- Email: [email protected]
Clinical utility of metabolic tumor volume in papillary thyroid carcinoma
abstracts
Annals of Oncology Conclusions: To date, this is the largest presented real-world analysis of the treatment patterns of L in pts with rDTC and our estimates of treatment duration as proxy for effectiveness are comparable to the phase 3 SELECT trial. Toxicity led to a minor proportion of discontinuations. Legal entity responsible for the study: The authors. Funding: Eisai Supported the Patient Support Program, hosted by Innomar Strategies, Inc. Disclosure: S.J. Hotte: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institu-
1864PD
Spatiotemporal intratumor genetic heterogeneity and clonal evolution in PTCs and paired DM
S. Gil Bernabe´1, N. Feas Rodrıguez1, M. Vega Herrero1, J.J. Este´banez Garcıa1, D. Soto de Prado2, J. Fra Rodrıguez3, G.M. Garcıa- Rostan1 1 Institute of Molecular Biology and Genetics (IBGM) - Department of Pathology, University of Valladolid, Valladolid, Spain, 2Medical Oncology, Hospital Cınico Universitario, Valladolid, Spain, 3Medical Oncology, Hospital Universitario Rıo Hortega, Valladolid, Spain Background: Papillary Thyroid Carcinoma (PTC) represents 80% of all thyroid cancers. Though the vast majority of PTC are indolent tumors, around 15% behave aggressively, developing distant metastases (DM), which cause patients death. The molecular mechanisms underlying DM are poorly understood. Little it is known about the contribution of intratumor heterogeneity to DM. Dynamic changes in mutation distribution through space and time have not been in deep characterized. Methods: By genotyping 13 cases of matched primary tumors (PrT) and DM, we sought to determine the prevalence of mutations in genes that have been associated with tumor progression and aggressiveness in follicular thyroid carcinogenesis. To assess the contribution of intratumor heterogeneity and clonal evolution to DM, 54 tumor areas, including different areas across space and time within the PrT and the DM were analyzed. Genotyping was approached by PCR and SSCP or DS. Results: Twelve cases (92%) were mutated in at least one of the genes screened [TERT 69%, BRAF 54%, KRAS 23%, NRAS 23%, HRAS 15.4%, PIK3CA 15.4%]. No mutations were seen at MED12 or EIF1AX. Among the mutated cases 67% exhibited more than 1 gene activated. Three mutated genes co-existed in 62.5% of the cases. Concurrent activation of TERTþRAS or TERTþBRAF was seen in 5 cases each event (62.5%). Simultaneous activation of BRAF and RAS was found in 4 cases (50%). In all the cases in which more than 1 area of DM, across space and time, was analyzed, the mutations at TERT, KRAS and HRAS resulted clonal. De novo mutations at DM were seen in 6 cases. Within PrT, subclonality was as follows TERT 33%; RAS 20%; BRAF 40% and PIK3CA 100%. Conclusions: The number of mutational events in PTC with DM is strikingly higher than in PTC without DM. While TERT and RAS mutations tend to be clonal within PrT and DM, BRAF mutations tend to be subclonal. TERT and RAS mutations may appear the novo at DM. PTC with DM display a much higher rate of genetic heterogeneity (67%). The coexistence of mutations in different genes is in agreement with the hypothesis that tumor progression relies on progressive accumulation of genetic alterations. MED12 and EIF1AX do not play a role in aggressive PTCs. Concurrent mutations at TERT, and different PI3K/AKT and MAPK pathway genes are common in metastatic PTC. Legal entity responsible for the study: Ginesa Garcıa Rostan. Funding: Head of Group "Pathobiology of Cancer: Inter-, Intra-tumoral heterogeneity and Molecular Targets at Institute of Molecular Biology and Genetics (IBGM) of Valladolid University. Disclosure: All authors have declared no conflicts of interest.
