Vivian E. Strong

Purpose: Perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is a guideline-recommended standard for patients with resectable gastric cancer or gastroesophageal junction adenocarcinoma globally. Guidance is limited on patient selection, nutritional optimization, and toxicity management within existing guidelines. This study aimed to develop an international consensus to address these management gaps. Methods: A modified Delphi methodology, informed by the RAND/UCLA Appropriateness Method, was conducted virtually between March and August 2025. A multidisciplinary panel of 16 experts independently rated draft clinical statements across multiple domains. Responses were anonymized, with structured, iterative rounds of feedback and re-rating. Consensus was defined a priori as a median score of 7-9 (appropriate) or 1-3 (inappropriate) with a disagreement index ≤1.0. Results: Consensus was reached on 66.3% of the statements. Experts agreed that patients aged >70 years should not be routinely excluded from perioperative FLOT but require comprehensive assessment; inclusion of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 is appropriate, and ECOG PS 0-2 may be considered on a case-by-case basis. Adequate organ function, correction of baseline conditions, hepatitis B screening, and dihydropyrimidine dehydrogenase testing are appropriate before FLOT initiation. Universal baseline nutritional screening and support, proactive intervention for malnourished patients, and structured physical activity were endorsed. Surgical planning was supported through multidisciplinary input, with defined perioperative windows, individualized dosing, and flexibility in pre-/postoperative cycles. For toxicity management, the panel supported dose modification over drug omission, where possible. Conclusion: This Delphi consensus provides expert-driven, practice-oriented advisories codifying fitness-based selection, nutrition-forward optimization, and pragmatic toxicity management. The resulting guidance builds on current standards and provides internationally applicable consensus statements to ultimately enhance patient care.

The immune composition of solid tumors is typically inferred from biomarkers, such as histologic and molecular classifications, somatic mutational burden, and PD-L1 expression. However, the extent to which these biomarkers predict the immune landscape in gastric adenocarcinoma—an aggressive cancer often linked to chronic inflammation—remains poorly understood. We leveraged high-dimensional spectral cytometry to generate a comprehensive single-cell immune landscape of tumors, normal tissue, and lymph nodes from patients in the Western Hemisphere with gastric adenocarcinoma. The immune composition of gastric tumors could not be predicted by traditional metrics such as tumor histology, molecular classification, mutational burden, or PD-L1 expression via IHC. Instead, our findings revealed that innate immune surveillance within tumors could be anticipated by the immune profile of the normal gastric mucosa. Additionally, distinct T-cell states in the lymph nodes were linked to the accumulation of activated and memory-like CD8+ tumor-infiltrating lymphocytes. Unbiased reclassification of patients based on tumor-specific immune infiltrate generated four distinct subtypes with varying immune compositions. Tumors with a T cell–dominant immune subtype, which spanned The Cancer Genome Atlas molecular subtypes, were exclusively associated with superior responses to immunotherapy. Parallel analysis of metastatic gastric cancer patients treated with immune checkpoint blockade showed that patients who responded to immunotherapy had a pretreatment tumor composition that corresponded to a T cell–dominant immune subtype from our analysis. Taken together, this work identifies key host-specific factors associated with intratumoral immune composition in gastric cancer and offers an immunological classification system that can effectively identify patients likely to benefit from immune-based therapies.

PURPOSE: We sought to characterize the genomic landscape of gastroesophageal adenocarcinoma (GEA) using next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA), compare the genomic profile to tissue NGS, and determine the association of circulating tumor DNA (ctDNA) detection with clinical outcomes. METHODS: In this prospective biospecimen-collection study (2017-2022), cfDNA was analyzed using a clinically validated 129-gene tumor-informed NGS assay Memorial Sloan Kettering-Analysis of Circulating cfDNA to Evaluate Somatic Status (MSK-ACCESS); tissue-NGS was performed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: In total, 169 patients with GEA underwent baseline molecular profiling of cfDNA; 93 had localized disease, 55 had untreated metastatic disease, and 21 had progressive metastatic disease. The frequency of the most common alterations was similar between platforms, although copy-number alterations were detected less frequently in plasma than in tissue (10% v 40%; P < .001). Matched-tumor NGS was conducted in 154 patients (91%). Baseline ctDNA detection and on-treatment clearance were associated with improved overall survival and recurrence-free survival in patients with localized disease and progression-free survival in patients with metastatic disease. Baseline ctDNA detection was a stronger predictor of overall survival than American Joint Committee on Cancer (AJCC) clinical stage and positively predicted lymph node metastasis in 87% of cases. Trends in variant allele fractions correlated with pathologic responses to neoadjuvant therapy more closely than fluorodeoxyglucose-positron emission tomography standard uptake values. Persistence or resurgence of ctDNA was associated with worse survival and forecasted recurrent disease a median of 7 months sooner than imaging. CONCLUSION: cfDNA analysis using MSK-ACCESS in patients with GEA is a valuable adjunctive clinical tool that enhances molecular profiling, prognostication, treatment response assessment, and detection of recurrent disease in conjunction with tissue NGS, imaging, and AJCC clinical staging criteria.