Impact of BRAFV600E Intratumor Heterogeneity in Thyroid Cancer Treated With Tyrosine Kinase Inhibitors

Study Overview
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Brief Summary
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Background: BRAFV600E is the most frequent oncogene in differentiated thyroid cancer (DTC) occurring in about 50% of cases. Clinical trials with tyrosine kinase inhibitors (TKI) with specific activity against BRAF in metastatic radioiodine-resistant DTC (MRR-DTC) are ongoing. Very recently it has been demonstrated that DTC often consists of a mixture of tumor cells with wild-type and mutant BRAF. The subclonal occurrence of BRAFV600E in MRR-DTC could disable the therapy with BRAF targeted TKI and be responsible of the frequent defeats of this treatment. A therapeutic strategy based upon BRAF inhibitors in tumors bearing subclonal BRAFV600E could be initially successful hitting the tumor cells expressing the oncogene, and after the initial tumor growth arrest and/or shrinkage, the oncogene negative cells insensitive or less sensitive to the treatment, could restart the growth of the tumor causing the progression of the disease and the escape from the clinical response. Aims: To determine the impact of subclonal BRAFV600E on the efficacy of BRAF inhibitors in the treatment of MRR-DTC. Study design: Primary tumor tissues will be analyzed for the presence of BRAFV600E by pyrosequencing or other quantitative assay. If available, synchronous metastases and post-therapy metachronous metastases will be analyzed as well. The clinical response will be determined according to RECIST, and the association with the percentage of BRAFV600E alleles will be evaluated. Attention will be paid to the possible difference of BRAFwild-type/BRAFV600E ratio between primary tumors and synchronous metastases, primary tumors and post-therapy metachronous metastases, and between responsive and resistant synchronous tumor lesions.

Official Title
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Impact of BRAFV600E Intratumor Heterogeneity on the Efficacy of Tyrosine Kinase Inhibitors in the Treatment of Radioiodine-resistant Thyroid Cancer

Conditions
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Differentiated Thyroid Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: subjects any sex any age with metastatic or unresectable thyroid carcinoma treated with tyrosine kinase inhibitors evidence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) availability of study end points including best response, duration of response, and time to disease progression (based on RECIST), clinical progression, or death availability of tumor tissue samples, frozen or formaldehyde fixed-paraffin embedded from block, genomic DNA already extracted from tumor tissue Exclusion Criteria: concurrent Hashimoto's thyroiditis
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sorafenib<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sorafenib | |
| Axitinib<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Axitinib | |
| Pazopanib<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Pazopanib | |
| TKI<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with different type of tyrosine kinase inhibitor | |
| Motesanib<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Motesanib | |
| Sunitinib<br>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sunitinib | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of BRAFV600E alleles in tumor tissue before TKI treatment |  | within 1 month after the patient has entered the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment |  | within 30 days from the availability of the tissue sample | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thyroid cancer, tyrosine kinase inhibitors, BRAF, Sorafenib, Pazopanib, Sunitinib, Cabozantinib