The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors

RESEARCH ARTICLE The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors a11111 Agnieszka Czarniecka1*, Monika Kowal2, Dagmara Rusinek2, Jolanta Krajewska2, Michal Jarzab3, Ewa Stobiecka4, Ewa Chmielik4, Ewa Zembala-Nozynska4, Stanislaw Poltorak1, Aleksander Sacher1, Adam Maciejewski1, Jadwiga Zebracka-Gala2, Dariusz Lange4, Malgorzata Oczko-Wojciechowska2, Daria Handkiewicz-Junak2, Barbara Jarzab2 1 The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2 Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland, 3 III Dept. of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland, 4 Department of Tumor Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland OPEN ACCESS Citation: Czarniecka A, Kowal M, Rusinek D, Krajewska J, Jarzab M, Stobiecka E, et al. (2015) The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors. PLoS ONE 10(7): e0132821. doi:10.1371/journal.pone.0132821 Editor: Paula Soares, IPATIMUP/Faculty of Medicine of the University of Porto, PORTUGAL Received: March 5, 2015 Accepted: June 18, 2015 Published: July 15, 2015 Copyright: © 2015 Czarniecka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The study was partially funded by Polish National Science Center grant NN 403 194340 to A. C. The study was also conducted as an internal research project in MSC Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. * Abstract Introduction The risk of over-treatment in low-advanced PTC stages has prompted clinicians to search for new reliable prognostic factors. The presence of BRAF mutation, the most frequent molecular event in PTC, seems to be a good candidate. However, there is still lack of randomised trials and its significance has been proved by retrospective analyses, involving a large group of patients. The question arises whether this factor is useful in smaller populations, characterised for specialised centres. Thus, the aim of the study was to evaluate the use of BRAF mutation as a potential predictive marker in PTC patients. Material 233 PTC subjects treated between 2004-2006, were retrospectively analysed. Stage pT1 was diagnosed in 64.8% patients and lymph node metastases in 30.9%. Median follow-up was 7.5 years. BRAFV600E mutation was assessed postoperatively in all cases. Results BRAF V600E mutation was found in 54.5%. It was more frequent in patients > 45 years (p=0.0001), and associated with larger tumour size (p=0.004). Patients with tumours <= 10 mm were over-represented among BRAF negative population (p=0.03). No association between BRAF mutation and other clinicopathological factors was observed. BRAF status was associated neither with relapse nor with disease-free survival (DFS) (p=0.76). Nodal status, extrathyroidal invasion and tumour size significantly influenced DFS. PLOS ONE | DOI:10.1371/journal.pone.0132821 July 15, 2015 1 / 14 BRAF as a Predictive Factor in PTC Patients Competing Interests: The authors have declared that no competing interests exist. Conclusion The risk of PTC recurrence is mainly related to the presence of lymph node metastases and extrathyroidal invasion, whereas no impact of BRAF V600E mutation has been demonstrated. Introduction The increasing incidence of thyroid cancer, especially low-risk stages has been recently observed worldwide [1,2,3,4]. The growing number of low-stage PTC has raised the discussion about the optimal therapeutic strategy, including the extent of surgery, indications to prophylactic central lymph node (LN) dissection and adjuvant radioiodine therapy [5–9]. The prognosis in differentiated thyroid cancer is generally good. However, about 10–15% of patients develop local or distant recurrences [8,10,11]. It is essential to create strategies of adequate patients stratification to avoid the risk of suboptimal treatment in high-risk patients [9,12–15] and simultaneously to prevent significant therapy de-escalation in patients with clinically indolent disease. Searching for molecular markers is a possible way to achieve this goal. BRAFV600E mutation, being the most frequent oncogenic event and observed in about 50% of PTCs, is one of the best candidates [2,16,17]. This mutation, activating the MAPK pathway, plays a crucial role in malignant phenotype of PTC. The presence of BRAF mutation may be detected preoperatively, at the time of initial diagnosis from a fine-needle aspiration specimen, and thus it may influence the choice of further treatment strategy [5,12,15,18–21]. The prognostic importance of BRAF mutation has been analysed since the landmark studies, however, with controversial conclusions [7,10,12,22–26]. So far, there has been still lack of randomised trials supporting the prognostic significance of BRAF mutation. Recently published retrospective, multicentre analyses, involving a large group of PTC patients have demonstrated the association between BRAF mutation and both cancer-related mortality and PTC recurrence, albeit partially depending on other disease risk factors [27,28]. The question arises whether BRAF mutation is also useful as a prognostic factor in smaller populations, characterised for specialised surgical centres. Thus, the aim of this study was to evaluate the presence of BRAF mutation as a potential predictive marker in PTC patients and its possible association with disease prognosis with reference to other clinicopathological risk factors. Material and Methods Two hundred thirty eight PTC patients diagnosed by fine needle aspiration biopsy were analysed in a retrospective manner (S1 Table). These patients were selected from the population of all patients treated surgically at the Department of Oncological and Reconstructive Surgery at Center of Oncology—M. Sklodowska-Curie Memorial Institute, Gliwice Branch, fulfilling the following criteria: 1) primarily operated between 2004–2006, 2) with FFPE material available for molecular analysis, 3) with PTC post-operative confirmation in histopathological assessment. The group consisted of 209 women (87.8%) and 29 men (12.2%). The presence of BRAFV600E mutation was evaluated in all (...truncated)