B-TREUH results: A single-arm phase II pilot study of euthyroid hypothyroxinemia in metastatic breast carcinoma.

e13111 Background: Thyroid abnormalities are prevalent in up to 1/3 breast cancer patients. T4/L-thyroxine is the most commonly prescribed treatment for hypothyroidism. However, T4 has been shown to be a potent pro-oncogenic agent by stimulating mitogenesis and angiogenesis, and inhibiting apoptosis, anti-PDL-1 and radiation effects. T3/triiodothyronine is significantly less oncogenic and mitogenic. Hence, using T3 rather than T4 might have anti-oncogenic effects, resulting in slower disease progression and improved outcomes. Methods: Adults with metastatic breast carcinoma on active treatment with estimated life expectancy of > 3months and hypothyroidism on T4 and normal TSH were eligible. Following informed consent, participants discontinued T4 and initiated T3 after a washout period. T3 dosing and titration was based on their previous dose of T4 and thyroid function testing to maintain levels of free T4 at < 50% normal range. The treatment period was 9 months and follow up for 12 months. The primary endpoint was progression free survival. Secondary endpoints were prevalence of hypothyroidism in the cohort, overall survival, quality of life, and time to achieve euthyroid hypothyroxinemia. Results: The trial was terminated early due to the pandemic and relocation of the PI and Sub-I. 7 female patients from a community medical oncology practice were enrolled between March 2019 and March 2022, Duration of metastatic breast cancer 7-223 months (average 62 months). Progression-free survival at 9 months was 5/7 (71%). Progression free survival (PFS) at 12 months, calculated in 6 patients due to data cut-off deadline and premature study closure, was 4/6 (67%). Overall survival at 9 months was 6/7 (85%). 1 patient died due to disease progression. The prevalence of hypothyroidism was 26/126 (21%). Euthyroid hypothyroxinemia was achieved in 100%, in average time of 59.6 days. 0% of the 14 serious adverse events were attributed to T3. Quality of life FACT-B scores on T4 vs T3 were not statistically significant. Conclusions: B-TREUH is the first prospective trial of euthyroid hypothyroxinemia in hypothyroid metastatic breast cancer. The transition from T4 to T3 was well tolerated with no serious adverse side effects or on quality of life. In this heavily pretreated population, PFS was 71% at 9 months and 67% at 12 months. The small number and heterogeneity of this cohort make interpretation of the PFS challenging. This unique study is simple yet provocative. Larger, broader studies are needed to explore this concept further. The low cost and easy availability of T3 and high prevalence of hypothyroidism make it an exceptionally attractive agent for future oncology research. Clinical trial information: NCT03787303 .