BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment

Yueye Huang, Shen Qu, Guangwu Zhu, Fei Wang, Rengyun Liu, Xiaopei Shen, David Viola, Rossella Elisei, Efisio Puxeddu, Laura Fugazzola, Carla Colombo, Barbara Jarzab, Agnieszka Czarniecka, Alfred K. Lam, Caterina Mian, Federica Vianello, Linwah Yip, Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Christine J. O'Neill & 1 others Michael Mingzhao Xing

Research output: Contribution to journalArticle

Abstract

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0cm and 4.0cm 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 chisquare test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrencefree 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 1.0cm and 4.0cm 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 2.0cm and 4.0cm 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 3.0cm and 4 cmor 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 2.0cm 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 2.0cm and 4.0cm 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 1.0cm and 4.0cm or less, particularly tumors larger than 2.0cm and 4.0cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume110
Issue number4
DOIs
StatePublished - Apr 1 2018

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Mutation
Recurrence
Confidence Intervals
Therapeutics
Factor IX
Kaplan-Meier Estimate
Papillary Thyroid cancer
Neoplasms
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. / Huang, Yueye; Qu, Shen; Zhu, Guangwu; Wang, Fei; Liu, Rengyun; Shen, Xiaopei; Viola, David; Elisei, Rossella; Puxeddu, Efisio; Fugazzola, Laura; Colombo, Carla; Jarzab, Barbara; Czarniecka, Agnieszka; Lam, Alfred K.; Mian, Caterina; Vianello, Federica; Yip, Linwah; Riesco-Eizaguirre, Garcilaso; Santisteban, Pilar; O'Neill, Christine J.; Xing, Michael Mingzhao.

In: Journal of the National Cancer Institute, Vol. 110, No. 4, 01.04.2018.

Research output: Contribution to journalArticle

Huang, Y, Qu, S, Zhu, G, Wang, F, Liu, R, Shen, X, Viola, D, Elisei, R, Puxeddu, E, Fugazzola, L, Colombo, C, Jarzab, B, Czarniecka, A, Lam, AK, Mian, C, Vianello, F, Yip, L, Riesco-Eizaguirre, G, Santisteban, P, O'Neill, CJ & Xing, MM 2018, 'BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment', Journal of the National Cancer Institute, vol. 110, no. 4. https://doi.org/10.1093/jnci/djx227
Huang, Yueye ; Qu, Shen ; Zhu, Guangwu ; Wang, Fei ; Liu, Rengyun ; Shen, Xiaopei ; Viola, David ; Elisei, Rossella ; Puxeddu, Efisio ; Fugazzola, Laura ; Colombo, Carla ; Jarzab, Barbara ; Czarniecka, Agnieszka ; Lam, Alfred K. ; Mian, Caterina ; Vianello, Federica ; Yip, Linwah ; Riesco-Eizaguirre, Garcilaso ; Santisteban, Pilar ; O'Neill, Christine J. ; Xing, Michael Mingzhao. / BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. In: Journal of the National Cancer Institute. 2018 ; Vol. 110, No. 4.
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title = "BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment",
abstract = "Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0cm and 4.0cm 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 chisquare test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrencefree 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 1.0cm and 4.0cm 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 2.0cm and 4.0cm 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 3.0cm and 4 cmor 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 2.0cm 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 2.0cm and 4.0cm 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 1.0cm and 4.0cm or less, particularly tumors larger than 2.0cm and 4.0cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.",
author = "Yueye Huang and Shen Qu and Guangwu Zhu and Fei Wang and Rengyun Liu and Xiaopei Shen and David Viola and Rossella Elisei and Efisio Puxeddu and Laura Fugazzola and Carla Colombo and Barbara Jarzab and Agnieszka Czarniecka and Lam, {Alfred K.} and Caterina Mian and Federica Vianello and Linwah Yip and Garcilaso Riesco-Eizaguirre and Pilar Santisteban and O'Neill, {Christine J.} and Xing, {Michael Mingzhao}",
year = "2018",
month = "4",
day = "1",
doi = "10.1093/jnci/djx227",
language = "English (US)",
volume = "110",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
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TY - JOUR

T1 - BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment

AU - Huang, Yueye

AU - Qu, Shen

AU - Zhu, Guangwu

AU - Wang, Fei

AU - Liu, Rengyun

AU - Shen, Xiaopei

AU - Viola, David

AU - Elisei, Rossella

AU - Puxeddu, Efisio

AU - Fugazzola, Laura

AU - Colombo, Carla

AU - Jarzab, Barbara

AU - Czarniecka, Agnieszka

AU - Lam, Alfred K.

AU - Mian, Caterina

AU - Vianello, Federica

AU - Yip, Linwah

AU - Riesco-Eizaguirre, Garcilaso

AU - Santisteban, Pilar

AU - O'Neill, Christine J.

AU - Xing, Michael Mingzhao

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0cm and 4.0cm 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 chisquare test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrencefree 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 1.0cm and 4.0cm 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 2.0cm and 4.0cm 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 3.0cm and 4 cmor 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 2.0cm 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 2.0cm and 4.0cm 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 1.0cm and 4.0cm or less, particularly tumors larger than 2.0cm and 4.0cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

AB - Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0cm and 4.0cm 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 chisquare test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrencefree 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 1.0cm and 4.0cm 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 2.0cm and 4.0cm 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 3.0cm and 4 cmor 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 2.0cm 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 2.0cm and 4.0cm 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 1.0cm and 4.0cm or less, particularly tumors larger than 2.0cm and 4.0cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

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