THE RELATIONSHIP OF BRAF V600E MUTATION STATUS TO FDG PET/CT AVIDITY IN THYROID CANCER: A REVIEW AND META-ANALYSIS

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP THE RELATIONSHIP OF BRAF V600E MUTATION STATUS TO FDG PET/CT AVIDITY IN THYROID CANCER: A REVIEW AND META-ANALYSIS Prasanna Santhanam MBBS,MD 1 ; Rodhan Khthir MD 2 ; Lilja B Solnes MD, MBA 3 ; Paul. W.Ladenson MD 1 From: 1 Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA-21287; 2 Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine,Joan C Edwards School of Medicine, Huntington,WV-25701; 3 Section of Nuclear Medicine, Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA Running title: BRAF mutation status and FDG PET/CT Corresponding author: Prasanna Santhanam MBBD, MD Johns Hopkins University School of Medicine Division of Endocrinology, Diabetes & Metabolism 1830 E. Monument St. / Ste. 333 Baltimore, MD Psantha1@jhmi.edu

2 Key Terms: BRAF Mutation and FDG PET/CT Total word count:1389 Table(s): 3, Figure(s): 4 Abstract Objectives: Papillary thyroid cancers harboring BRAF V600E gene mutation have been shown to exhibit aggressive tumor behaviors and higher risks of recurrence and disease-specific death. In this systematic review and meta-analysis, we examine and report published evidence related to the accuracy of FDG-PET-CT in detection of residual disease in patients with BRAF V600E mutated thyroid cancer. Methods: We extracted data from PUBMED/MEDLINE and EMBASE from January, 1995 to March, Studies that compared FDG PET SUV (Standardized Uptake Values) between BRAF V600E positive and BRAF V600E negative subjects as well as those that evaluated the odds of having FDG avidity between BRAF V600E positive and negative patients with thyroid cancer were included. Results: There were a total of 12 studies in the systematic review. There were 7 studies that qualified for the analysis for calculating the pooled odds ratio. The pooled cohort with binary data had 1144 patients out of which 843 were BRAF V600E positive and 301 were BRAF V600E negative. The patients with BRAF V600E mutation had significantly greater likelihood of having 18F-FDG avid lesions. The pooled odds ratio was 2.12 (CI , p value <0.01). The pooled mean SUV ( cohort of 315 patients) was significantly higher

3 in BRAF V600E positive compared to BRAF V600E negative patients with a pooled mean difference of 5.1 (CI ).Conclusion: Our meta-analysis shows that presence of BRAF V600E mutation in PTC confers a higher likelihood of 18-F FDG PET avidity as well as overall higher SUV uptake values compared to BRAF V600E mutation negative status. Abbreviations: BRAF= B-Raf proto-oncogene,serine/threonine kinase; FDG = Fluorodeoxyglucose; PET = Positron Emission Tomography; CT = Computerized Tomography; SUV = Standardized Uptake Values; GLUT = Glucose Transporter. Introduction Among patients with papillary thyroid cancer who have undergone primary treatment, residual disease is common and often challenging to localize (1). 18 Fluorodeoxyglucosepositron emission tomography fused with computed tomography (FDG-PET-CT) has been shown to be useful in detection of such residual thyroid cancer, particularly when iodine avidity has been lost (2). Preoperative FDG PET-CT assessment does not add to thyroid ultrasound in detecting cervical lymph node disease (3).However,high preoperative FDG PET- CT uptake in the primary lesion has been shown to be correlated to poor disease free survival in patients with increased prevalence of metastatic lymph node disease (4). Papillary thyroid cancers harboring BRAF V600E gene mutation have been shown to exhibit more aggressive tumor behaviors, including extrathyroidal extension, lymph node metastases, loss of iodine avidity, and higher risks of recurrence and diseasespecific death (5-7). Consequently, it is relevant to identify, analyze, and report published evidence related to the accuracy of FDG-PET-CT in detection of residual disease in patient s whose papillary thyroid cancer as well as other forms of

