Voss Rachel K, Feng Lei, Lee Jeffrey E, Perrier Nancy D, Graham Paul H, Hyde Samuel M, Nieves-Munoz Frances, Cabanillas Maria E, Waguespack Steven G, Cote Gilbert J, Gagel Robert F, Grubbs Elizabeth G
Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030.
Department of Biostatistics, University of Texas, MD Cancer Center, Houston, Texas 77030.
J Clin Endocrinol Metab. 2017 Aug 1;102(8):2807-2813. doi: 10.1210/jc.2017-00317.
High-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) and presumed increased aggressiveness compared with moderate-risk RET mutations.
To determine whether high-risk RET mutations are more aggressive.
Retrospective cohort study using institutional multiple endocrine neoplasia type 2 registry.
Tertiary cancer care center.
Patients with MTC and moderate- or high-risk germline RET mutation.
None (observational study).
Proxies for aggressiveness were overall survival (OS) and time to distant metastatic disease (DMD).
A total of 127 moderate-risk and 135 high-risk patients were included (n = 262). Median age at diagnosis was 42.3 years (range, 6.4 to 86.4 years; mean, 41.6 years) for moderate-risk mutations and 23.0 years (range, 3.7 to 66.8 years; mean, 25.6 years) for high-risk mutations (P < 0.0001). Moderate-risk patients had more T3/T4 tumors at diagnosis (P = 0.03), but there was no significant difference for N or M stage and no significant difference in OS (P = 0.40). From multivariable analysis for OS, increasing age [hazard ratio (HR), 1.05/y; 95% confidence interval (CI), 1.03 to 1.08], T3/T4 tumor (HR, 2.73; 95% CI, 1.22 to 6.11), and M1 status at diagnosis (HR, 3.93; 95% CI, 1.61 to 9.59) were significantly associated with worse OS but high-risk mutation was not (P = 0.40). No significant difference was observed for development of DMD (P = 0.33). From multivariable analysis for DMD, only N1 status at diagnosis was significant (HR, 2.10; 95% CI, 1.03 to 4.27).
Patients with high- and moderate-risk RET mutations had similar OS and development of DMD after MTC diagnosis and therefore similarly aggressive clinical courses. High-risk connotes increased disease aggressiveness; thus, future guidelines should consider RET mutation classification by disease onset (early vs late) rather than by risk (high vs moderate).
与中度风险的RET突变相比，高风险RET突变（密码子634）与甲状腺髓样癌（MTC）的早期发生相关，且推测其侵袭性增加。
确定高风险RET突变是否更具侵袭性。
使用机构性2型多发性内分泌肿瘤登记处进行的回顾性队列研究。
三级癌症护理中心。
患有MTC且有中度或高风险种系RET突变的患者。
无（观察性研究）。
侵袭性的替代指标为总生存期（OS）和远处转移疾病发生时间（DMD）。
共纳入127例中度风险患者和135例高风险患者（n = 262）。中度风险突变患者诊断时的中位年龄为42.3岁（范围6.4至86.4岁；平均41.6岁），高风险突变患者为23.0岁（范围3.7至66.8岁；平均25.6岁）（P < 0.0001）。中度风险患者诊断时T3/T4期肿瘤更多（P = 0.03），但N或M分期无显著差异，OS也无显著差异（P = 0.40）。从OS的多变量分析来看，年龄增加[风险比（HR），1.05/年；95%置信区间（CI），1.03至1.08]、T3/T4期肿瘤（HR，2.73；95%CI，1.22至6.11）以及诊断时M1状态（HR，3.93；95%CI，1.61至9.59）与较差的OS显著相关，但高风险突变并非如此（P = 0.40）。DMD的发生无显著差异（P = 0.33）。从DMD的多变量分析来看，仅诊断时N1状态具有显著性（HR，2.10；95%CI，1.03至4.27）。
MTC诊断后，高风险和中度风险RET突变患者的OS和DMD发生情况相似，因此临床病程的侵袭性相似。高风险意味着疾病侵袭性增加；因此，未来指南应考虑按发病时间（早发与晚发）而非风险（高风险与中度风险）对RET突变进行分类。
