Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness

• Published in: The journal of clinical endocrinology and metabolism 2017-08, Vol.102 (8), p.2807-2813
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Neuroendocrine - genetics; Carcinoma, Neuroendocrine - mortality; Carcinoma, Neuroendocrine - pathology; Child; Clinical s; Cohort Studies; Diagnosis; Female; Genotype; Germ-Line Mutation; Health risks; Humans; Male; Metastases; Metastasis; Middle Aged; Multiple endocrine neoplasia; Multiple Endocrine Neoplasia Type 2a - genetics; Mutation; Neoplasm Metastasis; Phenotype; Prognosis; Proto-Oncogene Proteins c-ret - genetics; Retrospective Studies; Risk groups; Survival; Survival Rate; Thyroid cancer; Thyroid carcinoma; Thyroid gland; Thyroid Neoplasms - genetics; Thyroid Neoplasms - mortality; Thyroid Neoplasms - pathology; Thyroxine; Triiodothyronine; Tumors; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2017-00317

Abstract Context 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. Objective To determine whether high-risk RET mutations are more aggressive. Design Retrospective cohort study using institutional multiple endocrine neoplasia type 2 registry. Setting Tertiary cancer care center. Patients Patients with MTC and moderate- or high-risk germline RET mutation. Intervention None (observational study). Main Outcome Measures Proxies for aggressiveness were overall survival (OS) and time to distant metastatic disease (DMD). Results 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). Conclusions 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). This study of aggressiveness of medullary thyroid cancer in patients with high- or moderate-risk RET mutations showed similar overall survival and distant metastatic disease for both groups.