Growth and differentiation factor-15 (GDF-15) is a divergent member of the transforming growth factor β family associated with pathological conditions, including myocardial ischemia, autoimmune disease, and cancer. Studies on the role of GDF-15 in cancer are limited and controversial. Radioactive iodine (131I) ablation of the post-surgical thyroid remnants, as an immunomodulatory tool, is the standard treatment for differentiated thyroid carcinomas (DTC) and DTC associated with type 2 diabetes mellitus (DTC+T2DM). Given the aggressive nature of HER2-positive breast cancer, neoadjuvant dual anti-HER2 blockade (trastuzumab + pertuzumab) in combination with chemotherapy has been shown to improve clinical outcomes through immune system activation. We hypothesized that the predictive value of GDF-15 as a biomarker in DTC and HER2-positive breast cancer might plausibly be linked to its immune-regulatory function.
Peripheral venous blood was collected from 56 female patients with DTC (mean age 57.3±9.1 years) and 11 with DTC+T2DM (mean age 61.6±7.8 years) before and four days after 131I therapy and from 22 female patients presenting HER2-positive breast tumors (mean age 55.5±9.8 years) before and after neoadjuvant treatment. The serum levels of GDF-15 were measured by ELISA.
GDF-15 concentration was higher in the HER2-positive breast tumors than in the DTC group (1522.4 pg/mL vs. 915.02 pg/mL, P < 0.001). Regarding the DTC study group, the association of DTC with T2DM led to higher GDF-15 serum levels (P < 0.001). A modulation in GDF-15 level was measured in response to HER2 inhibitors treatment (reduction by 18.8%). In the DTC and DTC+T2DM study groups, the 131I effect was illustrated by a GDF-15 significant increase (97.9% and 169.8%, respectively) in a dose-dependent fashion.
The described associations and mechanistic data suggest that GDF-15 might be a radiation-induced early biomarker in DTC patients. Furthermore, GDF-15 may act as a biomarker of response to action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. With a better understanding of the upstream cancer pathways reflected by GDF-15, new treatment targets may emerge.
The authors.
This work was supported by a grant from the Romanian Ministry of Education and Research, CCCDI - UEFISCDI, project number PN-III-P2-2.1-PED-2019-3313, within PNCDI III.
All authors have declared no conflicts of interest.