BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer

2018 ◽  
Vol 51 (01) ◽  
pp. 69-75 ◽  
Author(s):  
Jan Groener ◽  
Debora Gelen ◽  
Carolin Mogler ◽  
Esther Herpel ◽  
Csaba Toth ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Retinoic Acid ◽  
Papillary Thyroid Cancer ◽  
Initial Response ◽  
University Hospital ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Wild Type ◽  
Mutational Status ◽  
Before And After

AbstractRadioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.

scholarly journals BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer

2018 ◽  
Vol 36 (27) ◽  
pp. 2787-2795 ◽  
Author(s):  
Fei Wang ◽  
Shihua Zhao ◽  
Xiaopei Shen ◽  
Guangwu Zhu ◽  
Rengyun Liu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Mortality Rates ◽  
Interquartile Range ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Wild Type ◽  
Specific Mortality ◽  
Male Sex ◽  
Multivariable Adjustment

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.

scholarly journals BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment

2017 ◽  
Vol 110 (4) ◽  
pp. 362-370 ◽  
Author(s):  
Yueye Huang ◽  
Shen Qu ◽  
Guangwu Zhu ◽  
Fei Wang ◽  
Rengyun Liu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Risk Stratification ◽  
Papillary Thyroid Cancer ◽  
Braf Mutation ◽  
Hazard Ratio ◽  
Braf V600e ◽  
Independent Effect ◽  
Papillary Thyroid ◽  
Wild Type ◽  
Recurrence Rates

Abstract Background Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow–up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher’s exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

scholarly journals The Prevalence and Prognostic Value of BRAFV600E Mutation in Papillary Thyroid Cancer

2019 ◽  
Vol 3 (4) ◽  
pp. 223
Author(s):  
Alaa Al Maaitah ◽  
Moaath Alsmady ◽  
Shatha Dmour ◽  
Dana Alsmady ◽  
Ahmad Al Alwan ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Prognostic Value ◽  
Direct Sequencing ◽  
University Hospital ◽  
Braf V600e ◽  
P Value ◽  
Prognostic Impact ◽  
Papillary Thyroid ◽  
Brafv600e Mutation

Objective: B-type Raf kinase (BRAF)V600E mutation in papillary thyroid cancer (PTC) has variable prevalence worldwide and it is hypothesized to worsen tumor prognosis. This study was conducted to investigate the prevalence of BRAFV600E mutation among PTC patients and to find out its prognostic impact measured by its association with various clinicopathologic features, recurrence, and mortality.Methods: This is a retrospective study that included 123 PTC patients who underwent thyroidectomy at Jordan University Hospital between January 2010 and December 2015. They were followed up over a mean of 18 months (range: 4-72). BRAFV600E mutation was analyzed by direct sequencing. A p value less than 0.05 was defined as statistically significant.Results: Twenty three out of 123 (18.7%) PTC patients were BRAFV600E mutation positive. BRAFV600E- mutant patients were more likely to have larger tumor size (1.8 vs 2.5 cm, p=0.040), to present with lymph node metastasis (LNM) (41.2% vs 82.4%, p=0.002), and to develop recurrence (1 vs 3, p=0.0003). Moreover, tumor recurrence which was recorded in 4 patients was significantly associated with LNM (p=0.038). Cancer-specific mortality rate was null.Conclusion: BRAFV600E mutation rate in PTC was low relative to world-wide prevalence. BRAFV600E mutation has prognostic value for PTC management. However, its cost-effectiveness should be revised. Further larger prospective studies in the region are recommended.International Journal of Human and Health Sciences Vol. 03 No. 04 October’19 Page : 223-230

BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer

2021 ◽  
Author(s):  
Yubing Tao ◽  
Fei Wang ◽  
Xiaopei Shen ◽  
Guangwu Zhu ◽  
Rengyun Liu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Papillary Thyroid Cancer ◽  
Mortality Risk ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Wild Type ◽  
Node Metastasis ◽  
Multivariate Adjustment

Abstract Context How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. Objective To study whether BRAF V600E affected LNM-associated mortality in PTC. Design, Setting, Participants We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 (IQR 35–58) years and median follow-up time of 58 (IQR 26–107) months. Results Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAFV600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAFV600E patients; mortality rates were 2/659 (0.3%) versus 4/321 (1.2%) in non-LNM versus LNM patients (P=0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAFV600E CPTC, morality rates were 7/515 (1.4%) versus 28/363 (7.7%) in non-LNM versus LNM patients (P<0.001), corresponding to HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAFV600E versus absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. Conclusions LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

scholarly journals Does the TT Variant of the rs966423 Polymorphism in DIRC3 Affect the Stage and Clinical Course of Papillary Thyroid Cancer?

