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<p>Gastric adenocarcinoma carries high mortality despite modern multimodal therapy. Reliable biomarkers that refine prognosis and suggest therapeutic strategies are needed. We evaluated the clinicopathologic and prognostic significance of folate receptor-alpha (FOLR1) expression in a large single-institution cohort. We retrospectively analyzed 259 gastrectomy specimens (2016–2025). Immunohistochemistry included FOLR1 (H-score 0–300), HER2, PD-L1 (CPS; positive if ≥ 1), p53 status, and MMR proteins (MLH1/MSH2/MSH6/PMS2). The FOLR1 cut-off for recurrence-free survival (RFS) was derived by Receiver operating characteristic(ROC) analysis. Associations were tested with Chi-square or Fisher’s exact tests and Spearman correlation; survival was assessed by Kaplan–Meier and Cox regression. ROC for RFS yielded an area under the curve (AUC) of 0.653 (95% CI 0.578–0.728; <i>p</i> &lt; 0.001) and defined a FOLR1 H-score cut-off of 40; ROC for overall survival (OS) was not significant (AUC 0.528; <i>p</i> = 0.443). Using this threshold, FOLR1-high tumors (≥ 40; <i>n</i> = 48) showed significantly shorter RFS (mean 24.1 vs 266.6&#xa0;months; log-rank <i>p</i> &lt; 0.001) and shorter OS (mean 32.4 vs 53.9&#xa0;months; p = 0.047) than FOLR1-low tumors. On univariate analysis, FOLR1-high predicted inferior RFS (HR 4.15; 95% CI 2.67–6.47; <i>p</i> &lt; 0.001); in multivariate Cox modeling it remained an independent predictor (HR 1.99; 95% CI 1.15–3.45; <i>p</i> = 0.015). FOLR1-high status associated with advanced T stage (<i>p</i> = 0.045), vascular invasion (<i>p</i> &lt; 0.001), higher M1 frequency (<i>p</i> &lt; 0.001), and proximal location (<i>p</i> = 0.038). It correlated with PD-L1 positivity (<i>p</i> &lt; 0.001; FOLR1 H-score vs PD-L1 CPS Spearman r = 0.286; <i>p</i> &lt; 0.001), HER2 positivity (<i>p</i> &lt; 0.001), and p53 mutant pattern (<i>p</i> &lt; 0.001), and was inversely associated with MMR deficiency (<i>p</i> = 0.010). N-stage distribution was not different overall, although a linear trend toward higher nodal stage with FOLR1-high was observed (<i>p</i> = 0.013). No significant associations were found with Lauren or WHO subtype, histologic grade, lymphatic or perineural invasion, extracapsular extension, neoadjuvant therapy, age, or sex. High FOLR1 expression identifies a biologically aggressive subset of gastric adenocarcinoma with inferior RFS and independent prognostic value. Its concurrent association with PD-L1 and HER2, together with relative absence in dMMR tumors, supports biomarker-guided strategies that consider FOLR1 alongside HER2 and PD-L1, and provides a rationale to explore FOLR1-targeted therapies in selected patients.</p>

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Clinicopathologic and prognostic significance of FOLR1 expression in gastric adenocarcinoma and its association with PD-L1, HER2, MMR, and p53 status

  • 期刊论文

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  • 发表日期：

    2026年2月27日

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  • Ahmet Erbağcı,
  • Hatice Şeneldir,
  • Tuçe Söylemez Akkurt,
  • Şurahbil Yağbasa,
  • Ayşe Nur Toksöz Yıldırım

摘要

Gastric adenocarcinoma carries high mortality despite modern multimodal therapy. Reliable biomarkers that refine prognosis and suggest therapeutic strategies are needed. We evaluated the clinicopathologic and prognostic significance of folate receptor-alpha (FOLR1) expression in a large single-institution cohort. We retrospectively analyzed 259 gastrectomy specimens (2016–2025). Immunohistochemistry included FOLR1 (H-score 0–300), HER2, PD-L1 (CPS; positive if ≥ 1), p53 status, and MMR proteins (MLH1/MSH2/MSH6/PMS2). The FOLR1 cut-off for recurrence-free survival (RFS) was derived by Receiver operating characteristic(ROC) analysis. Associations were tested with Chi-square or Fisher’s exact tests and Spearman correlation; survival was assessed by Kaplan–Meier and Cox regression. ROC for RFS yielded an area under the curve (AUC) of 0.653 (95% CI 0.578–0.728; p < 0.001) and defined a FOLR1 H-score cut-off of 40; ROC for overall survival (OS) was not significant (AUC 0.528; p = 0.443). Using this threshold, FOLR1-high tumors (≥ 40; n = 48) showed significantly shorter RFS (mean 24.1 vs 266.6 months; log-rank p < 0.001) and shorter OS (mean 32.4 vs 53.9 months; p = 0.047) than FOLR1-low tumors. On univariate analysis, FOLR1-high predicted inferior RFS (HR 4.15; 95% CI 2.67–6.47; p < 0.001); in multivariate Cox modeling it remained an independent predictor (HR 1.99; 95% CI 1.15–3.45; p = 0.015). FOLR1-high status associated with advanced T stage (p = 0.045), vascular invasion (p < 0.001), higher M1 frequency (p < 0.001), and proximal location (p = 0.038). It correlated with PD-L1 positivity (p < 0.001; FOLR1 H-score vs PD-L1 CPS Spearman r = 0.286; p < 0.001), HER2 positivity (p < 0.001), and p53 mutant pattern (p < 0.001), and was inversely associated with MMR deficiency (p = 0.010). N-stage distribution was not different overall, although a linear trend toward higher nodal stage with FOLR1-high was observed (p = 0.013). No significant associations were found with Lauren or WHO subtype, histologic grade, lymphatic or perineural invasion, extracapsular extension, neoadjuvant therapy, age, or sex. High FOLR1 expression identifies a biologically aggressive subset of gastric adenocarcinoma with inferior RFS and independent prognostic value. Its concurrent association with PD-L1 and HER2, together with relative absence in dMMR tumors, supports biomarker-guided strategies that consider FOLR1 alongside HER2 and PD-L1, and provides a rationale to explore FOLR1-targeted therapies in selected patients.