Thyroid carcinoma is one of the fastest growing cancers in the United States with an estimated 44,670 new cases in 2010, of which 80-90% are papillary in type. With current multimodality therapies, 5-year survival is >95%, however prognosis is markedly influenced by patient age and older age at diagnosis is one of the strongest risk factor for differentiated thyroid cancer (DTC) tumor-related death. Age at presentation is such a determinant of prognosis that it is built into the current AJCC TNM thyroid cancer staging scheme with age >45 years set as the threshold for upstaging patients who have similar tumor size and nodal status. Indeed, 10- year DTC survival is 99.8% in patients with stage I disease and only 40.7% in those with stage IV disease. Despite the age-related differences in DTC prognosis, current treatment is characterized by protocols that are rarely modified for elderly patients. Recent knowledge of the genetic changes in thyroid carcinogenesis has led to a better understanding of DTC clinical behavior. An activating mutation of BRAF is now recognized to be frequently associated with aggressive biologic features including a higher risk of disease recurrence and mortality. But current clinical treatment does not yet take BRAF status into account, nor is testing for BRAF widely available. At our highvolume center (~500 cases of thyroid cancer/year) we have routinely tested cytology specimens and thyroid tissue for BRAFV600E since 2007. In this proposal, we hypothesize that older age is a risk modifier for BRAFpositive thyroid cancer.
We aim to 1) characterize the association between age, BRAF status and disease outcomes in a large cohort study with longitudinal follow-up, 2) identify novel clinical and molecular markers that are BRAF-dependent and independent risk modifiers and also contribute to the poor disease outcome observed in elderly patients and 3) prospectively study how augmented risk stratification using age and BRAF status can alter current surgical treatment algorithms and improve disease-specific outcomes.

Public Health Relevance

Older patients with thyroid cancer have a poorer prognosis yet current treatment modalities are not well optimized or modified. BRAFV600E is an activating mutation that is often associated with thyroid cancer with aggressive behavior. This study will define how older age and BRAF status are risk modifiers for thyroid cancer patients and evaluate outcomes after optimization of patient management algorithms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG042334-01
Application #
8339951
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
Program Officer
Eldadah, Basil A
Project Start
2012-08-15
Project End
2014-07-31
Budget Start
2012-08-15
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$76,250
Indirect Cost
$26,250
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Fei; Zhao, Shihua; Shen, Xiaopei et al. (2018) BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer. J Clin Oncol 36:2787-2795
Shen, Xiaopei; Zhu, Guangwu; Liu, Rengyun et al. (2018) Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer. J Clin Oncol 36:438-445
Wang, Fei; Yu, Xiaolong; Shen, Xiaopei et al. (2017) The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer. J Clin Endocrinol Metab 102:3241-3250
Shi, Xiaoguang; Liu, Rengyun; Basolo, Fulvio et al. (2016) Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. J Clin Endocrinol Metab 101:264-74
Yip, Linwah; Nikiforova, Marina N; Yoo, Jenny Y et al. (2015) Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients. Ann Surg 262:519-25; discussion 524-5
Xing, Mingzhao; Alzahrani, Ali S; Carson, Kathryn A et al. (2015) Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 33:42-50