ProGRP dynamics as a prognostic predictor in advanced medullary thyroid carcinoma

Objectives: Advanced medullary thyroid carcinoma (MTC) is commonly monitored using calcitonin (CT) and carcinoembryonic antigen (CEA) kinetics. Pro-gastrin-releasing peptide (ProGRP) and carbohydrate antigen 19-9 (CA 19.9) have emerged as potential complementary markers, but their longitudinal prognostic value remains unclear. Methods: This is a retrospective longitudinal cohort study including 23 patients with metastatic MTC followed for a median of 37 months. CT and CEA were measured routinely every three to six months, while ProGRP and CA 19-9 were retrospectively assessed in stored serum samples. Patient-specific log-linear regression was used to calculate biomarker slopes. Discriminative performance for structural progression and disease-related death was evaluated and associations assessed using Kaplan-Meier analysis and log-rank testing. Results: ProGRP slope showed the strongest discrimination for disease-related death, followed by CA 19-9 and CEA, whereas CT slope alone demonstrated limited prognostic value. For structural progression, ProGRP and CEA had the highest performance. A discordant pattern (i.e. increasing ProGRP and/or CA 19-9 vs. decreasing CT) was more frequent in fatal cases. In multivariable penalized models, ProGRP slope remained the most consistently associated marker after internal validation. Kaplan-Meier analysis confirmed earlier progression and reduced survival in patients with higher ProGRP slopes. Conclusions: Dynamic changes in ProGRP were more strongly associated with adverse outcomes than traditional markers in advanced medullary thyroid carcinoma and may reflect aggressive tumor behavior not captured by CT. Due to the limited number of disease-related deaths, hazard ratio estimates for overall survival were imprecise and prospective validation in larger cohorts is warranted.