liquid biopsy in gi cancers - iweventos · liquid biopsy in gi cancers ryan b. corcoran, md phd...
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Liquid Biopsy in GI cancers
Ryan B. Corcoran, MD PhD
Director, Gastrointestinal Cancer Center Program
Scientific Director, Termeer Center for Targeted Therapies
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine, Harvard Medical School
Disclosures
Consulting fees:
Amgen, Array, Astex, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, FOG Pharma, Fount Therapeutics, Genentech, Guardant, LOXO Oncology, Merrimack, N-of-one, Novartis, nRichDx, Revolution Medicine, Roche, Roivant, Shire, Shionogi, Spectrum, Symphogen, Taiho, Warp Drive Bio
Equity/Stock Options:
Avidity Biosciences, C4 Therapeutics, Fount Therapeutics, nRichDx, Revolution Medicines
Research funding:
Asana, AstraZeneca, Sanofi
Liquid biopsy and cfDNA
Corcoran and Chabner, NEJM 2018
Clinical applications of liquid biopsy
Corcoran and Chabner, NEJM 2018
Predicting treatment response
Monitoring therapeutic resistance
Detection of residual disease post-surgery
Topics
0 100 200 300 400 5000
2
4
6
Days
BA
P1 G
13V
(allele
%)
Kinetics of ctDNA during treatment response
Treatment start Radiographic response Disease progression
Real-time ctDNA monitoring for early prediction of response
Aparna ParikhJaime Schneider
Pro
gre
ss
ion
-fre
e s
urv
iva
l
Months
ctDNA drop <30% : mPFS 2.0 months
ctDNA drop >30% : mPFS 7.5 months
HR = 3.96; p < 0.0001
PR
SD
PD
-1 0 0
0
1 0 0
2 0 0
4 W e e k c tD N A
R E C IS T R e s p o n s e
% C
ha
ng
e i
n c
tDN
A
-50
p < 0.0001
Can change in ctDNA be an early surrogate for therapeutic response?
Predicting treatment response
Monitoring therapeutic resistance
Detection of residual disease post-surgery
Topics
Secondary (acquired) Resistance
Pre-treatment + Vemurafenib 15 weeks + Vemurafenib 23 weeks
Wagle et al, JCO 2011
Interlesional
Heterogeneity between
distinct metastatic lesions
Intralesional
Heterogeneity within a
single metastatic lesion
• A single needle biopsy may vastly underrepresent molecular heterogeneity• Liquid biopsy may detect alterations in ctDNA shed by tumor cells throughout the body
Adapted from Bardelli, ASCO 2013; Misale, Cancer Discovery 2014
Tumor heterogeneity and acquired resistance
Pat
ien
ts
Strickler et al, Cancer Discovery 2018
With Aparna Parikh
N=44
Identification of resistance mechanisms in ctDNA
Mechanism of resistance identified in 75% (vs. 48% in tissue) 41% with multiple resistance mechanisms (range 2-9; median 3)
(vs only 9% in tissue)
In 23 patients with matched tumor biopsies, ctDNA identified additional resistance mechanisms in 78% of cases
(UNPUBLISHED DATA)
RAS WT CRC
(n=26)
BRAF CRC (n=5)
FGFR2 biliary (n=4)
MET amp Gastric
(n=3)
HER2 amp CRC
(n=3)HER2 amp gastric
(n=2)
FGFR2 gastric (n=1)
Liquid Biopsy
Tumor Biopsy
Single mechanism identified (n=16)
Multiple mechanisms identified (n=17)
No mechanism identified (n=11)
Single mechanism identified (n=9)
Multiple mechanisms identified (n=2)
No mechanism identified (n=12)
Siravegna et al, Nature Medicine 2015
Real-time adaptation of therapy guided by ctDNA
Predicting treatment response
Monitoring therapeutic resistance
Detection of residual disease post-surgery
Topics
Cured
NotCured
Minimal Residual Disease
None
Present
Curative IntentSurgery
Residual disease: The Problem
We have no way to determine who is cured and who will recur
Stage II CRC:SOC is NO adjuvant chemo10-15% of patients recur
Stage III CRC:All patients get adjuvant chemo>50% cured by surgery alone
ctDNA
Negative
Positive
Personalized mutation-specificassay for detection of ctDNA
Sequencing panel to identify one or more mutations
Strategy for sensitive and specific detection of
residual disease
Post-operative ctDNA
Clinical Risk Factors
Prediction of relapse in stage II CRC
Post-operative CEA
Tie et al, STM 2016
Prediction of relapse post-SOC in CRC
Assay Performance by Analysis
Genomic (N)
Integrated Genomic and Epigenomic (N)
PPV (N of patients with ctDNAdetected who recurred)
100% (11 / 11)
100% (14 / 14)
NPV (N of patients with ctDNA not detected who were recurrence free)
72%(42 / 58)
76%(42 / 55)
Sensitivity for recurrence within one year of surgery
56%( 9 / 16)
69%(11 / 16)
Specificity for recurrence within one year of surgery
96%(51 / 53)
94%(50 / 53)
Detecting residual disease with circulating tumor DNA
Observation only
Additional therapy
Conclusions
• Liquid biopsy offers many promising potential clinical applications
• Liquid biopsy can effectively identify multiple heterogeneous resistance
alterations and can help guide treatment decisions
• ctDNA monitoring can provide real-time insight into response and
resistance and may help guide treatment adaptation
• Use of liquid biopsy to detect post-operative residual disease may
transform adjuvant therapy increasing opportunity to salvage cure
• Integration of liquid biopsy into clinical trials will be critical
AcknowledgementsCorcoran Laboratory
• Leanne Ahronian
• Mehlika Hazar-Rethinam
• Mariana Kleyman
• Meagan Ryan
• Ferran Fece
• Ispita Guha
• Jason Godfrey
• Koki Nishimura
• Brandon Nadres
• Emily Van Seventer
• Bezaye Teshome
• Heather Shahzade
• Lifeng Chen
• Sarah Phat
• David Myers
• Will Bradford
• Trina Hong
MGH
• Jeff Engelman
• Jeff Settleman
• Hiromichi Ebi
• Erin Sennott
• Nabeel Bardeesy
MGH Center for GI Cancers
• Aparna Parikh
• Eunice Kwak
• Jason Faris
• David Ryan
• Larry Blaszkowsky
• Ted Hong
• Jeff Clark
• Andrew Zhu
• Lipika Goyal
• Jill Allen
MGH Center for Melanoma
• Keith Flaherty
• Jen Wargo
MGH Pathology
• John Iafrate
• Dora Dias-Santagata
• Joe Lennerz
• Nicholas Jessop
• Hayley Robinson
• Kerry Lynch
• Mari Mino-Kenudson
• Adriano Piris
• Michiya Nishino
Funding
• Damon Runyon Clinical Investigator Award
• NIH/NCI R01
• NIH/NCI K08
• NIH/NCI DF/HCC GI SPORE
• NIH/NCI U54 Drug Resistance Center Grant
• SU2C Colorectal Dream Team Award
Univesrity of Torino, IRCC
• Alberto Bardelli
• Federica Di Nicolantonio
• Giulia Siravegna
• Mariangela Russo
• Benedetta Mussolin
Broad/DFCI
• Gad Getz
• Ignaty Leshchiner
• Levi Garraway
• Eli Van Allen
• Nikhil Wagle
Duke
• John Strickler
MDACC
• Scott Kopetz