D M Allin1, R Shaikh2, P Carter2, K Thway3, M T A Sharabiani4, D Gonzales-de-Castro2, B O'Leary5, I Garcia-Murillas5, S Bhide6, M Hubank2, K Harrington7, D Kim8, K Newbold7. 1. Radiotherapy and Imaging Division, The Institute of Cancer Research, London, UK. Electronic address: davidallin@nhs.net. 2. Centre for Molecular Pathology, The Royal Marsden Hospital, London, UK. 3. Histopathology Department, The Royal Marsden Hospital, London, UK. 4. Statistics Unit, The Royal Marsden Hospital, London, UK. 5. Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK. 6. Head & Neck/Thyroid Oncology Department, The Royal Marsden Hospital, London, UK. 7. Radiotherapy and Imaging Division, The Institute of Cancer Research, London, UK; Head & Neck/Thyroid Oncology Department, The Royal Marsden Hospital, London, UK. 8. ENT/Head & Neck Department, St George's Hospital, London, UK.
Abstract
BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.
BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.
Authors: Marianna Alunni-Fabbroni; Kerstin Rönsch; Thomas Huber; Clemens C Cyran; Max Seidensticker; Julia Mayerle; Maciej Pech; Bristi Basu; Chris Verslype; Julia Benckert; Peter Malfertheiner; Jens Ricke Journal: J Transl Med Date: 2019-10-01 Impact factor: 5.531
Authors: Keith C Bible; Electron Kebebew; James Brierley; Juan P Brito; Maria E Cabanillas; Thomas J Clark; Antonio Di Cristofano; Robert Foote; Thomas Giordano; Jan Kasperbauer; Kate Newbold; Yuri E Nikiforov; Gregory Randolph; M Sara Rosenthal; Anna M Sawka; Manisha Shah; Ashok Shaha; Robert Smallridge; Carol K Wong-Clark Journal: Thyroid Date: 2021-03 Impact factor: 6.568
Authors: Sally L George; Elisa Izquierdo; James Campbell; Eleni Koutroumanidou; Paula Proszek; Sabri Jamal; Deborah Hughes; Lina Yuan; Lynley V Marshall; Fernando Carceller; Julia C Chisholm; Sucheta Vaidya; Henry Mandeville; Paola Angelini; Ajla Wasti; Tomas Bexelius; Khin Thway; Susanne A Gatz; Matthew Clarke; Bissan Al-Lazikani; Giuseppe Barone; John Anderson; Deborah A Tweddle; David Gonzalez; Brian A Walker; Jack Barton; Sarita Depani; Jessica Eze; Saira W Ahmed; Lucas Moreno; Andrew Pearson; Janet Shipley; Chris Jones; Darren Hargrave; Thomas S Jacques; Michael Hubank; Louis Chesler Journal: Eur J Cancer Date: 2019-09-19 Impact factor: 9.162