Laura Boucai

6099 Background: For patients with radioactive iodine (RAI)-refractory, recurrent/metastatic thyroid cancer, treatment entails indefinite exposure to tyrosine kinase inhibitors and their associated toxicities. The mitogen activated protein kinase (MAPK) signaling pathway is commonly activated in thyroid cancer and suppresses genes required for iodine uptake and retention, leading to RAI refractoriness. In a previous pilot study, the MEK inhibitor selumetinib restored RAI uptake; however, the response was attenuated in patients with BRAF-mutant tumors. Methods: We are conducting a study to determine whether direct targeting of BRAF activity with vemurafenib in patients with BRAF-mutant thyroid cancer reverses RAI-refractoriness. The primary objective is to determine the proportion of patients with restoration of RAI uptake sufficient to enable therapeutic RAI. Patients were stimulated with thyrotropin alfa and underwent 124I PET scans prior to and 4 weeks after treatment with vemurafenib (960mg oral twice daily). Patients whose second 124I PET scan demonstrated that > 2000 cGy could be delivered to a lesion using < 300 mCi of 131I, received therapeutic 131I while continuing vemurafenib. Results: 12 patients with BRAF-mutant thyroid cancer were enrolled; 2 were removed from study prior to the second 124I PET scan and were replaced. The median age was 68 (range 43-72) with 7 (58%) men. Vemurafenib increased 124I PET lesional dosimetry sufficient to warrant therapeutic 131I in 4 of 9 evaluable patients. Of these, 3 exhibited tumor regression (1 PR, 2 SD) at 6 months following RAI and 1 has yet to undergo follow-up imaging. Decrease in thyroglobulin levels and tumor regressions on vemurafenib prior to RAI were observed. Analysis of transcriptional signatures to assess MAPK pathway inhibition and thyroid-specific gene expression is ongoing. Conclusions: These preliminary results suggest that vemurafenib can enhance RAI incorporation and efficacy in a subset of patients with BRAF-mutant thyroid cancer. We are currently investigating whether MAPK or thyroid-specific transcriptional output markers in tumor specimens identify patients most likely to respond. Clinical trial information: NCT02145143.

Background: The use of age- and ethnicity-specific thyrotropin (TSH) reference limits decreases misclassification of patients with thyroid dysfunction. Developing such limits requires TSH measurements in different subpopulations. Methods: We determined, in the National Health and Nutrition Examination Survey III, the TSH median, 2.5th and 97.5th centiles as a function of age, and anti-thyroid antibodies (ABs) in specific racial/ethnic groups (REGs) designated as non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans, as classified by the U.S. Office of Management and Budget (OMB) Directive 15. We compared TSH limits of a thyroid disease-free population ( n = 15,277) to a reference population ( n = 13,344) formed by exclusion of AB+ subjects and TSH >10 mIU/L or <0.1 mIU/L. With quantile regression, we examined the effect of age, REG, gender, body weight, and urinary iodine concentration on TSH reference limits in the AB− population. Results: AB status did not affect the 2.5th centile and median TSH in any REG or the 97.5th centile in Blacks. The average 97.5th centile of the disease-free Whites and Mexican Americans was 1.0 mIU/L higher than the reference population group. The TSH 2.5th, 50th, and 97.5th centiles increased with age and were lower in Blacks than in Whites or Mexican Americans. Women had lower 2.5th and 50th centiles than males. From these data, we developed equations to predict subpopulation-specific TSH reference limits. Conclusions: Our study provides a method to determine TSH limits in individual patients of different ages, gender, and REG criteria whose AB status is uncertain and it will enable clinicians to better classify patients within their subpopulation-specific TSH reference range.

Summary: Objective  The suitability of TSH reference limits derived from national databases to outpatient practices has not been established. We aimed to determine whether race and age influence the distribution of TSH and free T4 (fT4).Design  A cross‐sectional study of an urban outpatient medical practice.Participants  Patients (n = 22 116) without clinical evidence of thyroid disease or use of thyroid‐specific medications.Measurements  Comparison of TSH and fT4 distributions in specific racial and age groups including blacks, whites and Hispanics.Results  TSH was distributed at higher concentrations, without skew, in whites compared to blacks (median, 1·54 mIU/l vs. 1·18 mIU/l, P < 0·001) and in old (>80 years old) compared to young (20–29 years old) (median, 1·61 mIU/l vs. 1·13 mIU/l, P < 0·001). In all patients, blacks and whites, 3%, 8% and 5%, respectively, of those aged > 80 years were misclassified as having high TSH compared to those aged 20–29 years (P < 0·001). Using TSH limits from national databases resulted in significant misclassification of patients with raised or lowered TSH. Mean fT4 was significantly lower in blacks than whites (17·5 ± 4·38 pmol/l vs. 18·3 ± 3·99 pmol/l, P < 0·001), did not differ between young and old, but decreased progressively (average 7%) as TSH increased to > 4·5 mIU/l.Conclusions  Reference limits for TSH differ between races and with age. Use of race‐ and age‐specific reference limits decreases misclassification of patients with lowered or raised TSH in an urban practice. The unique fT4:TSH relationships of blacks and whites may be genetically determined. The implications of the small decrement in fT4 as TSH increases remain to be explored.