Embed Size (px)
Citation preview
Modulo dichiarazione conflitto di interessi
Tutti i rapporti finanziari intercorsi negli ultimi due anni devono essere dichiarati.
Non ho rapporti (finanziari o di altro tipo) con le Aziende del farmaco
Ho / ho avuto rapporti (finanziari o di altro tipo) con le Aziende del farmaco
Relationship Company/Organization
Grant supporting LiqHERcept/GIM21 Roche Pharmaceuticals
Grant supporting anti HER2 antibody development
Ibi Lorenzini
Invasive Bias in tissue sampling Single time point Analyte virtually unlimited Many aberrations at once (large panels) high sensitivity
Minimally invasive No bias Longitudinal ctDNA degraded and scarce Limits in panel complexity low sensitivity
+
+
-
-
Tissue Biopsy & Liquid Biopsy: complementary
+ combining
tissue biopsy, liquid biopsy and re-biopsy
+
metastatico
stadi precoci
localmente avanzato
Terapia medica
pre-sintomatico
DNA circolante tumorale (ctDNA): ‘azionabile’ a tutti gli stadi di malattia
esempi ricaduta clinica
Scopo del ctDNA
stadi avanzati
CancerSEEK
Prevenzione primaria e secondaria, sorveglianza
intensificata
TRACERx
anticipazione del rischio di recidiva
F-One Liquid
sospensione di terapia inefficace
evoluzione e complessità della
malattia
Assegnazione terapia bersaglio
anche non-standard
chirurgia avviamento al trattamento chirurgico
sorveglianza post-chirurgica; trattamenti
adiuvanti etc.
HER2 breast cancer T-DM1
Allegretti, M. … and Fabi, A. 2019, in preparation
Cycle 1 T-DM1
Cycle 2 T-DM1
Cycle 3 T-DM1
Cycle n T-DM1
relapse
Ado-Trastuzumab-emtansine (T-DM1)
Alessandra Fabi
Michelangelo Russillo
Edoardo Pescarmona
Simonetta Buglioni
Francesco Cognetti
Matteo Allegretti
Elena Giordan
i
Paolo Romania
LiqBreasTrack: tracking mutational trajectories in T-DM1-treated HER2 breast carcinoma patients by Liquid Biopsy
TTZ/PTZ + taxanes etc Time 0
baseline
NGS
dPCR
LiqBreasTrack: monitoring by NGS & dPCR
1. Lead time to progression (ctDNA PD vs. RECIST PD)
2. Recurrent mutational patterns on progression
LiqBreasTrack: primary aims
LiqBreasTrack: HER2 amplification
NGS
dPCR
“My mom always said life was like a box of chocolates. You never know what you're gonna get.”
Plasma (on T-DM1) Pre-T-DM1 at progression
Tissues (pre T-DM1)
Evaluation of HER2 status dPCR assay: HER2/EFTUD
Progression
R= 0.99
R= 0.94
R= 1.17
R=2.28
R= 1.08
R= 1.12
R= 1.04
R= 1.46
pt#2
pt#4
pt#5
pt#6
pt#9
pt#15
pt#18
pt#17
Cutoff 1.15 Cutoff 2.00
Post T-DM1 Re-biopsy
R= 1.31
Yr 2018
R= 0.98
R= 1.04
R= 1.09
on treatment
on treatment
on treatment
on treatment
on treatment
Monitoring T-DM1 treated patients by liquid biopsy - HER2 amplification
VIC
FAM
HER2
EFTUD non-amplified
double positives
HER2/EFTUD ratio - R
R= 2.55
Yr 2015
R= 1.92
Yr 1995
R= 1.33
Yr 2000
R= 10.1
Yr 2001
R= 0.85
Yr 2012
R= 1.25
Yr 2006
R= 1.11
Yr 2012
R= 2.74
Yr 2015
R= 30.5
Yr 2016
R= 3.44
Yr 2017
Yr 2015
R= 1.27
Yr 2018
R= 0.61
Yr 2017
R= 0.59
Yr 2018
R= 5.00
Yr 2012
R= 9.50
LiqBreasTrack: other genomic alterations (SNVs) in blood (and tissues)
NGS
dPCR
Blood drawings
0,0%
1,0%
2,0%
3,0%
4,0%
5,0%
6,0%
1 2 3 4 5 6 7 8 9
pt#1 age 54
0,0%
0,2%
0,4%
0,6%
0,8%
1,0%
1 2 3 4 5 6 7 8 9 10 11 12
pt#2 age 59
pt#7 age 52
0,0%
0,2%
0,4%
0,6%
0,8%
1,0%
1 2 3 4 5 6 7
Blood drawings Blood drawings
VA
F (b
loo
d)
0,00%
0,04%
0,08%
0,12%
0,16%
0,20%
1 2 3 4 5 6 7 8 9 10 11 12 13
Lead time: 0.9 months
Lead time: 2.8 months
Lead time: 2.9 months
Lead time: 2.1 months
ctDNA present at time 0, and slowly going up
ctDNA NOT present at time 0, but de novo appearing some time after the beginning of
treatment
intersecting ctDNA trajectories
delayed ctDNA appearance
NGS dPCR
resistance (primary) resistance
