:The MSAF-high group (n = 41) demonstrated significantly inferior OS compared with the MSAF-low group (n = 67; median OS, 10.0 vs 17.6 months; log-rank p = 0.006). PFS showed a nonsignificant trend favoring the MSAF-low group (median PFS, 4.5 vs 8.0 months; p = 0.1). In multivariate analysis (complete-case analysis, n = 70), high MSAF remained independently associated with worse OS (hazard ratio, 2.14; 95% confidence interval: 1.04–4.41; p = 0.039), along with older age and multiple metastatic sites. Tumors in the MSAF-high group more frequently exhibited molecular features such as deficient mismatch repair and high tumor mutational burden.Conclusion:Baseline MSAF is an independent prognostic biomarker in metastatic GC and may reflect underlying biological aggressiveness. Incorporating MSAF into risk stratification frameworks could enhance prognostic classification and inform personalized treatment strategies.

Conversion therapy enables curative-intent resection in patients with initially unresectable or metastatic cancers after effective systemic therapy. Recently, advances in systemic therapy with molecular targeted agents and immune checkpoint inhibitors (ICIs) have renewed clinical and research interest in this approach, particularly for metastatic gastric cancer (GC). This review aimed to summarize the international guidelines and expert consensus informed by contemporary evidence on conversion therapy for metastatic GC, emphasizing the central role of systemic therapy, the emergence of biomarker-driven strategies, and the optimal timing for surgical intervention. Key consensus statements (Bertinoro, OMEC, and KINGCA WEEK 2024) and pivotal studies covering the cytotoxic, targeted, and immunotherapy eras were reviewed, focusing on regimen selection, treatment duration, and prognostic determinants associated with surgical outcomes. According to global guidelines, conversion surgery is not yet standard of care but may be considered for biologically and clinically selected patients demonstrating a major response to systemic therapy. Retrospective and prospective studies have reported a median overall survival of 24-36 months in the cytotoxic era and >48 months in the ICI/targeted era among patients who underwent R0 resection. Emerging evidence supports approximately 6 months of preoperative systemic therapy, followed by R0 resection, and up to one year of postoperative maintenance therapy. Therefore, conversion surgery should be viewed as the culmination of effective systemic therapy rather than as a substitute. A biology-driven, multidisciplinary strategy integrating treatment response assessment and prognostic factor evaluation represents the next frontier in potentially curative management of metastatic GC.