Abstract 1925P
Background
Despite good prognosis, about 5% of patients (pts) with DTC will develop metastasis (mDTC) which eventually fails to respond to radioactive iodine (RAI). Currently, no effective biomarkers are available to identify prognostic groups in DTC. DNA methylation, one of the most studied epigenetic mechanisms, is altered in thyroid cancer. DNA hypomethylation is associated with the progression of thyroid cancer, and our group identified a prognostic signature of 156-CpGs associated with mDTC, independently of histology and BRAF/RAS mutations, that differs between metastatic (both synchronous and metachronous) and low-risk non-metastatic primary tumors. The aim of this study is to evaluate the prognostic and predictive value of the 156-CpG signature and global DNA hypomethylation in RAI-refractory (RAI-R) mDTC pts.
Methods
RAI-R mDTC pts treated with at least one multikinase inhibitor (MKI) were included. DNA methylation was profiled using Illumina Infinium Human MethylationEPIC. The stepwise AIC method was used for variable selection and leave-one-out cross-validation method to evaluate predictive performance of the model. Selected candidate biomarkers were validated by bisulfite pyrosequencing. DNA global hypomethylation was assessed using Quantification of Unmethylated Alu (QUAlu) technique.
Results
15 RAI-R mDTC pts were included. The 156-CpG methylation signature identified in DTC was validated in RAI-R mDTC. Using 4 CpGs from the 156-signature we developed a high classification power model that predicted metastasis and RAI-R status in thyroidectomy samples. In addition, we established new quantitative DNA methylation assays based on pyrosequencing to measure the DNA methylation of these 4 CpGs. Predictive analysis revealed that most pts with complete or partial response to MKI did not show global DNA hypomethylation while those presenting stable or progressive disease were increasingly affected by global DNA hypomethylation.
Conclusions
We developed a methylation algorithm to predict distant metastases and RAI-R status in pts with DTC, easily implementable in clinical practice. Increased global DNA hypomethylation seems to be associated with a worse response to MKI in RAI-R mDTC pts.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Vall d'Hebron Institute of Oncology (VHIO).
Funding
Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE).
Disclosure
J. Hernando: Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: AAA; Speaker Bureau/Expert testimony: Angelini. J. Capdevila: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Ipsen; Honoraria (self): Exelixis; Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): AAA; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Merck Serono. All other authors have declared no conflicts of interest.