(acquired/adaptive)
sensitivity & resistance
(bi-clonal ear-marking)
sensitivity (best responders)
LiqBreastTrack: recurrent ctDNA patterns
Blood drawings
PIK3CA p.H1047R
TP53 p.R273H
ESR1 p.Y357C p.D538G
pt#3 age 38
PIK3CA E545K (NGS IRE Anat Patol)
tDNA (breast, 2015)
FoundationOne (Roche) report
Trastuzumab/Pertuzumab neoadjuvant
tDNA (ax lympho, 2016)
Lymph node resection
tDNA (skin, 2017)
LiqBreasTrack: ultra-fast ctDNA clearance
pt#6, age 47
0,0%
2,0%
4,0%
6,0%
8,0%
10,0%
1 2 3 4 5 6
Alle
le f
req
uen
cy
Blood drawings
PIK3CA E545K
LiqBreasTrack: convergent Darwinian evolution leading to vulnerability
0,0%
2,0%
4,0%
6,0%
8,0%
10,0%
1 2 3 4 5 6 7 8
ESR1 p.Y537S ESR1 p.D538G ESR1 p.Y537N
VA
F
Blood drawings
NGS data
dPCR data
CT scan progression
Baseline
T-DM1
ESR1 p.D538G VAF: 1.4%
ESR1 p.D538G VAF: 0.4%
ESR1 p.Y537S VAF: 0.05%
ESR1 p. Y537N VAF: 0.0%
ESR1 p. Y537N VAF: 0.2%
ESR1 p.Y537S VAF: 8.8%
pt#6, age 47
www.oncokb.org
LiqBreastTrack: assigning NON-SOC therapy by ctDNA
Mut frequency 8.3% advanced BrCa
ESR1 p.Y537S
ESR1 p.D538G
ESR1 p.Y537N
bioinformatician
surgeon
biostatistician
Molecular Biologist
medical oncologist
nurse
Pharmacologist – Hospital Pharmacist
IRE Molecular Tumor Board hematologist
pathologist
June 2019
October 2019
LiqBreastTrack: response to NON-SOC therapy
LiqBreasTrack reveals new vulnerabilities not present in archival tumor tissues
ID
Tissue mutations (number)
Plasma mutations Clinical behaviour (imaging)
Plasma behaviour (ctDNA)
Actionable (OncoKB level ≤3)
Primary Metastasis T=0 Prog T=0 Prog
pt#1 - - PD
pt#2 12 1 PD
pt#3 - - PD
pt#4 - 43, 11, 7 PD
pt#5 4 64 NA SD NA
pt#6 1 1, 1, 1 PD
pt#7 - - PD
pt#9 2 - NA SD NA
pt#10 2 PD
pt#12 - - NA SD NA
pt#13 - - PD
pt#14 - 1 - SD not available yet -
pt#15 2 - - SD not available yet -
pt#16 - - - SD not available yet -
pt#17 - 0 - SD not available yet -
brain metastasis
Pts w/actionable SNVs on progression
5/8 (62.5%)
NA: Not Applicable
- Tumor vulnerabilities only seen in blood
- Tumor vulnerabilities not present at the beginning of T-DM1 treatment
https://www.oncotech.org/gim21
PI Città Centro
Chairman: F. Cognetti Study coordinator: A. Fabi
RM IRCSS Istituto Nazionale
Tumori Regina Elena
C. Tondini BG A.O. Papa Giovanni XXIII
L. Moscetti MO A.O.U. Modena
L. Del Mastro GE IRCSS A.O.U. San
Martino IST
P. Marchetti RM A.O.U. Sant’Andrea
G. De Placido NA Università degli Studi
Federico II
Moving forward: from LiqBreasTrack to GIM21
LiqBreasTrack: preliminary conclusions
1. HER2 amplification may be a marginal cancer driver at the time of T-DM1 administration
2. Yet, T-DM1 is active on HER2 tumors that have lost HER2-amp (implications upon the industrial ADC pipeline)
3. Clinical response may be broken down into independent clonal trajectories 4. Resistant clones may be ear-marked and anticipate progression by 2-3 months on
average 5. Target therapy may wipe off in DAYS a resistance selected through YEARS of ERBB2
blockade … Molecular cancer evolution under T-DM1 pressure occurs on a strikingly short timescale, as short as a few days or weeks
6. … sometimes resulting in the disappearance of actionable alterations (you cannot treat something that is no longer there)…
7. … and sometimes resulting in de novo appearance (during T.DM1 treatment) of actionable aberrations that are not present in archival tumor DNA
8. Why basket trials do not work as one would expect? 9. Liquid biopsy and tissue biopsy in combination drive optimal therapeutic decisions 10.Liquid biopsy must go on beyond progression (additional lines of therapy) 11.Ethics, deontology, regulatory issues (and a personal perspective)
Alessandra Fabi
Matteo Allegretti
