Genetic modification of the AJCC classification of papillary thyroid cancer: an international, multicentre, retrospective cohort study

Background

The four-stage American Joint Committee on Cancer (AJCC) staging system has been used for almost 50 years for assessing the risk of multiple cancers; the AJCC classification for papillary thyroid cancer is solely based on clinical parameters, and despite updated editions its accuracy remains suboptimal. We aimed to evaluate whether the performance of the AJCC system could be improved by integrating tumour genetic statuses of BRAF and TERT genes.

Methods

This retrospective multicentre cohort study used patient medical records from 15 medical centres across ten countries for patients (of all ages) with papillary thyroid cancer who had been surgically treated with 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 promotor (TERTp) mutations was performed on genomic DNA isolated from surgical or cytological specimens of primary papillary thyroid cancer tumours at each centre. Data from all medical centres were pooled for aggregated analyses of the relationship between the genetic status and papillary thyroid cancer-specific mortality for each of the four classical stages of the 7th and 8th editions of the AJCC system (AJCC7E and AJCC8E). The primary endpoint was papillary thyroid cancer-specific mortality, characterised by mortality rates per 1000 person-years.

Findings

Using patients who were treated for papillary thyroid cancer between January 1979, to July 2023 at the 15 centres, our cohort comprised of 4746 patients (3612 [76·1%] females and 1134 [23·9%] males), with median age of 48 years (IQR 37–59; 89 [1·9%] patients aged ≤18 years). For the 4400 patients with available ethnicity data, the majority were Asian (2140 [48·6%]) and 2096 (47·6%) were White. For AJCC7E, compared with the original stages, the genetic duet of BRAF^V600E and TERTp mutations was associated with increased mortality in all stages versus the corresponding original stages, although the HR for stage I did not reach statistical significance. Those with wildtype BRAF^V600E and TERTp had flat survival curves for stages I–III with AJCC7E and stages I–II of AJCC8E. Patients with dual mutations had reductions in survival across all stages for the AJCC7E (stage I HR 5·96 [95% CI 0·73–48·66]; p=0·10; stage II 5·94 [95% CI 1·42–24·91]; p=0·015; stage III 4·04 [95% CI 1·87–8·70]; p=0·00037; and stage IV 1·79 [95% CI 1·15–2·76]; p=0·0092). TERTp mutation alone was also significantly associated with a significant increase in mortality for stage IV (3·57 [2·01–6·37]; p<0·0001). For AJCC8E, we observed a similar pattern of increased mortality when both mutations were present compared to mortality in the original staging, with significant differences in HR for stages I and II (stage I adjusted HR 10·30 [95% CI 3·43–30·93], p<0·0001; stage II HR 3·95 [95% CI 1·92–8·15]; p=0·00020). Stage III also showed increased mortality with dual mutations, but the increase was not statistically significant (HR 1·77 [0·95–3·31]; p=0·072). In contrast to AJCC7E, the dual mutations did not increase mortality compared with the original stage IV (HR 0·95 [0·47–1·92], p=0·89), but the TERTp mutation did significantly increase mortality in stage IV papillary thyroid cancer (HR 2·75 [1·36–5·58], p=0·0049).

Interpretation

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.

Funding

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 the American Association for Cancer Research Fellowship 21–40–69-ESTR (USA); Ministry of Health (Czech Republic); Prémio Francisco Augusto da Fonseca Dias e Maria José Melenas da Fonseca para Jovens Investigadores (Portugal); Italian Ministry of Health-Ricerca Corrente (Italy); JSPS KAKENHI (Japan); MINCIENCIAS, L’OREAL-UNESCO-ICETEX-COLCIENCIAS, Universidad del Tolima (Colombia); STRATEGMED2/267398/4/NCBR/2015, the National Centre for Research and Development (Poland); RISBIN IPTEKDOK 2014, Ministry of Health (Indonesia); and the Information and Communications Technology and Future Planning of the Basic Science Research Program via the National Research Foundation of Korea (NRF) funded by the Ministry of Science (Korea).