1866P
N. Takemoto1, J. Miyabe2, T. Fukusumi1, M. Suzuki1, H. Inohara1 Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan, 2Department of Head and Neck Surgery, Osaka International Cancer Institute, Osaka, Japan
1
Background: The management of papillary thyroid carcinoma (PTC) should be decided by Risk-adapted approach. However, intermediated risk PTC needs to be stratified more precisely. Otherwise, the utility of 18F-FDG PET images in patients with PTC is restrictive. The aim of this study was to investigate the prognostic value of Metabolic Tumor Volume (MTV) measured on 18F-FDG PET images in patients with papillary thyroid carcinoma treated with surgery. Methods: We retrospectively analyzed 102 patients with PTC who underwent 18F-FDG PET/CT between Feburary 2009 and June 2017 at Osaka University Medical School Hospital for initial staging before surgery. We evaluated the association of MTV of primary tumor (T-MTV) with relapse-free survival (RFS) using Cox regression analysis. Receiver operating characteristic (ROC) curves were used to estimate the optimal cutoff values for T-MTV. We also conducted recursive partitioning analyses to offer a novel risk stratification system. Results: The 3-year RFS for all patients were 81.2% with median follow-up of 42 months (range 11-111). In Cox model, T-MTV (Hazard Ratio, 1.23; 95% CI, 1.08 to 1.38; P ¼ 0.002) was significantly associated with RFS. ROC analyses showed that the optimal cutoff value of T-MTV was 10.3ml. We classified the patients as having a low, intermediate, or high risk of relapse or death on the basis of T-MTV and lymph node metastasis. Conclusions: MTV of primary tumor was a significant prognostic factor for RFS in patients with PTC treated with surgery. Incorporation of T-MTV into staging may lead to a better risk stratification. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1867P 1865PD
Specific patterns of long non-coding RNA expression in benign and malignant thyroid nodules
V. Yakushina1, A. Lavrov2 1 Epigenetics Laboratory, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation, 2Genome Editing Laboratory, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation Background: Although there are increasing evidences of lncRNA role in cancer progression, and of its possible diagnostic and therapeutic significance, lncRNA in thyroid neoplasms are poorly investigated: studies are limited to papillary cancer, the differences in variants of papillary carcinoma are rarely considered, there are no investigations of lncRNA in benign nodules, follicular and anaplastic carcinomas.
Volume 30 | Supplement 5 | October 2019
Clinical utility of metabolic tumor volume in papillary thyroid carcinoma
Correlation of thyroglobulin (Tg) oscillations with progression-free survival (PFS) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid carcinoma (DTC) treated with multikinase inhibitors (MKI)
1 , M. Roca Herrera1, D. Acosta1, M. Diez1, J. Hernando Cubero1, A. Garcıa Alvarez R. Ferrer2, A. Garcia Burillo3, C. Zafon4, C. Iglesias5, J. Capdevila1 1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, 2Clinical Biochemistry, Vall d’Hebron University Hospital, Barcelona, Spain, 3Nuclear Medicine, Vall d’Hebron University Hospital, Barcelona, Spain, 4Endocrinology, Vall d’Hebron University Hospital, Barcelona, Spain, 5Pathology, Vall d’Hebron University Hospital, Barcelona, Spain
Background: Role of Tg levels as a biomarker in RAI-R DTC during MKI is unclear. Falling levels of Tg after starting MKI treatment has been previously reported, with a higher reduction in patients who achieve response. However, transient Tg oscillations
doi:10.1093/annonc/mdz267 | v757
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz267.004/5578222 by guest on 24 October 2019
tion): Eisai. E. Winquist: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai. N. Chua: Honoraria (self), Advisory / Consultancy: Eisai. J..D. Ruether: Honoraria (self), Advisory / Consultancy: Eisai. N. Lamond: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai. S. Ezzat: Advisory / Consultancy: Eisai. M. Massicotte: Honoraria (self), Advisory / Consultancy: Eisai. R. Wong: Advisory / Consultancy: Eisai. P. Lam: Full / Part-time employment: Eisai. B. Yap: Full / Part-time employment: Eisai. M.K. Krzyzanowska: Honoraria (self), Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Exilixis. All other authors have declared no conflicts of interest.
