Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma

Abstract

Purpose: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

Materials and methods: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

Results: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21).

Conclusion: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

FIG 1.

Somatic Mutations in 202 patients with ATC. OncoPrint showing recurrently mutated genes identified within the overall ATC cohort. RAS gene family (NRAS, KRAS, and HRAS) mutations are shown together and individually. Of 19 genes that are recurrently mutated, 11 were covered across panels. In the eight genes that were covered in selected panels only, the number assayed indicates the number of patients who were tested with panels covering the specific gene(s). The number and percent mutated indicate the proportion of patients who had mutation(s) detected among those who were assayed. Color key for the types of genetic alterations identified is shown on the bottom legend. ATC, anaplastic thyroid carcinoma.

FIG 2.

OS of patients with ATC by driver mutation status: (A) OS rates at 1, 2, 3, and 5 years and (B) survival analysis. ATC, anaplastic thyroid carcinoma; OS, overall survival.

FIG 3.

Survival outcomes analyses in BRAFV600E-mutated ATC: (A) OS in all patients by driver mutation status and BRAF-directed therapy, (B) OS in BRAFV600E-mutated patients by BRAF-directed therapy status, (C) PFS by TP53 mutation status in patients treated with BRAF-directed therapy, and (D) OS by TP53 mutation status in patients treated with BRAF-directed therapy. ATC, anaplastic thyroid carcinoma; OS, overall survival; PFS, progression-free survival.