GENCONCOR-2 is a translational research aimed to compare the molecular profile of primary tumors and their matched brain metastases in gastroesophageal cancers, including cancer of the esophagus, gastroesophageal junction, and stomach. The study is based on the previously established international GASTROBRAIN cohort (ClinicalTrials.gov ID: NCT07448493), which provides comprehensive clinicopathological and treatment data for over 230 patients. It will be conducted by retrospective analysis of paired samples of histological material (primary tumor and corresponding brain metastasis) with determination of HER2 expression status (IHC ± FISH), MSI status (IHC ± PCR), PD-L1 combined positive score (CPS), and CLDN18.2 expression status (IHC)
Men and women aged 18 years or older included in the GASTROBRAIN study with available clinicopathological and treatment data.
Histologically confirmed gastric adenocarcinoma, esophageal carcinoma (adenocarcinoma or squamous cell carcinoma), or gastroesophageal junction adenocarcinoma.
History of neurosurgical resection of brain metastases with available archival tissue material, and histological confirmation of metastatic lesion originating from gastroesophageal cancer.
Availability of paired FFPE tissue samples from primary tumor and matched brain metastasis.
Synchronous or metachronous multiple primary malignancies involving sites other than the stomach, esophagus, or gastroesophageal junction.
Primary tumor located outside the gastrointestinal tract.
Histologically confirmed non-epithelial gastrointestinal malignancy (e.g., neuroendocrine tumors, sarcoma, gastrointestinal stromal tumor, lymphoma).
Intact brain parenchyma (e.g., metastases confined to skull bones or soft tissues of the head without brain parenchymal involvement).
The study population consists of adult patients (≥ 18 years) with histologically confirmed adenocarcinoma of the stomach, adenocarcinoma or squamous cell carcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction, and radiologically ± histologically documented brain metastases. All patients were previously enrolled in the parent GASTROBRAIN study and have available paired archival FFPE tissue samples from both the primary tumor and the matched brain metastasis.
Cohort
Retrospective
HER2 Testing
Diagnostic testAssessment of HER2 status by immunohistochemistry (IHC) using SP3 antibody clone (DAKO) on Ventana GX platform with OptiView detection system. Cases with IHC 2+ will undergo confirmatory in situ hybridization (FISH, CISH, or SISH).
MSI Testing
Diagnostic testDetermination of microsatellite instability status by immunohistochemistry (IHC) for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) ± PCR-based analysis using five mononucleotide repeat markers (BAT25, BAT26, NR21, NR24, NR27).
PD-L1 Testing
Diagnostic testAssessment of PD-L1 expression by immunohistochemistry (IHC) using DAKO 22C3 antibody clone on Dako Link48 platform with EnVision Flex detection system. Results reported as Combined Positive Score (CPS), defined as number of PD-L1-stained cells divided by total viable tumor cells, multiplied by 100.
CLDN18.2 Testing
Diagnostic testAssessment of CLDN18.2 expression by immunohistochemistry (IHC) using VENTANA CLDN18 (43-14A) assay on Ventana platform. Positive expression defined as moderate-to-strong (2+/3+) complete, basolateral, or lateral membranous staining in ≥ 75% of viable tumor cells.
Overall Molecular Discordance Rate (%)
Proportion of cases with discordant biomarker status (HER2, MSI, PD-L1 CPS, CLDN18.2) between primary gastroesophageal cancer and matched brain metastasis, calculated as the number of discordant pairs divided by total number of analyzed paired samples. Discordance will be assessed both overall and for each individual biomarker.
Overall Survival (OS)
Time from the date of brain metastasis diagnosis to the date of death from any cause or last follow-up (censored)
Time to Intracranial Progression (TTIP)
Time from the date of initial gastric and esophageal cancer diagnosis to the date of first BM detection. Based on this interval, patients will be categorized as synchronous (≤ 60 days from primary diagnosis) or metachronous (\> 60 days)
Central Nervous System Progression-Free Survival (CNS-PFS)
Time from the date of first local treatment for brain metastases to the date of subsequent intracranial progression or last instrumental follow-up (censored). Intracranial progression includes: continued growth of treated lesion (≤ 6 months after treatment), local recurrence of treated lesion (\> 6 months after treatment), or development of new intracranial lesions
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