Exp Clin Endocrinol Diabetes 2014; 122 - OP7_37
DOI: 10.1055/s-0034-1372012

Association between tumor BRAF and RAS mutation status and clinical outcomes in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) randomized to sorafenib or placebo: sub-analysis of the phase III DECISION trial

R Paschke 1, MS Brose 2, C Nutting 3, YK Shong 4, SI Sherman 5, JWA Smit 6, J Chung 7, I Molnar 8, M Jeffers 8, C Pena 9, M Schlumberger 10
  • 1Leipzig University, Department of Endocrinology, Leipzig, Germany
  • 2Abramson Cancer Center of the University of Pennsylvania, Department of Medicine Division of Hematology/Oncology, Philadelphia, United States
  • 3Royal Marsden Hospital and The Institute of Cancer Research, Clinical Oncology, London, United Kingdom
  • 4Asan Medical Center and University of Ulsan College of Medicine, Department of Internal Medicine, Seoul, Korea, Republic of
  • 5MD Anderson Cancer Center, Department of Endocrine Neoplasia & Hormonal Disorders, Houston, United States
  • 6Radboud University Nijmegen Medical Center, Department of Medicine Division of Endocrinology, Nijmegen, Netherlands
  • 7Bayer HealthCare Pharmaceuticals, Global Clinical Development, Whippany, United States
  • 8Bayer HealthCare Pharmaceuticals, Clinical Sciences, Whippany, United States
  • 9Bayer HealthCare Pharmaceuticals, Clinical Biomarkers, Whippany, United States
  • 10Institut Gustave-Roussy, Nuclear Medicine and Endocrine Oncology, Villejuif, France

Background: We recently reported that treatment of RAI-refractory DTC patients with sorafenib reduced the risk of progression or death by 42% compared to placebo in the randomized, phase III trial DECISION. We now examined BRAF and RAS mutations as possible prognostic biomarkers and as predictors of sorafenib efficacy in RAI-refractory DTC patients.

Methods: Archived tumor samples were analyzed for 238 mutations in 19 common oncogenes (Sequenom OncoCarta 1.0).

Results: Tumor mutation data was available from 256 patients (61.4% of the study population); 126 in sorafenib arm and 130 in the placebo arm. Demographics of the genetic subgroup were similar to the overall study population. BRAF and RAS mutations were detected in 30.1% and 19.5% of patients, respectively, and were well balanced across arms. Other point mutations occurred in less than 5% of patients, with 47.3% of patients having no detectable mutations. Both wtBRAF (n = 92) and mutant (n = 34) patients treated with sorafenib had improved PFS vs. placebo (n = 87 and 43, respectively) (wtBRAF: HR = 0.55, p < 0.001; mBRAF: HR = 0.46, p = 0.02; interaction p-value = 0.65). BRAF mutations were primarily observed in patients with papillary histology (72 of 77) and analysis of this subset yielded similar results; wtBRAF: HR = 0.58, p = 0.05; mBRAF: HR = 0.40, p = 0.008; interaction p-value = 0.39.

Likewise, sorafenib-treated patients benefited independently of RAS mutation status in terms of PFS prolongation (wtRAS: sorafenib n = 102, placebo n = 104, HR = 0.60, p = 0.004; mRAS: sorafenib n = 24, placebo n = 26, HR = 0.49, p = 0.045; interaction p-value = 0.42 Multivariate analysis indicated that neither BRAF or RAS mutations were independently prognostic for PFS.

Conclusion: These exploratory analyses suggest that mutant RAS and mutant BRAF are not prognostic or predictive factors for PFS in RAI-refractory DTC patients. Patients benefited from sorafenib treatment in terms of PFS prolongation independent of BRAF and RAS mutation status.