In an international, multicenter retrospective cohort study reported in The Lancet Oncology, Xing et al found that incorporating the genetic status of BRAF and TERT genes into the American Joint Committee on Cancer (AJCC) staging system for papillary thyroid cancer resulted in a modification of AJCC risk stages and improved mortality risk classification.
As stated by the investigators, “…the [four-stage] AJCC classification for papillary thyroid cancer is solely based on clinical parameters, and despite updated editions its accuracy remains suboptimal.”
Study Details
The study used patient medical records from 15 medical centers in 10 countries, covering January 1979 to July 2023, for patients with papillary thyroid cancer who had undergone total thyroidectomy or hemithyroidectomy with or without neck dissection, followed by postoperative radioiodine ablation and appropriate thyroid-stimulating hormone level targeting. Testing for BRAF V600E and TERT promoter (TERTp) mutations was performed on genomic DNA from surgical or cytological specimens of primary tumors. The primary outcome measure was papillary thyroid cancer–specific mortality.
Key Findings
The cohort consisted of 4,746 patients. Among 4,400 with available ethnicity data, 48.6% were Asian and 47.6% were White. Overall, 76.1% were female, and median age was 48 years.
Compared with original stages in the AJCC 7th edition (AJCC7), the genetic duet of BRAF V600E and TERTp mutations was associated with increased mortality in all stages, although the hazard ratio (HR) for stage I did not reach statistical significance. Those with wild-type BRAF V600E and TERTp had flat survival curves compared with AJCC7 stages I to III and stages I to II of AJCC8.
In particular, patients with dual mutations had HRs of: 5.96 (95% confidence interval [CI] = 0.73–48.66, P = .10) vs original AJCC7 stage I; 5.94 (95% CI = 1.42–24.91, P = .015) vs stage II; 4.04 (95% CI = 1.87–8.70, P = .00037) vs stage III; and 1.79 (95% CI = 1.15–2.76, P = .0092) vs stage IV. In addition, TERTp mutation alone increased mortality risk vs original stage IV (HR = 3.57, 95% CI = 2.01–6.37, P < .0001).
Patients with dual mutations had a similar pattern of increased mortality risk compared with original AJCC8 staging, with significant differences for stage I (HR = 10.30, 95% CI = 3.43–30.93, P < .0001) and stage II (HR = 3.95, 95% CI = 1.92–8.15, P = .00020). Significant differences were not observed vs original stages III or IV. The presence of TERTp mutation alone was associated with increased mortality vs original stage IV (HR = 2.75, 95% CI = 1.36–5.58, P = .0049).
The investigators concluded: “Integrating the genetic statuses of BRAF and TERTp into the AJCC system changes the original risk stages of the AJCC system and significantly improves the accuracy of its mortality risk classification for papillary thyroid cancer.”
Mingzhao Xing, MD, PhD, of the Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institute on Aging, the Auburn Community Cancer Endowed Chair in Basic Research, the Heart, Breast, and Brain Health Equity Research program, National Institutes of Health, and others. For full disclosures of all study authors, visit thelancet.com.
