Dynamic Changes in Circulating and Tissue Biomarkers and Therapeutic Response to HER2/PD-1 Dual Blockade in
Yueyan Shi1, Jie Zhang1, Jianmei Gu2
1Department of Laboratory Medicine, Nantong Tumor Hospital (Affiliated Tumor Hospital of Nantong University), Nantong, China.
Introduction:
HER2-positive gastric adenocarcinoma demonstrates heterogeneous responses to dual HER2/PD-1 blockade therapy. This study investigated integrated circulating tumor DNA (ctDNA), protein biomarkers, and immune cell profiling for predicting treatment outcomes and monitoring therapeutic resistance.
Methods:
This retrospective analysis included 72 patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma receiving anti-HER2 therapy plus PD-1 inhibitors. Serial blood samples underwent ctDNA sequencing, protein biomarker measurement, and flow cytometric immune cell characterization. Multivariable analysis identified independent predictors and developed an integrated biomarker model for patient stratification.
Results:
Objective response rate was 40.3% with a median progression-free survival of 11.4 months. Sustained ctDNA suppression in 24 patients correlated with prolonged survival compared to early rebound patterns (p = 0.048). Co-occurring genomic alterations in EGFR, PIK3CA, MYC, and FGFR2 were detected in ctDNA and were associated with shorter progression-free survival. CD8+ T-cell increases and natural killer cell activity patterns differed between responders and nonresponders. Multivariable analysis identified composite immune score (HR: 0.58, p = 0.003), tumor stage (HR: 2.31, p < 0.001), and performance status as independent predictors. An exploratory integrated biomarker model stratified patients into risk categories of differing outcomes, although discrimination was modest (area under the curve: 0.65) and requires prospective validation.
Conclusion:
Integrated ctDNA and immune biomarker monitoring may provide prognostic information for dual HER2/PD-1 blockade therapy. Serial molecular profiling enables early resistance detection and identifies evolutionary patterns that may inform therapeutic strategies, though prospective validation is required.
