Percentage of BRAFV600E Alleles and Outcome in Thyroid Carcinoma (ABOUT)

December 10, 2020 updated by: Mario Vitale, University of Salerno

Correlations Between Percentage of BRAFV600E Alleles and Outcome in Thyroid Carcinoma

BRAFV600E is the most frequent oncogene in Papillary thyroid carcinoma (PTC). It correlates with greater extension, lymph node metastasis, and advanced stage. However, the prognostic value of BRAFV600Eis weak and the search of this mutation is not recommended in clinical management of thyroid cancer.

PTC are characterized by intratumor heterogeneity with wild-type and BRAFV600E tumoral cells. In a previous study, the BRAFV600E/BRAFwild-type ratio correlated with patient age, tumor volume, lymph node metastasis and with worst disease outcome. While the existence of intratumor heterogeneity in PTC is supported by many evidences, its extension, biological significance and clinical utility is questioned and must be further investigated.

Primary endpoint of the study is to determine the relationship between the percentage of BRAFV600E alleles and outcome in PTC patients. Secondary endpoints are to determine the mean and median BRAFV600E/BRAFwild-type allele ratio in heterogeneous tumors; determine the relationship between the percentage of BRAFV600E alleles and clinicopathological features.

The study protocol entails the assessment by digital-droplet PCR the BRAFV600E/BRAFwild-type allele ratio in a series of PTC and its correlation with clinicopathology features and outcome.

Study Overview

Status

Unknown

Conditions

Detailed Description

BACKGROUND Papillary thyroid carcinoma (PTC) generally shows an excellent prognosis with a 5-year survival of over 95%. Even when PTC metastasizes to the regional lymph nodes, a frequent occurrence, it generally has an excellent prognosis. However, there are some patients who present with an aggressive background or with specific clinicopathological features who exhibit aggressive developmental behavior. Several clinicopathological features, namely pathology subtype, age, distant and lymph node metastasis, extrathyroid extension, and completeness of resection can be used to predict prognosis and have been adopted in staging systems such as the AMES, MACIS, and AJCC TNM classifications.

The genetic background is a powerful prognostic determinant only when applied to some gene mutations such as TERT promoter and p53 mutations. The prognostic value of BRAFV600E, the most frequent oncogene in PTC, is weak. It correlates with greater extension, lymph node metastasis, and advanced stage (III/IV). Its correlation with outcome in PTC has been the object of many not always concordant studies. A large multicenter study was necessary to unequivocally demonstrate the association between BRAFV600E and cancer recurrence and mortality. The risk of PTC harboring BRAFV600E remains weak (recurrence hazard ratio 2.66) and the search of this mutation is not recommended in clinical management of low-risk patients with thyroid cancer.

Different research groups provided evidence on the heterogeneity of PTC that consist of a mixture of tumor cells with wild-type and BRAFV600E (5, 6). The importance of the percentage of BRAFV600E positive cells within the tumor was demonstrated in 168 PTC. The analysis of BRAFV600E/BRAFwild-type ratio was performed by pyrosequencing and higher ratio positively correlated with patient age, tumor volume, lymph node metastasis and with worst disease outcome. Patients with tumors with BRAFV600E/BRAFwild-type ratio ≥ 30% displayed an odds risk of tumor recurrence of 5.1, whereas it was only 1.75 in BRAFV600E positive tumors if the allele ratio was not considered. The qualitative analysis BRAFV600E positive versus negative PTC can explain the discordant correlations with clinicopathological features and outcome in different cohorts of patients with different ratio of BRAFV600E alleles, and ultimately the qualitative analysis BRAF mutational status can reduce the strength of its clinical significance and utility.

While the existence of intratumor heterogeneity in PTC is supported by many evidences, its extension, biological significance and clinical utility is questioned and must be further investigated.

Digital-droplet PCR (ddPCR) is an analytical method recently developed, suitable for absolute quantification of target DNA in a DNA mixture. It is the most accurate method to determine the BRAFV600E/BRAFwild-type allele ratio.

AIM OF THE RESEARCH

  1. Determine how frequent are subclonal-BRAFV600E PTC and to determine the mean and median BRAFV600E/BRAFwild-type allele ratio in heterogeneous tumors;
  2. Determine the relationship between the percentage of BRAFV600E alleles and clinicopathological features;
  3. Determine the relationship between the percentage of BRAFV600E alleles and outcome in PTC patients (primary endpoint)

STUDY DESIGN

  • A large series of PTC formalin-fixed, paraffin-embedded (FFPE) tissues with a clinical follow up > 3 years will be analyzed by ddPCR to determine the percentage of BRAFV600E alleles.
  • The purity of PTC samples and the ratio neoplastic cell/contaminating cells will be assessed by the a) analysis by rt-PCR of expression of a panel of RNA specific for lymphoreticular cells and stromal cells; b) microscopic review of adjoining tissue sections.
  • Statistical analysis will be performed to search correlations between percentage of BRAFV600E alleles and a) pathology features, TNM, staging; b) recurrence and survival

Study Type

Observational

Enrollment (Anticipated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Salerno
      • Baronissi, Salerno, Italy, 84081
        • Department of Medicine and Surgery, Univeristy of Salerno

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Any patient 18 years age or more with a diagnosis of papillary thyroid carcinoma, subjected to thyroidectomy no less than 3 years before

Description

Inclusion Criteria:

  • Patients undergone surgery because of any PTC subtypes 3 years before or more
  • Availability of PTC tissue samples, well annotated
  • Availability of clinical data of the patients including gender, age at diagnosis, type and extension of surgery, radiation therapy, radio-iodide therapy, TSH suppressive therapy
  • Follow up of 3 years or more after surgery, including periodical 6 months assessment of TSH, thyroglobulin and AbTG, neck ultrasound evaluation and episodic hrTSH stimulation test

Exclusion Criteria:

  • Inadequate tissue samples or clinical data and follow up
  • Purity of PTC samples < 50%

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intratumor BRAFV600E heterogeneity and outcome
Time Frame: 6 months
3. Determine the relationship between the percentage of BRAFV600E alleles and outcome in PTC patients
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intratumor BRAFV600E heterogeneity quantification
Time Frame: 5 months
1. Determine how frequent are subclonal-BRAFV600E PTC and to determine the mean and median BRAFV600E/BRAFwild-type allele ratio in heterogeneous tumors
5 months
Intratumor BRAFV600E heterogeneity and clinicopathological features
Time Frame: 5 months
2. Determine the relationship between the percentage of BRAFV600E alleles and clinicopathological features
5 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Salerno

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

February 1, 2021

Primary Completion (ANTICIPATED)

April 30, 2021

Study Completion (ANTICIPATED)

May 30, 2021

Study Registration Dates

First Submitted

December 5, 2020

First Submitted That Met QC Criteria

December 5, 2020

First Posted (ACTUAL)

December 11, 2020

Study Record Updates

Last Update Posted (ACTUAL)

December 14, 2020

Last Update Submitted That Met QC Criteria

December 10, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ABOUT

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

All results, will be shared before any submission to scientific journal

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Papillary Thyroid Cancer

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Chile

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe