Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma

Jennifer Rui Wang; Matthew Montierth; Li Xu; Maitrayee Goswami; Xiao Zhao; Gilbert Cote; Wenyi Wang; Priyanka Iyer; Ramona Dadu; Naifa L Busaidy; Stephen Y Lai; Neil D Gross; Renata Ferrarotto; Charles Lu; Gary Brandon Gunn; Michelle D Williams; Mark Routbort; Mark E Zafereo; Maria E Cabanillas

doi:10.1200/PO.21.00504

Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma

Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21).

CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

Original language	English (US)
Pages (from-to)	e2100504
Journal	JCO Precision Oncology
Volume	6
DOIs	https://doi.org/10.1200/PO.21.00504
State	Published - Aug 2022

Keywords

Humans
Mutation
Proto-Oncogene Proteins B-raf/genetics
Thyroid Cancer, Papillary
Thyroid Carcinoma, Anaplastic/genetics
Thyroid Neoplasms/genetics

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10.1200/PO.21.00504

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Wang, J. R., Montierth, M., Xu, L., Goswami, M., Zhao, X., Cote, G., Wang, W., Iyer, P., Dadu, R., Busaidy, N. L., Lai, S. Y., Gross, N. D., Ferrarotto, R., Lu, C., Gunn, G. B., Williams, M. D., Routbort, M., Zafereo, M. E., & Cabanillas, M. E. (2022). Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma. JCO Precision Oncology, 6, e2100504. https://doi.org/10.1200/PO.21.00504

Wang, JR, Montierth, M, Xu, L, Goswami, M, Zhao, X, Cote, G, Wang, W , Iyer, P , Dadu, R , Busaidy, NL , Lai, SY , Gross, ND , Ferrarotto, R , Lu, C , Gunn, GB , Williams, MD , Routbort, M , Zafereo, ME & Cabanillas, ME 2022, 'Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma', JCO Precision Oncology, vol. 6, pp. e2100504. https://doi.org/10.1200/PO.21.00504

@article{58261f18664646079dcf6d6ea5713205,

title = "Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma",

abstract = "PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21).CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.",

keywords = "Humans, Mutation, Proto-Oncogene Proteins B-raf/genetics, Thyroid Cancer, Papillary, Thyroid Carcinoma, Anaplastic/genetics, Thyroid Neoplasms/genetics",

author = "Wang, {Jennifer Rui} and Matthew Montierth and Li Xu and Maitrayee Goswami and Xiao Zhao and Gilbert Cote and Wenyi Wang and Priyanka Iyer and Ramona Dadu and Busaidy, {Naifa L} and Lai, {Stephen Y} and Gross, {Neil D} and Renata Ferrarotto and Charles Lu and Gunn, {Gary Brandon} and Williams, {Michelle D} and Mark Routbort and Zafereo, {Mark E} and Cabanillas, {Maria E}",

year = "2022",

month = aug,

doi = "10.1200/PO.21.00504",

language = "English (US)",

volume = "6",

pages = "e2100504",

journal = "JCO Precision Oncology",

issn = "2473-4284",

publisher = "American Society of Clinical Oncology",

}

TY - JOUR

T1 - Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma

AU - Wang, Jennifer Rui

AU - Montierth, Matthew

AU - Xu, Li

AU - Goswami, Maitrayee

AU - Zhao, Xiao

AU - Cote, Gilbert

AU - Wang, Wenyi

AU - Iyer, Priyanka

AU - Dadu, Ramona

AU - Busaidy, Naifa L

AU - Lai, Stephen Y

AU - Gross, Neil D

AU - Ferrarotto, Renata

AU - Lu, Charles

AU - Gunn, Gary Brandon

AU - Williams, Michelle D

AU - Routbort, Mark

AU - Zafereo, Mark E

AU - Cabanillas, Maria E

PY - 2022/8

Y1 - 2022/8

N2 - PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21).CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

AB - PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21).CONCLUSION: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

KW - Humans

KW - Mutation

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Thyroid Cancer, Papillary

KW - Thyroid Carcinoma, Anaplastic/genetics

KW - Thyroid Neoplasms/genetics

U2 - 10.1200/PO.21.00504

DO - 10.1200/PO.21.00504

M3 - Article

C2 - 35977347

SN - 2473-4284

VL - 6

SP - e2100504

JO - JCO Precision Oncology

JF - JCO Precision Oncology

ER -

Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma

Abstract

Keywords

MD Anderson CCSG core facilities

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