Genomic Landscape and Clinical Features of Advanced Thyroid Carcinoma: A National Database Study in Japan

Abstract

Context: The relationship between the genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported.

Objective: To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy.

Methods: We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53 543 patients in the database.

Results: The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53 alterations independently predicted worse overall survival (hazard ratio = 2.205, 95% confidence interval: 1.135-4.283). In anaplastic thyroid carcinoma, no genetic alterations were associated with overall survival.

Conclusion: Genetic abnormalities with treatment options were found in 62.7% of advanced thyroid carcinomas. TP53 abnormality was an independent poor prognostic factor for overall survival in differentiated thyroid carcinoma. The time to treatment failure for lenvatinib was not different based on genetic profile.

Keywords: comprehensive genetic profiling test; fusions; gene; mutations; targeted therapy; thyroid carcinoma.

Figure 1.

Flow diagram of the study.

Figure 2.

(A) Overview of the most common genomic alterations. The right bar shows the number and the frequency of cases with gene alterations in each gene. (B) The frequency of representative driver genes. Abbreviations: ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; WDTC, well-differentiated thyroid carcinoma.

Figure 3.

Kaplan–Meier curves of TTF according to first-line lenvatinib therapy. (A) TTF by histological types; (B) TTF of DTC and PDTC classified as BRAF-positive, RAS-positive, and both negative; (C) TTF of ATC classified as BRAF-positive, RAS-positive, and both negative; (D) TTF of PTC by BRAF and TERT promoter mutations. Abbreviations: ATC, anaplastic thyroid carcinoma; DTC, differentiated thyroid carcinoma; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; TTF, time to treatment failure; WT, wild-type.

Figure 4.

Kaplan–Meier curves of OS. (A) OS by histological types; (B) OS of DTC and PDTC by BRAF V600E mutation status; (C) OS of DTC and PDTC by TP53 abnormality; (D) OS of PTC by BRAF and TERT promoter mutations. Abbreviations: ATC, anaplastic thyroid carcinoma; DTC, differentiated thyroid carcinoma; FTC, follicular thyroid carcinoma; OS, overall survival; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma.