Ignite Creation Date:
2024-05-06 @ 3:33 PM
Last Modification Date:
2024-10-26 @ 1:51 PM
Study NCT ID:
NCT04664413
Status:
UNKNOWN
Last Update Posted:
2020-12-14
First Post:
2020-12-05
Brief Title:
Percentage of BRAFV600E Alleles and Outcome in Thyroid Carcinoma
Sponsor:
University of Salerno
Organization:
University of Salerno
Study Overview
Official Title:
Correlations Between Percentage of BRAFV600E Alleles and Outcome in Thyroid Carcinoma
Status:
UNKNOWN
Status Verified Date:
2020-12
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ABOUT
Brief 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
PTC are characterized by intratumor heterogeneity with wild-type and BRAFV600E tumoral cells In a previous study the BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-type allele ratio in a series of PTC and its correlation with clinicopathology features and outcome
PTC are characterized by intratumor heterogeneity with wild-type and BRAFV600E tumoral cells In a previous study the BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-type allele ratio in a series of PTC and its correlation with clinicopathology features and outcome
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 IIIIV 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 266 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 BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-type ratio 30 displayed an odds risk of tumor recurrence of 51 whereas it was only 175 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 BRAFV600EBRAFwild-type allele ratio
AIM OF THE RESEARCH
1 Determine how frequent are subclonal-BRAFV600E PTC and to determine the mean and median BRAFV600EBRAFwild-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 cellcontaminating 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
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 IIIIV 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 266 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 BRAFV600EBRAFwild-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 BRAFV600EBRAFwild-type ratio 30 displayed an odds risk of tumor recurrence of 51 whereas it was only 175 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 BRAFV600EBRAFwild-type allele ratio
AIM OF THE RESEARCH
1 Determine how frequent are subclonal-BRAFV600E PTC and to determine the mean and median BRAFV600EBRAFwild-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 cellcontaminating 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None