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Exploratory Study Identifies Prognostic Biomarkers in Differentiated Thyroid Cancer

Darcy Lewis
Published Online:4:01 PM, Tue October 29, 2019
Marcia S. Brose, MD, PhD
Marcia S. Brose, MD, PhD
A new exploratory study has found that increased levels of plasma VEGF-A and serum thyroglobulin adversely affected clinical outcomes in patients with radioactive iodine-refractory (RAI) differentiated thyroid cancer (DTC), although no biomarker successfully predicted sorafenib (Nexavar) response. This study, which was published recently in Clinical Cancer Research, was a retrospective analysis conducted using samples from the earlier phase III DECISION trial.1,2

“[E]levated baseline levels of plasma VEGF-A, serum thyroglobulin, and a combined thyroglobulin/VEGF-A signature were independently associated with poor prognosis,” wrote the study authors, led by Marcia S. Brose, MD, PhD, of the University of Pennsylvania. “[T]hyroglobulin changes over time may be a pharmacodynamic biomarker of tumor response or progression. BRAF and RAS mutations were prognostic of PFS [progression-free survival] in univariate analyses but not independently prognostic in multivariate models.”

Elevated baseline VEGF-A was independently associated with poor prognosis for progression-free survival (PFS; HR, 1.82; 95% CI, 1.38-2.44; = .0007), overall survival (OS; HR, 2.13; 95% CI, 1.37-3.36; = .013), and disease control rate (DCR; odds ratio [OR], 0.30; = .009). 

Brose et al also found that elevated baseline thyroglobulin was independently associated with poor PFS (HR, 2.03; 95% CI, 1.52-2.71; <.0001) and DCR (OR, 0.32; = .01). Combined VEGF-A/thyroglobulin signatures correlated only with a poor PFS (HR, 2.12; 95% CI, 1.57-2.87; <.00001).

DECISION was a double-blind, randomized phase III study that showed that sorafenib significantly improved PFS compared with placebo in patients with locally advanced or metastatic, progressive DTC that was refractory to RAI. The primary endpoint was PFS, assessed by central review every 8 weeks. Patients received study medication until disease progression or unacceptable toxicity, and those randomized to placebo were allowed to receive sorafenib upon disease progression.

This analysis was based on plasma protein samples that were collected at baseline in DECISION. Of the randomized population of 417 patients, baseline plasma biomarker data were available for 395 patients (94.7%). Serum thyroglobulin data were available for 403 patients (96.6%). Additionally, plasma protein subpopulation patient demographics were similar to those in the overall study population, including histologic distribution, and were well balanced between the sorafenib and placebo arms.

Brose et al analyzed 15 potential biomarkers that were known or suspected to be relevant to the mechanism of action of sorafenib and/or to thyroid carcinoma outcomes. They used commercially available bead-based multiplex assays and enzyme-linked immunosorbent assay kits to test the plasma proteins.

The authors analyzed the biomarkers for their prognostic value as well as their ability to predict benefit from sorafenib. They also analyzed PFS, OS, and DCR.

Brose et al found that patients who initially received placebo but crossed over to sorafenib treatment also experienced a decrease in serum thyroglobulin over time. Additionally, 76.0% of patients in the sorafenib group and 13.6% of patients in the placebo group had a thyroglobulin decrease of ≥30% (<.001), while 58.9% and 7.3%, respectively, achieved a decrease of ≥50% (<.001). A decrease in serum thyroglobulin of ≥30% during treatment correlated with improved best response, they wrote.

Upon analyzing the prognostic value of tumor mutations in the placebo cohort, Brose et al found that BRAFmutations were associated with longer PFS than wild-type in the genetic subpopulation (HR, 0.51; 95% CI, 0.32-0.83; = .006). The results were similar in the papillary carcinoma patient subset (HR, 0.60; 95% CI, 0.35-1.04; = .066). However, patients with a RAS mutation experienced shorter PFS compared with those who had wild-type disease (HR, 1.8; 95% CI, 1.08-2.99; = .022).

In attempting to stratify patients who had elevated VEGF-A at baseline into low and high risk groups, the authors identified an optimal VEGF-A cut point of approximately 9.0 pg/mL, which corresponds to approximately the 40th percentile of VEGF-A levels. Because both the low-VEGF-A and high-VEGF-A groups showed benefit from treatment with sorafenib, they concluded that VEGF-A levels were not predictive for sorafenib benefit.

Although elevated baseline serum thyroglobulin levels were independently associated with poor prognosis for PFS and DCR, they did not affect OS. The authors performed various analyses to determine the optimal thyroglobulin cutoff level for effective risk stratification. These results ranged from 324 ng/mL (equivalent to the 46th percentile) to 2882 ng/mL (equivalent to the 71st percentile). 

“All thyroglobulin subgroups benefited from sorafenib treatment for PFS, suggesting that baseline serum thyroglobulin levels do not predict benefit from sorafenib in DTC,” Brose et al wrote.

In considering the effects of changes in thyroglobulin levels during treatment, Brose et al found that a decrease of ≥30% during treatment was associated with improved best response and longer PFS. But since many patients with stable disease experienced a rapid decrease in thyroglobulin levels during treatment, radiologic criteria should still be used to determine treatment length since individual serum measurements may not capture tumor progression, they wrote.

As for study limitations, Brose et al noted that the DECISION trial was powered only to evaluate clinical endpoints, not biomarker analyses. 
  1. Brose MS, Schlumbeger M, Jeffers M, et al. Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase 3 DECISION Trial [published online September 26, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-3439. 
  2. Brose MS, Nutting CM, Jarzab Bet al; DECISION Investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet.2014;384(9940):319-328. doi: 10.1016/S0140-6736(14)60421-9.

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