TERT Mutations Indicative of Poor Outcomes in Non-Aggressive Thyroid Cancer

A prospective, observational study recently published in theEuropean Journal of Cancerhelped to clarify the prognostic role ofTERTpromoter mutations among patients with localized thyroid cancer, revealing thatTERTmutations were associated with poor outcomes among patients with nonmetastatic disease that do not have an aggressive histology.¹

“The present study suggests that the prognosis of patients with mutated tumors is not independent from histological features,” the study authors, led by Claire Bournaud, MD, of the Nuclear Medicine Service at Hospices Civils de Lyon, wrote.

The investigators suggested that an understanding of the prognostic role ofTERTpromoter mutations could help physicians better define prognosis for patients with localized thyroid cancer with non-aggressive histological features and help identify patients that may need closer follow-up.

Previous retrospective studies have suggested thatTERTpromoter mutations are predictive of a poor prognosis for patients with differentiated thyroid carcinomas, except in the case of micropapillary cancer. One meta-analysis identifiedTERTpromoter mutations in 14.3% of patients with thyroid cancer, with higher proportions among aggressive histology subtypes, including 33.4% found among poorly differentiated thyroid cancers (PDTCs) and 30.23% among tall-cell variant papillary thyroid cancers.²

The prospective study reviewed the prognostic value ofTERTpromoter mutations among 173 patients with intermediate- to high-risk differentiated thyroid cancer who were referred for radioiodine (RAI) treatment after thyroidectomy in Lyon, France. Patients were tested forTERT, BRAF,andRASalterations.

The mean age of the included patients was 51 (range, 18-93) and 60.7% of the patients were female. Eighty-two percent had a well-differentiated thyroid cancer and 18% had PDTC; 28.3% of patients (n = 49) had tumors with aggressive histological features.

Thirty patients (17.3%) were metastatic as of initial treatment, and of the patients with nonmetastatic disease, the majority (95.0%) had pT3 stage disease.

Most patients (76.3%) had a good response to initial treatment, which was defined as an excellent or indeterminate response, although 23.7% had an incomplete response. Nearly 66% (114 of 173) of patients received  1 course of RAI after surgery. Twenty patients underwent further surgery after initial treatment, 12 received local therapy, and 10 received systemic therapy. After follow-up, 28 patients were metastatic or had died and 119 were still in remission.

TERTmutations were found in 20.2%, and the proportion was significantly higher (32.7%) in tumors with aggressive histological features, including PDTC, tall cell variant of papillary cancer, or widely invasive follicular cancer compared with non-aggressive tumors (15.3%;P= .020).

BRAFmutations were identified in 28.9% of patients, making up 34.5% of differentiated thyroid carcinomas versus 3.2% of PDTC (P<.001).RASmutations were found in 15.6% of patients, comprising 12% of differentiated thyroid carcinomas versus 32.3% of PDTCs (P= .011).

Co-occurringBRAFandTERTmutations were discovered in 7.5% of tumors, and co-occurringTERTandRASmutations in 5.2%. Additionally, 62.8% of tumors withTERTmutations also expressed another mutation.

The investigators studied the relationship between TERT mutational status, clinicopathological features, and patient outcomes. TERT promoter mutation existence was associated with age &ge;45 years (P= .005), pT4 stage (P= .015), metastatic disease (P= .014), extrathyroidal extension (P= .002), occurrence of extracervical RAI uptake on post-therapeutic scan (P= .011), and structural incomplete response at restaging.

Among nonmetastatic patients, those withTERTmutations were less likely to have an excellent or indeterminate response to initial treatment (P= .042) and to have no evidence of disease upon last follow-up (P= .003) than wild-type patients. For patients who were initially metastatic, their final status did not change significantly with aTERTmutation.

The association between outcome andTERTmutation status was more significant in patients with non-aggressive histology than those with an aggressive histology. In the group of patients with an aggressive histology (n = 49), the rates of remission and metastasis were similar regardless ofTERTmutation status. In the group of patients with non-aggressive histologies (n = 124), the rates of good responses to initial treatment (P= .006) and that of no evidence of disease after follow-up (P= .001) were lower among those withTERTmutations versus those without. &nbsp;

TERTpromoter mutations were significantly associated with poor prognosis in the total population (P<.001) but not in patients with nonmetastatic disease (P= .051).

&ldquo;Interestingly, when focusing on M0 patients without aggressive histological features, the subgroup of the cohort less prone to experience recurrence,TERTmutations were strongly associated with a worse event-free survival. These results&hellip;suggest thatTERTmutations should help to identify patients requiring more intensive treatment and close follow-up,&rdquo; the investigators commented.

Upon univariate analysis,TERTmutations were not associated with event-free survival (EFS), but by multivariate analysis,TERTmutations were strongly associated with EFS in patients with nonmetastatic disease with non-aggressive histological features.

NeitherBRAFnorRASmutation status was associated with EFS. &ldquo;One potential explanation could be the relatively low prevalence ofBRAFmutation in the present.... But it must also be underlined that the prognostic value ofBRAFmutation has been questioned, some studies failing to demonstrate that BRAF mutation was an independent prognostic factor,&rdquo; the study authors noted.

References:

1. Bournaud C, Descotes F, Decaussin-Petrucci M, et al. TERT promoter mutations identify a high-risk group in metastasis-free advanced thyroid carcinoma.Eur J Cancer.2019;108:41-49. doi: 10.1016/j.ejca.2018.12.003.
2. Su X, Jiang X, Wang W, et al. Association of telomerase reverse transcriptase promoter mutations with clinicopathological features and prognosis of thyroid cancer: a meta-analysis.Onco Targets Ther.2016;9:6965-6976. doi: 10.2147/OTT.S116594.