Chantal Bourrier1, Jean-Yves Pierga2,3,4, Laura Xuereb5, Hélène Salaun2,4, Charlotte Proudhon3, Michael R Speicher6,7, Jelena Belic6, Ellen Heitzer6,7,8, Brian Paul Lockhart1, Nolwen Guigal-Stephan1. 1. Division of Biotechnology, Servier Research Institute, 125, Chemin de ronde, 78290 Croissy Sur-seine, France. 2. Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France. 3. Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, INSERM CIC 1428, 26 rue d'Ulm, 75005 Paris, France. 4. Université de Paris, 75005 Paris, France. 5. Division of Methodology and Valorisation of Data, Servier Research and Development Institute, 50 rue carnot, 92150 Suresnes, France. 6. Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria. 7. BioTechMed-Graz, 8010 Graz, Austria. 8. Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, 8010 Graz, Austria.
Abstract
Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened for FGFR1 amplification by FISH, and positive cases were confirmed with a microarray platform (OncoscanTM). Subsequently, cfDNA was evaluated by two approaches, i.e., mFAST-SeqS and shallow whole-genome sequencing (sWGS), to estimate the circulating tumor DNA (ctDNA) allele fraction (AF) and to evaluate the FGFR1 status. Results: Tissue-based analyses identified FGFR1 amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n = 12) showed concordance for FGFR1 status between tissue and cfDNA. In one case, we were able to detect a high-level FGFR1 amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival. Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.
Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients. Methods:Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened for FGFR1 amplification by FISH, and positive cases were confirmed with a microarray platform (OncoscanTM). Subsequently, cfDNA was evaluated by two approaches, i.e., mFAST-SeqS and shallow whole-genome sequencing (sWGS), to estimate the circulating tumor DNA (ctDNA) allele fraction (AF) and to evaluate the FGFR1 status. Results: Tissue-based analyses identified FGFR1 amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n = 12) showed concordance for FGFR1 status between tissue and cfDNA. In one case, we were able to detect a high-level FGFR1 amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival. Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.
Entities:
Keywords:
FGFR1; breast Cancer; clinical trials; ctDNA; liquid biopsy; sWGS