Methods: To evaluate lncRNA expression in follicular adenoma (FA), follicular and classical variants of papillary carcinoma (fvPTC/clPTC), follicular (FTC) and anaplastic (ATC) carcinomas, a comprehensive dataset of 8 independent Microarray experiments on Affymetrix Human Genome U133 Plus 2.0 Array and RNA-Seq experiments (TCGA and PRJEB11591 projects) was analyzed. In silico validation of differential expression was performed. Putative functions of aberrantly expressed lncRNA were determined via co-expression and enrichment analysis of Gene Ontology, KEGG, Reactome terms. Results: The analysis revealed 8 lncRNA general for all investigated neoplasms, 22 general for papillary carcinomas, 32 - specific for clPTC, 1 - for fvPTC, and 177 - specific for ATC. No lncRNA differentially expressed in FTC and FA was found. There are strong clustering of ATC, clustering of clPTC and fvPTC, no clustering within the FTC and FA. LncRNA found to be specific for ATC are probably associated with anaplastic features and cancer progression. Potential functions of lncRNA general for all studied neoplasms - L1CAM interactions; general for papillary carcinomas - tryptophan metabolism; specific for fvPTC - cell polarity and WNT signaling; specific for clPTC extracellular matrix organization and endoderm formation; specific for ATC - cell cycle and mitosis. Known oncogenic and tumor suppressor lncRNA (NR2F1-AS1, LINC00511, SLC26A4-AS1, CRNDE, LINC01116, RMST) are found in thyroid carcinomas for the first time. Conclusions: Common and specific patterns of lncRNA expression in main histological subtypes of thyroid nodules are determined. The findings enhance the understanding of lncRNA in thyroid cancer progression. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology Conclusions: To date, this is the largest presented real-world analysis of the treatment patterns of L in pts with rDTC and our estimates of treatment duration as proxy for effectiveness are comparable to the phase 3 SELECT trial. Toxicity led to a minor proportion of discontinuations. Legal entity responsible for the study: The authors. Funding: Eisai Supported the Patient Support Program, hosted by Innomar Strategies, Inc. Disclosure: S.J. Hotte: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institu-
1864PD
Spatiotemporal intratumor genetic heterogeneity and clonal evolution in PTCs and paired DM
S. Gil Bernabe´1, N. Feas Rodrıguez1, M. Vega Herrero1, J.J. Este´banez Garcıa1, D. Soto de Prado2, J. Fra Rodrıguez3, G.M. Garcıa- Rostan1 1 Institute of Molecular Biology and Genetics (IBGM) - Department of Pathology, University of Valladolid, Valladolid, Spain, 2Medical Oncology, Hospital Cınico Universitario, Valladolid, Spain, 3Medical Oncology, Hospital Universitario Rıo Hortega, Valladolid, Spain Background: Papillary Thyroid Carcinoma (PTC) represents 80% of all thyroid cancers. Though the vast majority of PTC are indolent tumors, around 15% behave aggressively, developing distant metastases (DM), which cause patients death. The molecular mechanisms underlying DM are poorly understood. Little it is known about the contribution of intratumor heterogeneity to DM. Dynamic changes in mutation distribution through space and time have not been in deep characterized. Methods: By genotyping 13 cases of matched primary tumors (PrT) and DM, we sought to determine the prevalence of mutations in genes that have been associated with tumor progression and aggressiveness in follicular thyroid carcinogenesis. To assess the contribution of intratumor heterogeneity and clonal evolution to DM, 54 tumor areas, including different areas across space and time within the PrT and the DM were analyzed. Genotyping was approached by PCR and SSCP or DS. Results: Twelve cases (92%) were mutated in at least one of the genes screened [TERT 69%, BRAF 54%, KRAS 23%, NRAS 23%, HRAS 15.4%, PIK3CA 15.4%]. No mutations were seen at MED12 or EIF1AX. Among the mutated cases 67% exhibited more than 1 gene activated. Three mutated genes co-existed in 62.5% of the cases. Concurrent activation of TERTþRAS or TERTþBRAF was seen in 5 cases each event (62.5%). Simultaneous activation of BRAF and RAS was found in 4 cases (50%). In all the cases in which more than 1 area of DM, across space and time, was analyzed, the mutations at TERT, KRAS and HRAS resulted clonal. De novo mutations at DM were seen in 6 cases. Within PrT, subclonality was as follows TERT 33%; RAS 20%; BRAF 40% and PIK3CA 100%. Conclusions: The number of mutational events in PTC with DM is strikingly higher than in PTC without DM. While TERT and RAS mutations tend to be clonal within PrT and DM, BRAF mutations tend to be subclonal. TERT and RAS mutations may appear the novo at DM. PTC with DM display a much higher rate of genetic heterogeneity (67%). The coexistence of mutations in different genes is in agreement with the hypothesis that tumor progression relies on progressive accumulation of genetic alterations. MED12 and EIF1AX do not play a role in aggressive PTCs. Concurrent mutations at TERT, and different PI3K/AKT and MAPK pathway genes are common in metastatic PTC. Legal entity responsible for the study: Ginesa Garcıa Rostan. Funding: Head of Group "Pathobiology of Cancer: Inter-, Intra-tumoral heterogeneity and Molecular Targets at Institute of Molecular Biology and Genetics (IBGM) of Valladolid University. Disclosure: All authors have declared no conflicts of interest.
1866P
N. Takemoto1, J. Miyabe2, T. Fukusumi1, M. Suzuki1, H. Inohara1 Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan, 2Department of Head and Neck Surgery, Osaka International Cancer Institute, Osaka, Japan
1
Background: The management of papillary thyroid carcinoma (PTC) should be decided by Risk-adapted approach. However, intermediated risk PTC needs to be stratified more precisely. Otherwise, the utility of 18F-FDG PET images in patients with PTC is restrictive. The aim of this study was to investigate the prognostic value of Metabolic Tumor Volume (MTV) measured on 18F-FDG PET images in patients with papillary thyroid carcinoma treated with surgery. Methods: We retrospectively analyzed 102 patients with PTC who underwent 18F-FDG PET/CT between Feburary 2009 and June 2017 at Osaka University Medical School Hospital for initial staging before surgery. We evaluated the association of MTV of primary tumor (T-MTV) with relapse-free survival (RFS) using Cox regression analysis. Receiver operating characteristic (ROC) curves were used to estimate the optimal cutoff values for T-MTV. We also conducted recursive partitioning analyses to offer a novel risk stratification system. Results: The 3-year RFS for all patients were 81.2% with median follow-up of 42 months (range 11-111). In Cox model, T-MTV (Hazard Ratio, 1.23; 95% CI, 1.08 to 1.38; P ¼ 0.002) was significantly associated with RFS. ROC analyses showed that the optimal cutoff value of T-MTV was 10.3ml. We classified the patients as having a low, intermediate, or high risk of relapse or death on the basis of T-MTV and lymph node metastasis. Conclusions: MTV of primary tumor was a significant prognostic factor for RFS in patients with PTC treated with surgery. Incorporation of T-MTV into staging may lead to a better risk stratification. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1867P 1865PD
Specific patterns of long non-coding RNA expression in benign and malignant thyroid nodules
V. Yakushina1, A. Lavrov2 1 Epigenetics Laboratory, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation, 2Genome Editing Laboratory, Federal State Budgetary Institution "Research Centre for Medical Genetics", Moscow, Russian Federation Background: Although there are increasing evidences of lncRNA role in cancer progression, and of its possible diagnostic and therapeutic significance, lncRNA in thyroid neoplasms are poorly investigated: studies are limited to papillary cancer, the differences in variants of papillary carcinoma are rarely considered, there are no investigations of lncRNA in benign nodules, follicular and anaplastic carcinomas.