4 differentiated thyroid cancers is BRAF V600E -mutated, as we have done in this systematic review and meta-analysis. Materials and Methods Study selection, Eligibility criteria and data extraction We extracted data from PUBMED/MEDLINE and EMBASE using the search terms BRAF PET thyroid cancer for the period ranging from January, 1995 to March, It yielded 69 results from EMBASE and 20 from PUBMED. Duplicate studies, case reports, and editorials and other opinion articles were excluded. Studies that compared FDG PET SUV (Standardized Uptake Values) between BRAF V600E positive and BRAF V600E negative subjects as well as those that evaluated the odds of having FDG avidity between BRAF V600E positive and negative patients with differentiated thyroid cancer were included. The data from the individual studies was tabulated for the following variables; mean age (in years), gender distribution, mean tumor size (in cm), presence of lymph node metastasis (in %) and patients with BRAF V600E mutation positivity (in %). The data on radio-iodine avidity was scant in the studies and we surmise that this was most likely related to the diagnostic use of 18F-FDG PET/CT in persons with elevated thyroglobulin in whom I- 123 or post-treatment I-131 was negative. Statistical Analysis We assessed the Heterogeneity of data using the i-square as well as H value (i.e., the square root of the chi 2 heterogeneity statistic divided by its degrees of freedom) and created a heterogeneity funnel plot to illustrate the variation in the studies (8). The random effects model was used for computational purpose(9). The pooled odds ratio for the studies with binary data (BRAF V600E mutational status and FDG avidity) and the pooled mean FDG uptake SUV difference (for studies with mean SUV value) was

5 computed. MIX 2.0 was used for statistical analysis. Results There were a total of 12 studies of relevance out of which 10 were included in the systematic review (10-21). The Study by Alzahrani A, et al had a solitary patient (16). The study by Ho et al, evaluated the use of selumatinib in increasing the radio-iodine avidity of BRAF V600E and RAS mutated patients and had limited data on FDG PET/CT avidity (20). Both these studies were not included in the systematic review and metaanalysis. There were 6 studies from Republic of Korea, 2 from USA, and one each from Turkey and Italy. The details are shown in table 1 and 2. There was significant variation in the studies with respective to the composition of the different tumor types-follicular neoplasms, classic papillary thyroid cancer as well as poorly differentiated thyroid cancer. BRAF V600E positive tumors frequently encompass different cytopathological diagnosis, and so the results were pooled across different tumor subtypes (like follicular, tall cell variant etc.). There were 7 studies that qualified for the analysis for calculating the pooled odds ratio (11, 14, 15, 17-19, 21). The pooled cohort with binary data had 1144 patients, out of which 843 were BRAF V600E positive and 301 were BRAF V600E negative. The patients with BRAF V600E mutation had significantly greater chance of having 18F-FDG avid lesions. The pooled odds ratio was 2.12 (CI , p value <0.01). The Heterogeneity statistics for the studies with binary data were as follows; Q 5.64, H-1.00, I 2 0.0%, 70.8 % with no significant heterogeneity (p=0.46). The results of the individual studies are shown in table 3. The forest plot is shown in figure 1 and the heterogeneity funnel plot in figure 2. There were 4 studies that were included in the meta-analysis looking at 18F-FDG PET/CT mean SUV uptake difference between BRAF V600E positive and BRAF V600E negative

