# Plasma WFDC2 (HE4) as a Predictive Biomarker for Clinical Outcomes in Cancer Patients Receiving Anti-PD-1 Therapy: A Pilot Study

## TL;DR

This study suggests that measuring plasma WFDC2 levels could help predict which cancer patients may not benefit from anti-PD-1 therapy, potentially guiding personalized treatment decisions.

## Contribution

The study introduces plasma WFDC2 as a novel predictive biomarker for anti-PD-1 therapy outcomes, outperforming existing biomarkers like soluble PD-L1 and PD-1.

## Key findings

- Higher increases in plasma WFDC2 levels after treatment correlated with worse overall and progression-free survival.
- WFDC2 demonstrated better predictive performance than soluble PD-L1 and PD-1 in ROC analyses.
- Combining WFDC2 with other biomarkers improved prediction accuracy for treatment outcomes.

## Abstract

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, selecting patients who will benefit from ICIs remains challenging. In this exploratory study, we evaluated plasma WFDC2 (HE4) levels as potential dynamic biomarkers in patients treated with anti-PD-1 antibodies. WFDC2 levels increased significantly after treatment initiation, and greater increases correlated with worse overall survival, progression-free survival, and tumor progression. Compared with soluble PD-L1 and PD-1, WFDC2 demonstrated higher predictive performance in receiver operating characteristic (ROC) analyses. Combining WFDC2 with other biomarkers enhanced prediction accuracy. These findings suggest that monitoring WFDC2 levels during treatment could enable the early identification of patients unlikely to respond to ICIs and support personalized therapy decisions. However, larger studies are needed to validate its utility across different cancer types and treatment settings.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy.