For locally advanced gastric adenocarcinoma/esophagogastric junction adenocarcinoma, the currently recommended treatment strategy per clinical guidelines is radical gastrectomy combined with perioperative therapy (including chemotherapy, immunotherapy, etc.). This approach involves several cycles of neoadjuvant therapy prior to surgery, followed by the surgical procedure, and then several cycles of adjuvant therapy post-surgery. This regimen is generally considered to offer favorable efficacy, ultimately leading to improved survival outcomes for patients. However, some patients are unable to complete the prescribed postoperative adjuvant therapy due to factors such as poor physical condition after surgery or cumulative treatment toxicity. Findings from the retrospective SPACE-FLOT study preliminarily suggest that for patients with a favorable response to neoadjuvant therapy, postoperative adjuvant therapy may not confer additional survival benefit, while potentially increasing the risk of treatment-related adverse events. Therefore, the investigators aim to utilize the latest technological approaches to identify patients who could safely forgo adjuvant therapy, enabling personalized treatment decisions, reducing unnecessary treatment, and thereby maximizing patients' long-term survival benefits.

To achieve this objective, the investigators have identified circulating tumor DNA (ctDNA) testing as a potential solution. ctDNA refers to DNA fragments released by tumor cells into the extracellular space (e.g., into the bloodstream). By drawing a small amount of peripheral blood and analyzing the ctDNA within, it is possible to detect minimal residual disease (MRD) that is difficult to identify through conventional imaging methods (such as CT or MRI) after treatment. MRD is considered a critical factor that may lead to tumor recurrence. Utilizing ctDNA to detect MRD enables a convenient and accurate assessment of tumor status and treatment efficacy, thereby offering the potential for personalized treatment.

Colorectal cancer represents a cancer type where ctDNA testing has been applied early and is relatively mature. In the field of colorectal cancer, the GALAXY study confirmed that ctDNA positivity can effectively predict patient survival outcomes, with superior performance to other traditional indicators. The study also found that patients with postoperative ctDNA MRD positivity tended to benefit from postoperative adjuvant chemotherapy, whereas those with ctDNA MRD negativity often did not derive such benefit. Subsequently, another randomized controlled trial (the DYNAMIC study) revealed that using ctDNA MRD to guide postoperative adjuvant chemotherapy strategies could effectively reduce unnecessary chemotherapy without adversely impacting patient survival outcomes.

In the field of gastric cancer, studies such as MENCA-GC, CRITICS, and PLAGAST have all demonstrated that postoperative ctDNA can effectively predict patient prognosis in the treatment model of radical gastrectomy combined with perioperative therapy. Additionally, preliminary findings from the ongoing MRD-GATE study indicate that in treatment models without preoperative neoadjuvant therapy (i.e., surgery followed by adjuvant therapy), utilizing ctDNA MRD to guide postoperative adjuvant treatment can also reduce unnecessary chemotherapy without compromising patient survival outcomes.

This study focuses on patients with locally advanced gastric cancer, integrating the latest clinical research advancements, and aims to fill the research gap concerning the efficacy of using ctDNA MRD to guide adjuvant therapy within the context of radical gastrectomy combined with perioperative therapy. This holds significant importance for optimizing treatment strategies and maximizing patient benefits.

Inclusion Criteria:

1. Able to provide written informed consent (ICF) and capable of understanding and agreeing to comply with the study requirements and assessment schedule;

2. Male or female aged ≥ 18 years;

3. Histologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, with clinical TNM stage (according to the 8th edition of the AJCC/UICC clinical TNM staging system for gastric cancer; see Appendix 1) of cIIB-IVA, and the primary gastric tumor assessed as amenable to radical resection;

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix 2), fit to undergo surgical treatment with no contraindications to surgery;

5. Capable of providing adequate tumor tissue obtained via gastroscopy (or other means) prior to neoadjuvant treatment for whole-exome sequencing;

6. Females of childbearing potential must have a negative pregnancy test within 7 days before initiation of neoadjuvant treatment. Males and females of childbearing potential must agree to use adequate contraception during the study period and for 24 months after the last dose of study treatment (see Appendix 3);

7. Hematologic and biochemical parameters meeting the following criteria prior to neoadjuvant treatment:

   • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
   • Platelet count (PLT) ≥ 75 × 10⁹/L
   • Hemoglobin (Hb) ≥ 80 g/L
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)
   • Serum creatinine (Cr) ≤ 1.5 × ULN or estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m²
   • Serum albumin (ALB) ≥ 30 g/L
   • For subjects not receiving anticoagulant therapy: international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; for subjects receiving anticoagulant therapy: PT within the expected therapeutic range for the anticoagulant;

8. No prior anticancer therapy for the current study-related tumor prior to initiation of neoadjuvant treatment.

Exclusion Criteria:

1. Patients deemed by the investigator to have significant contraindications to or intolerance of neoadjuvant/adjuvant therapy;
2. Female patients of childbearing potential who have not undergone surgical sterilization or are not using adequate contraceptive measures, pregnant or lactating women, or male patients planning to father a child within a short period;
3. Any severe or uncontrolled systemic disease, including but not limited to uncontrolled hypertension, active hemorrhage, diabetes mellitus, etc.;
4. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis, human immunodeficiency virus (HIV) infection, etc.;
5. Prior history of malignancy or current presence of another malignancy, except for completely resected basal cell or squamous cell skin cancer, superficial bladder cancer, or in situ carcinoma of the prostate, cervix, or breast with at least 5 years without recurrence;
6. Other conditions deemed by the investigator to render the patient unsuitable for study participation.