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Papillary Thyroid CancerABOUTNCT04664413

Percentage of BRAFV600E Alleles and Outcome in Thyroid Carcinoma

An observational study of Papillary Thyroid Cancer, run by University of Salerno at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Papillary Thyroid Cancer
How many people
300 participants
Where
1 siteItaly
Study dates
1 Feb 2021to 30 May 2021
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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

Who may be able to join

  • 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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Italy1 site
  • Department of Medicine and Surgery, Univeristy of Salerno

    Baronissi, Salerno, 84081

Other trials in Italy

About this study

Official title: 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.

Read more

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.

Read the 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
Medical subject headings
Thyroid Cancer, Papillary

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Intratumor BRAFV600E heterogeneity and outcome

    1. Determine the relationship between the percentage of BRAFV600E alleles and outcome in PTC patients

    Measured: 6 months

Secondary outcomes (2)
  1. Intratumor BRAFV600E heterogeneity quantification

    1. Determine how frequent are subclonal-BRAFV600E PTC and to determine the mean and median BRAFV600E/BRAFwild-type allele ratio in heterogeneous tumors

    Measured: 5 months

  2. Intratumor BRAFV600E heterogeneity and clinicopathological features

    1. Determine the relationship between the percentage of BRAFV600E alleles and clinicopathological features

    Measured: 5 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Dec 2020
  2. Study start1 Feb 2021 (estimated)
  3. Primary completion30 Apr 2021 (estimated)
  4. Study completion30 May 2021 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Case only
Time perspective
Retrospective
Enrolment
300 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04664413
Sponsor's protocol ID
ABOUT
Acronym
ABOUT
Status last verified
Dec 2020
First submitted
5 Dec 2020
Last updated
14 Dec 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: All results, will be shared before any submission to scientific journal

Publications

  • Ito Y, Miyauchi A, Kihara M, Fukushima M, Higashiyama T, Miya A. Overall Survival of Papillary Thyroid Carcinoma Patients: A Single-Institution Long-Term Follow-Up of 5897 Patients. World J Surg. 2018 Mar;42(3):615-622. doi: 10.1007/s00268-018-4479-z.

    PubMed 29349484
  • Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005 Dec;90(12):6373-9. doi: 10.1210/jc.2005-0987. Epub 2005 Sep 20.

    PubMed 16174717
  • Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O'Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Clifton-Bligh R, Tallini G, Holt EH, Sykorova V. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2015 Jan 1;33(1):42-50. doi: 10.1200/JCO.2014.56.8253. Epub 2014 Oct 20.

    PubMed 25332244
  • Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O'Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Tufano RP, Pai SI, Zeiger MA, Westra WH, Clark DP, Clifton-Bligh R, Sidransky D, Ladenson PW, Sykorova V. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013 Apr 10;309(14):1493-501. doi: 10.1001/jama.2013.3190.

    PubMed 23571588
  • Guerra A, Sapio MR, Marotta V, Campanile E, Rossi S, Forno I, Fugazzola L, Budillon A, Moccia T, Fenzi G, Vitale M. The primary occurrence of BRAF(V600E) is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012 Feb;97(2):517-24. doi: 10.1210/jc.2011-0618. Epub 2011 Dec 14.

    PubMed 22170714
  • Gandolfi G, Sancisi V, Torricelli F, Ragazzi M, Frasoldati A, Piana S, Ciarrocchi A. Allele percentage of the BRAF V600E mutation in papillary thyroid carcinomas and corresponding lymph node metastases: no evidence for a role in tumor progression. J Clin Endocrinol Metab. 2013 May;98(5):E934-42. doi: 10.1210/jc.2012-3930. Epub 2013 Mar 26.

    PubMed 23533235
  • Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab. 2012 Jul;97(7):2333-40. doi: 10.1210/jc.2011-3106. Epub 2012 Apr 16.

    PubMed 22508706

Questions about this trial

What is this clinical trial studying?

An observational study of Papillary Thyroid Cancer, run by University of Salerno at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Intratumor BRAFV600E heterogeneity and outcome (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04664413, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2020.

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