High tissue factor (CD142) expression identifies a poor-prognosis subgroup of esophageal and esophagogastric junction adenocarcinoma

Background Tissue Factor (TF/CD142) is an emerging antibody–drug conjugate (ADC) target, but its prevalence, prognostic value and molecular context in adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJ) remain uncharacterized. Methods TF immunohistochemistry was scored by H-score (0–300) on a tissue microarray of 1,120 resected EAC/EGJ adenocarcinomas (1996–2020); the 1,006 assessable primary tumors formed the analysis cohort. Tumors were graded TF-negative (≤ 10), TF-low (11–100) or TF-high (> 100) and related to clinicopathologic features, tissue compartment, neoadjuvant therapy, HER2, Claudin 18.2 (CLDN18.2), MET, mismatch-repair (MMR) status and overall survival. Primary tumors and lymph-node metastases were compared within patients. Results TF was positive in 486 of 1,006 tumors (48.3%) and high in 225 (22.4%). TF-positive tumors were more often pT3–4 ( p < 0.001) and node-positive ( p = 0.002), and TF grade agreed moderately between paired primary tumors and lymph-node metastases ( n = 247; κ 0.57 at H-score > 100) without a systematic shift ( p = 0.91). TF was independent of HER2 ( p = 0.80) and MMR status ( p = 0.14), inversely associated with CLDN18.2 (TF-high vs. TF-negative: 12.8% vs. 30.2%; p < 0.001) and positively with MET overexpression (8.6% vs. 1.0%; p < 0.001). Over a median follow-up of 67 months (749 patients, 428 deaths), the survival detriment was confined to TF-high tumors (median overall survival 19.3 vs. 36.8 and 42.2 months; p < 0.001). Adjusted for age, pT, nodal status and neoadjuvant therapy, TF-high remained adverse (HR 1.67, 95% CI 1.32–2.11; p < 0.001) whereas TF-low did not (HR 0.97; p = 0.83). The TF-high association held with TF as a continuous variable (HR 1.11 per 50 points; p < 0.001) and after adjustment for treatment era, margin, grade and lymphovascular invasion. TF positivity was similar in treatment-naïve and in residual post-neoadjuvant tumors ( p = 0.89), but TF-high concentrated in poorly regressed tumors (29.2% vs. 11.6%; trend p < 0.001). Conclusions TF is expressed in nearly half of EAC/EGJ adenocarcinomas and at high level in about one quarter, where it is independently associated with shorter overall survival. TF expression remains prevalent in residual tumors after neoadjuvant therapy and marks a compartment distinct from HER2 and CLDN18.2 and enriched for MET. TF-high is a candidate biomarker for prospective trials of TF-directed ADCs, in which its predictive value and the H-score > 100 threshold need testing.