LIQUID'BIOPSYIBASED'MONITORING'OF'EZH2'MUTATIONS'IN'FOLLICULAR'
LYMPHOMA:'IMPLICATIONS'FOR'NONIINVASIVE'DISEASE'MONITORING'AND'
POSTER'38'
TARGETED'THERAPY'
'
Ákos!Nagy1,!Bence!Bátai1,!Alexandra!Balogh2,!Illés!Sarolta2,!Gábor!Mikala3,!Noémi!Nagy4,!Laura!Kiss1,!
Lili!Kotmayer1,!András!Matolcsy1,5,!Donát!Alpár1,!Tamás!Masszi2,!András!Masszi2!and!Csaba!Bödör4,!!
!
(1)MTAUSE! Momentum! Molecular! Oncohematology! Research! Group,! 1st! Department! of! Pathology!
and!Experimental!Cancer!Research,!Semmelweis!University,!Budapest,!Hungary,!(2)3rd!Department!of!
Internal! Medicine,! Semmelweis! University,! Budapest,! Hungary,! (3)SouthUPest! Central! HospitalU!
National! Institute! of! Hematology! and! Infectious! Diseases,! Budapest,! Hungary,! (4)Semmelweis!
University,! Budapest,! Hungary,! (5)Department! of! Laboratory! Medicine,! Division! of! Pathology,!
Karolinska!Institutet,!Karolinska!University!Hospital,!Stockholm,!Sweden!
!
CONTEXT:! Follicular! lymphoma! (FL)! is! the! most! common! type! of! indolent! nonJHodgkin!
lymphomas,! with! an! average! overall! survival! rate! of! 15! years.! The! majority! of! FL! patients!
experience! disease! progression! or! high! grade! transformation! to! a! more! aggressive!
lymphoma,!raising!the!need!for!effective!treatment!response!monitoring,!which!however!is!
hampered!by!the!limited!specificity!and!sensitivity!of!the!most!widely!used,!imaging!based!
PETJCT! method.! Molecular! analysis! of! tumor! derived! circulating! DNA! (ctDNA),! frequently!
referred!as!liquid!biopsy,!is!a!promising!minimally!invasive,!radiationJfree!disease!monitoring!
tool! for! patients! suffering! from! a! wide! range! of! different! tumor! types.! Recent! studies!
interrogating! the! genomic! background! of! FL! have! revealed! activating! mutations! in! the!
epigenetic!regulator!EZH2!gene!in!25%!of!patients!at!diagnosis.!
OBJECTIVE:! In! this! feasibility! study,! we! tested! the! power! of! detection! and! timeJresolved!
monitoring!of!EZH2!mutations!in!ctDNA!of!FL!patients!receiving!immunochemotherapy!(ICT).!
METHODS:!Fifty!blood!plasma!samples!have!been!collected!from!26!EZH2!mutant!FL!patients!
treated!with!ICT.!After!ctDNA!isolation,!EZH2!mutations!were!screened!in!each!sample!using!
digital!droplet!PCR!(BioJRad!Laboratories,!USA).!The!acquired!genetic!results!were!compared!
with!PETJCT!based!imaging!data!where!available.!
RESULTS:!EZH2!mutations!were!detected!in!plasma!samples!of!eight!patients!suffering!from!
active!or!transformed!FL.!All!patients!with!EZH2!wild!type!plasma!samples!were!in!complete!
or!partial!remission.!In!patients!with!EZH2!mutation!positive!ctDNA,!allele!frequencies!of!the!
mutations!correlated!with!the!amount!of!metabolically!active!tumor!sites!observed!on!PETJ
CT! scan! images.! Variant! allele! frequencies! of!EZH2!mutations! rapidly! declined! or! dropped!
below!the!detection!limit!upon!successful!treatment,!while!in!one!patient,!treatment!failure!
was! associated! with! high!EZH2!variant! allele! frequency.! We! also! demonstrated! spatial!
heterogeneity! of!EZH2!mutations! in! another! case! where! different!EZH2!mutations! deriving!
from!distinct!anatomical!sites!could!simultaneously!be!detected!in!the!plasma.!
CONCLUSIONS:! Our! results! suggest! that! liquid! biopsy! based!EZH2!mutation! analysis! with!
sensitive! digital! droplet! PCR! method! offers! a! realJtime,! radiation! free,! sensitive! treatment!
response!monitoring!tool!for!patients!with!active!EZH2!mutant!FL.!
! !