Shallow Whole-Genome Sequencing from Plasma Identifies FGFR1 Amplified Breast Cancers and Predicts Overall Survival

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 evaluateFGFR1copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients.Methods:Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened forFGFR1amplification by FISH, and positive cases were confirmed with a microarray platform (Oncoscan(TM)). 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 theFGFR1status.Results:Tissue-based analyses identifiedFGFR1amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n= 12) showed concordance forFGFR1status between tissue and cfDNA. In one case, we were able to detect a high-levelFGFR1amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival.Conclusions:Screening forFGFR1amplification 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.