6 patients (10, 12, 13, 21). The pooled cohort included 315 patients. The synthesis forest plots as well as heterogeneity funnel plots are shown in figures - 3 and 4 respectively. There was no significant heterogeneity in these studies (Q = 6.2, p = 0.1 and I 2 = 51.7). The pooled mean SUV difference between BRAF V600E positive and BRAF V600E negative patients was 5.1 (CI ) with BRAF V600E positive patients showing significant higher FDG PET/CT uptake compared to BRAF V600E mutation negative patients. Discussion FDG-PET-CT imaging has been employed in differentiated thyroid cancer patients who despite primary surgical treatment with or without postoperative radioiodine therapy have a persistently detectable serum thyroglobulin level. Typically, initial attempts are made to localize residual disease with cervical sonography, CT, and/or either I-123 or I- 131 diagnostic imaging. Radioiodine imaging also helps determine if residual disease is amenable to re-treatment with I-131. In the setting of negative imaging using the techniques, and particularly when the serum thyroglobulin concentration is greater than or equal to 10 ng/ml, 18F-FDG-PET-CT imaging is often performed. A meta-analysis performed by Dong et al, determined that 18F-FDG-PET-CT has a pooled sensitivity and specificity of 93.5 % and 83.9 %,respectively, for identification of residual disease sites in patient s with radioiodine scan negative differentiated thyroid cancer (22). Further, combined 18F-FDG-PET-CT versus 18F-FDG-PET alone increases the detection rate of metastatic lesions (23). Studies have shown that the higher the serum thyroglobulin level, the greater the diagnostic sensitivity of imaging with 18f-FDG PET CT, though there is lack of consensus on the precise threshold level of thyroglobulin for detection of metastatic disease (24, 25). Bertagana et al. concluded that a thyroglobulin level of 10 ng/ml rendered a reasonable level of diagnostic accuracy for

7 the detection of residual differentiated thyroid cancer in I-131 scan negative patients (24). However, others have suggested that a thyroglobulin level of 5.5 ng/ ml and/or a thyroglobulin doubling time of less than 1 year offered the highest diagnostic accuracy for detection of DTC in I-131 scan negative patients (26).. Our meta-analysis shows that BRAF V600E -positive DTC patients have significantly higher odds of having 18F-FDG-PET avid lesions with relatively higher mean SUV values. It has been shown that papillary thyroid cancer with BRAF V600E mutation demonstrate underexpression of sodium-iodine symporter, thyroid peroxidase, and thyroglobulin mrnas as well as overexpression of the glucose transporter-1 (GLUT-1) compared to wild type PTC(27). However, another study has shown that GLUT-1 and GLUT-3 mrna expression did not differ with either BRAF V600E mutation or RET/PTC rearrangements compared to wild type tumors (28). Consequently, it appears that BRAF V600E mutation might confer an increased sensitivity to 18F-FDG-PET compared to wild type PTC. The detection of BRAF V600E mutation should prompt the treating clinician to consider 18-F FDG PET as a diagnostic test in I-131 refractory PTC, for localizing residual disease. As a corollary, detection of residual cancer in 18-F FDG PET may guide physicians with respect to the higher likelihood of BRAF V600E mutational status of the tumor, enabling the prospect of other potential therapies targeting the specific biochemical pathways related to the mutation. There are some limitations to our study. There might be selection bias since a high percentage of patients were BRAF V600E positive. The protocol for 18-F FDG PET study varies across institutions and the measurement of SUV depends on multiple factors. The SUV max in oncological conditions in 18F-FDG PET CT, has a tumor within-subject coefficient of variation of 10%(29). Also, reductions in SUV of up to 25 % and increases

8 of up to 33 % may be due to measurement variability(29). Conclusion Our meta-analysis shows that presence of BRAF V600E mutation in PTC confers a higher likelihood of 18-F FDG PET avidity as well as overall higher SUV uptake values compared to BRAF V600E mutation negative status. References 1. Mazzaferri EL, Robbins RJ, Spencer CA, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab. 2003;88: Caetano R, Bastos CR, de Oliveira IA, et al. Accuracy of positron emission tomography and positron emission tomography-ct in the detection of differentiated thyroid cancer recurrence with negative (131) I whole-body scan results: A meta-analysis. Head Neck. 2016;38: Choi WH, Chung YA, Han EJ, Sohn HS, Lee SH. Clinical value of integrated [18F]fluoro- 2-deoxy-D-glucose positron emission tomography/computed tomography in the preoperative assessment of papillary thyroid carcinoma: comparison with sonography. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 2011;30: Kwon SY, Choi EK, Kong EJ, et al. Prognostic value of preoperative 18F-FDG PET/CT in papillary thyroid cancer patients with a high metastatic lymph node ratio: a multicenter retrospective cohort study. Nuclear medicine communications. 2017;38: Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. Jama. 2013;309:

