Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna.
ESMO Open. 2023 Dec;8(6):102039. doi: 10.1016/j.esmoop.2023.102039. Epub 2023 Oct 23.
Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making.
We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development.
A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006).
Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.
肿瘤基因分型对于优化晚期分化型甲状腺癌（DTC）患者的临床管理至关重要；然而，其在临床实践中的应用仍未得到明确。本研究报告了我们采用下一代测序方法进行分子水平晚期 DTC 检测的单中心经验，以更好地确定肿瘤基因分型如何以及何时可以辅助临床决策。
我们回顾性收集了 2008 年至 2022 年期间在 IRCSS Sant'Orsola-Malpighi 医院接受分子谱分析的所有成人晚期 DTC 患者的数据。分析基因改变与放射性碘难治（RAI-R）、RAI 摄取/疾病状态和放射性碘抵抗（RAI-R）发展时间（TTRR）之间的相关性。
RAI-R 与基因改变之间存在显著相关性（P=0.0001）。约 48.7%的 RAI-R 病例存在 TERT/TP53 突变（无论是单一事件还是与其他驱动基因突变如 BRAF 突变、RAS 突变或基因融合），而大多数 RAI 敏感病例携带基因融合（41.9%）或野生型（WT；41.9%）。RAI 摄取/疾病状态和 TTRR 时间与基因改变显著相关（P=0.0001）。特别是，仅存在 TERT/TP53 突变或 TERT/TP53 突变与其他驱动基因突变共存的 DTC 患者，其 TTRR 中位数更短（35.4 个月，范围 15.0-55.8 个月）。多变量 Cox 分析显示，在 TERT/TP53 突变仅存在或与其他驱动基因突变共存时，与 RAI-R 独立相关（风险比 4.14，95%CI 1.51-11.32；P=0.006）。
常规进行基因改变检测应作为临床评估的一部分，以识别更具侵袭性肿瘤亚组和具有可操作基因融合的肿瘤亚组，从而确保对所有晚期 DTC 患者进行适当的管理。