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 423 ◽  
Author(s):  
Kinga Hińcza ◽  
Artur Kowalik ◽  
Iwona Pałyga ◽  
Agnieszka Walczyk ◽  
Danuta Gąsior-Perczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Endocrine System ◽  
Therapy Response ◽  
Initial Response ◽  
Response To Therapy ◽  
Braf V600e ◽  
Low Grade ◽  
Papillary Thyroid ◽  
The Impact

Thyroid cancer (TC) is the most common cancer of the endocrine system. Most new diagnoses are of low-grade papillary thyroid cancer (PTC), suggesting that PTC may be over-diagnosed. However, the incidence of advanced-stage PTC has increased in recent years. It is therefore very important to identify prognostic factors for advanced PTC. Somatic mutation of the BRAF gene at V600E, or the coexistence of the BRAF V600E mutation and mutations in the TERT promoter are associated with more aggressive disease. It would also be valuable to identify genetic risk factors affecting PTC prognosis. We therefore evaluated the impact of the rs966423 polymorphism in the DIRC3 gene, including its relationship with unfavorable histopathological and clinical features and mortality, in differentiated thyroid cancer (DTC). The study included 1466 patients diagnosed with DTC from one center. There was no significant association between the DIRC3 genotype at rs966423 (CC, CT, or TT) and any histopathological or clinic factor examined, including initial response to therapy, response at follow-up, or overall mortality, in DTC patients.

A mouse model of BRAF V600E mutated papillary thyroid cancer imitating sporadic conditions

2018 ◽  
Author(s):  
Iva Jakubikova ◽  
Elin Schoultz ◽  
Ellen Johansson ◽  
Shawn Liang ◽  
Konrad Patyra ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Papillary Thyroid Cancer ◽  
Braf V600e ◽  
Papillary Thyroid

scholarly journals Epigenetically upregulated WIPF1 plays a major role in BRAF V600E-promoted papillary thyroid cancer aggressiveness

Oncotarget ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 900-914 ◽  
Author(s):  
Tao Zhang ◽  
Xiaopei Shen ◽  
Rengyun Liu ◽  
Guangwu Zhu ◽  
Justin Bishop ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Cancer Aggressiveness

scholarly journals Correlation between F18-FDG PET/CT Imaging and BRAF V600E Genetic Mutation for the Early Assessment of Treatment Response in Papillary Thyroid Cancers

2020 ◽  
Vol 10 (2) ◽  
pp. 52
Author(s):  
Andra Piciu ◽  
Maria-Iulia Larg ◽  
Doina Piciu
Keyword(s):  
Thyroid Cancer ◽  
Prognostic Factors ◽  
Papillary Thyroid Cancer ◽  
Genetic Mutation ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Early Assessment ◽  
Pet Ct ◽  
Ct Evaluation

In thyroid neoplastic pathology, the BRAF V600E mutation is shown to be involved in the oncogenesis of papillary thyroid cancer and its subtypes. The purpose of this study is to evaluate the correlation between the mutation of the BRAF V600E oncogene and the pathological standardized uptake values (SUV) at the F18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) evaluation, for a group of 20 patients with radically treated (total thyroidectomy and radioiodine therapy) papillary thyroid cancer, with subclinical persistent disease, at 6 months after the initial treatment. We analyzed the correlations between the values of SUV and the presence of the BRAF mutation as well with other prognostic factors such as stage, age, specific tumor markers (thyroglobulin and anti-thyroglobulin), extrathyroid extension, the presence of metastatic lymph nodes or distant metastasis. The value of SUV in the case of BRAF+ (positive) patients was higher than in the negative ones, but without statistical significance, thus, the values of the SUV cannot be a predictable factor for the presence of the genetic mutation. There was a statistically significant correlation in BRAF+ subgroup between the SUV values and the positive resection limit following surgery, showing a higher SUV value in the PET/CT evaluation. No correlation was observed between the aforementioned prognostic factors involved in papillary thyroid cancer and the BRAF V600E mutation.

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