9 6. Alzahrani AS, Xing M. Impact of lymph node metastases identified on central neck dissection (CND) on the recurrence of papillary thyroid cancer: potential role of BRAFV600E mutation in defining CND. Endocr Relat Cancer. 2013;20: Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90: Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21: Welton NJ, White IR, Lu G, Higgins JP, Hilden J, Ades AE. Correction: interpretation of random effects meta-analysis in decision models. Med Decis Making. 2007;27: Yoon S, An YS, Lee SJ, et al. Relation Between F-18 FDG Uptake of PET/CT and BRAFV600E Mutation in Papillary Thyroid Cancer. Medicine (Baltimore). 2015;94(48):e Nagarajah J, Ho AL, Tuttle RM, Weber WA, Grewal RK. Correlation of BRAFV600E Mutation and Glucose Metabolism in Thyroid Cancer Patients: An (1)(8)F-FDG PET Study. J Nucl Med. 2015;56: Yoon M, Jung SJ, Kim TH, et al. Relationships between transporter expression and the status of BRAF V600E mutation and F-18 FDG uptake in papillary thyroid carcinomas. Endocr Res. 2016;41: Ozderya A, Temizkan S, Gul AE, Ozugur S, Sargin M, Aydin K. Correlation of BRAF mutation and SUVmax levels in thyroid cancer patients incidentally detected in 18Ffluorodeoxyglucose positron emission tomography. Endocrine. 2017;55: Kim SK, So Y, Chung HW, et al. Analysis of predictability of F-18 fluorodeoxyglucose- PET/CT in the recurrence of papillary thyroid carcinoma. Cancer Med. 2016;5:

10 15. Hwang SO, Lee SW, Kang JK, et al. Clinical value of visually identifiable 18Ffluorodeoxyglucose uptake in primary papillary thyroid microcarcinoma. Otolaryngol Head Neck Surg. 2014;151: Alzahrani AS, AlQaraawi A, Al Sohaibani F, Almanea H, Abalkhail H. Pancreatic metastasis arising from a BRAF(V600E)-positive papillary thyroid cancer: the role of endoscopic ultrasound-guided biopsy and response to sorafenib therapy. Thyroid. 2012;22: Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69: Kim H, Na KJ, Choi JH, Ahn BC, Ahn D, Sohn JH. Feasibility of FDG-PET/CT for the initial diagnosis of papillary thyroid cancer. Eur Arch Otorhinolaryngol. 2016;273: Kim MH, Ko SH, Bae JS, et al. Non-FDG-avid primary papillary thyroid carcinoma may not differ from FDG-avid papillary thyroid carcinoma. Thyroid. 2013;23: Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368: Choi EK, Chong A, Ha JM, Jung CK, O JH, Kim SH. Clinicopathological characteristics including BRAF V600E mutation status and PET/CT findings in papillary thyroid carcinoma. Clin Endocrinol (Oxf) : Dong MJ, Liu ZF, Zhao K, et al. Value of 18F-FDG-PET/PET-CT in differentiated thyroid carcinoma with radioiodine-negative whole-body scan: a meta-analysis. Nucl Med Commun. 2009;30:

