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Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: a phase II study.

Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: a phase II study.
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Hanna GJ, Busaidy NL, Chau NG, Wirth LJ, Barletta JA, Calles A, Haddad RI, Kraft S, Cabanillas ME, Rabinowits G, O'Neill A, Limaye SA, Alexander EK, Moore FD, Misiukiewicz K, Thomas T, Nehs MA, Marqusee E, Lee SL, Janne PA, Lorch JH,


Hanna GJ, Busaidy NL, Chau NG, Wirth LJ, Barletta JA, Calles A, Haddad RI, Kraft S, Cabanillas ME, Rabinowits G, O'Neill A, Limaye SA, Alexander EK, Moore FD, Misiukiewicz K, Thomas T, Nehs MA, Marqusee E, Lee SL, Janne PA, Lorch JH, (click to view)

Hanna GJ, Busaidy NL, Chau NG, Wirth LJ, Barletta JA, Calles A, Haddad RI, Kraft S, Cabanillas ME, Rabinowits G, O'Neill A, Limaye SA, Alexander EK, Moore FD, Misiukiewicz K, Thomas T, Nehs MA, Marqusee E, Lee SL, Janne PA, Lorch JH,

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Clinical cancer research : an official journal of the American Association for Cancer Research 2018 01 04() pii 10.1158/1078-0432.CCR-17-2297

Abstract
PURPOSE
Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer (TC). We evaluated the efficacy of everolimus in aggressive, radioactive iodine refractory (RAIR) TC and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic TC cohorts were included.

EXPERIMENTAL DESIGN
This single-arm, multi-institutional phase II study was conducted from 2009-2013 in patients with incurable RAIR TC who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.

RESULTS
Thirty-three patients with differentiated TC (DTC), 10 with medullary TC (MTC), and 7 with anaplastic TC (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months post study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.  Conclusions: Everolimus has significant anti-tumor activity in TC. While genomic profiling does not currently guide therapeutic selection in TC patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.

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