Volume 30 | Supplement 5 | October 2019
Clinical utility of metabolic tumor volume in papillary thyroid carcinoma
Correlation of thyroglobulin (Tg) oscillations with progression-free survival (PFS) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid carcinoma (DTC) treated with multikinase inhibitors (MKI)
1 , M. Roca Herrera1, D. Acosta1, M. Diez1, J. Hernando Cubero1, A. Garcıa Alvarez R. Ferrer2, A. Garcia Burillo3, C. Zafon4, C. Iglesias5, J. Capdevila1 1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, 2Clinical Biochemistry, Vall d’Hebron University Hospital, Barcelona, Spain, 3Nuclear Medicine, Vall d’Hebron University Hospital, Barcelona, Spain, 4Endocrinology, Vall d’Hebron University Hospital, Barcelona, Spain, 5Pathology, Vall d’Hebron University Hospital, Barcelona, Spain
Background: Role of Tg levels as a biomarker in RAI-R DTC during MKI is unclear. Falling levels of Tg after starting MKI treatment has been previously reported, with a higher reduction in patients who achieve response. However, transient Tg oscillations
doi:10.1093/annonc/mdz267 | v757
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz267.004/5578222 by guest on 24 October 2019
tion): Eisai. E. Winquist: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai. N. Chua: Honoraria (self), Advisory / Consultancy: Eisai. J..D. Ruether: Honoraria (self), Advisory / Consultancy: Eisai. N. Lamond: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai. S. Ezzat: Advisory / Consultancy: Eisai. M. Massicotte: Honoraria (self), Advisory / Consultancy: Eisai. R. Wong: Advisory / Consultancy: Eisai. P. Lam: Full / Part-time employment: Eisai. B. Yap: Full / Part-time employment: Eisai. M.K. Krzyzanowska: Honoraria (self), Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Exilixis. All other authors have declared no conflicts of interest.
Methods: To evaluate lncRNA expression in follicular adenoma (FA), follicular and classical variants of papillary carcinoma (fvPTC/clPTC), follicular (FTC) and anaplastic (ATC) carcinomas, a comprehensive dataset of 8 independent Microarray experiments on Affymetrix Human Genome U133 Plus 2.0 Array and RNA-Seq experiments (TCGA and PRJEB11591 projects) was analyzed. In silico validation of differential expression was performed. Putative functions of aberrantly expressed lncRNA were determined via co-expression and enrichment analysis of Gene Ontology, KEGG, Reactome terms. Results: The analysis revealed 8 lncRNA general for all investigated neoplasms, 22 general for papillary carcinomas, 32 - specific for clPTC, 1 - for fvPTC, and 177 - specific for ATC. No lncRNA differentially expressed in FTC and FA was found. There are strong clustering of ATC, clustering of clPTC and fvPTC, no clustering within the FTC and FA. LncRNA found to be specific for ATC are probably associated with anaplastic features and cancer progression. Potential functions of lncRNA general for all studied neoplasms - L1CAM interactions; general for papillary carcinomas - tryptophan metabolism; specific for fvPTC - cell polarity and WNT signaling; specific for clPTC extracellular matrix organization and endoderm formation; specific for ATC - cell cycle and mitosis. Known oncogenic and tumor suppressor lncRNA (NR2F1-AS1, LINC00511, SLC26A4-AS1, CRNDE, LINC01116, RMST) are found in thyroid carcinomas for the first time. Conclusions: Common and specific patterns of lncRNA expression in main histological subtypes of thyroid nodules are determined. The findings enhance the understanding of lncRNA in thyroid cancer progression. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.