11 23. Zoller M, Kohlfuerst S, Igerc I, et al. Combined PET/CT in the follow-up of differentiated thyroid carcinoma: what is the impact of each modality? Eur J Nucl Med Mol Imaging. 2007;34: Bertagna F, Biasiotto G, Orlando E, Bosio G, Giubbini R. Role of (1)(8)Ffluorodeoxyglucose positron emission tomography/computed tomography in patients affected by differentiated thyroid carcinoma, high thyroglobulin level, and negative (1)(3)(1)I scan: review of the literature. Jpn J Radiol. 2010;28: Marcus C, Whitworth PW, Surasi DS, Pai SI, Subramaniam RM. PET/CT in the management of thyroid cancers. AJR Am J Roentgenol. 2014;202: Giovanella L, Trimboli P, Verburg FA, et al. Thyroglobulin levels and thyroglobulin doubling time independently predict a positive 18F-FDG PET/CT scan in patients with biochemical recurrence of differentiated thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2013;40: Durante C, Puxeddu E, Ferretti E, et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab. 2007;92: Romei C, Ciampi R, Faviana P, et al. BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocr Relat Cancer. 2008;15: Lodge MA. Repeatability of Standardized Uptake Value in Oncologic 18F-FDG PET. J Nucl Med ;58:

12 Table 1; Characteristics of studies included in the systematic review. PDTC-Poorly differentiated thyroid cancer Table 1: Characteristics of studies included in the systematic review. PDTC-Poorly differentiated thyroid cancer Study N Study Design (Prospective or Retrospective) Diagnosis (n) Comments t al Retrospective PTC 150, Follicular 14,Tall cell 2,oncocytic 2,Diffuse Sclerosing 1 Preop. Mean SUV in BRAF patients was significantly ah, et al Retrospective PTC 48 (82 Including PDTC) Postop. Mean SUV in BRA patients was significantly et al Retrospective PTC 52 Preop. Mean SUV in BRAF patients was significantly a, et al Retrospective PTC 31 (follicular variant 3, oncocytic 5, tall cell 1) Preop. Mean SUV in BRAF patients was significantly t al Retrospective PTC 385, Follicular Variant 20, squamous metaplasia 4, Tall cell 1, Warthin like 1 preop. FDG uptake was n significantly higher in BRA patients Hwang S.O, et al Retrospective PTC 219 (all Microscopic), 2 Follicular variant, 1 Tall cell Variant Preop. FDG uptake was more significant in BRAF + patients J. R Filho, et al Retrospective PTC 4, tall cell variant 5 postop. 100% of FDG positive PTC vs 39% (9/23) of poorly DTC Choi, et al Retrospective PTC 95, Follicular variant 9, Tall cell variant 1 FDG uptake was higher BRAF + Patients Kim H, et al Retrospective PTC. 197 (246 foci) Preop. FDG positivity was not significantly higher in BRAF positive patients MH Kim, et al Retrospective classic PTC 167, follicular 20, Oncocytic 1 Preop. More patient with BRAF mutation has FDG positivity (51/62 vs 15/24) but was not statistical sig (p=0.052) PDTC = Poorly differentiated thyroid cancer

13 Table 2; Characteristics of individual studies patients, tumor extent, BRAF status, and FDG PET Findings Study Mean Age Tumor Size Gender Lymph Nodes + Number B (years) (cm) (m/f) (%) (%) S Yoon Et al (± 12) 1.4 (± 1.2) 37/132 87/169(51%) 139/169 (8 J. Nagarajah et al (± 11) NA 20/28 23/48 (28%) 24/48 (5 M Yoon et al (± 14.5) 1.5 (± 1.2) 11/ /52 (57.7%) 34/52 (65 A. Ozderya et al 13 NA NA 4/23 (17%) 17/31 (5 SK. Kim et al (± 12.2) 1.07 (± 0.74) 72/340 39% 277 /301 ( Hwang S.O et al (± 10.9) 5.6 (± 1.9) 29/190 77/219 (35%) 178/219 (8 J. R Filho et al. 17 NA NA NA NA 9/9 (100 H Kim et al / % 153/246 ( Choi et al / % 78/95(82 M H Kim et al ( ±13) 1.25 (±1.11) 44/144 88/161 (54.7%) 66/86 (76 + Values are mean ± SD for data when appropriate. NA = Not available

14 Study N Calculated Odds Confidence Intervals P Value Hwang et al Julio C et al Kim SK et al Kim H et al Min-Hee Kim et al Choi et al Nagarajah et al Table 3: The calculated odds and confidence intervals of the 7 studies that qualified for the pooled odds ratio calculation

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