Liquid Biopsy in GI cancers - IWEVENTOS · Liquid Biopsy in GI cancers Ryan B. Corcoran, MD PhD Director, Gastrointestinal Cancer Center Program Scientific Director, Termeer Center

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?




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




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

Liquid Biopsy in GI cancers - IWEVENTOS · Liquid Biopsy in GI cancers Ryan B. Corcoran, MD PhD Director, Gastrointestinal Cancer Center Program Scientific Director, Termeer Center

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