Leveraging the “field effect” for precision molecular ...collaboration.aacr.org/sites/CPS/Shared...

transcript

February 3-5, 2016 | Lansdowne Resort, Leesburg, VA

Leveraging the “field effect” for precision molecular diagnostics: Opportunities and Challenges

Avi Spira, MD

Department of Medicine

Boston University Medical Center

aspira@bu.edu

Disclosures

Founder of Allegro Diagnostics Inc. (acquired by Veracyte Inc.

on Sept 4, 2014)

Sponsored Research Agreements with Janssen

(PCGA and DECAMP)

Most cancers arise in a “field” of

molecular alterations from

exposure to cancer-causing

agents

Measuring the physiological

response of the host to exposure

within the “field” could provide:

- Early markers of

individualized cancer risk in

relatively accessible tissue

The “field effect” impacts most cancers

There is more than one “field”:

field cancerization vs. field of injury

Modern Pathology 2015

Translational Opportunities for precision

medicine via the “field” Diagnostic Biomarker

• Prevent unnecessary invasive procedures in those with benign disease

Screening biomarkers

• Identify those at highest risk who should undergo screening

Precision approaches to prevention (therapeutic targets)

• Genomic alterations in the “field” to stratify into intervention

Monitoring premalignant disease progression

• Prognostic markers regarding indolent vs. aggressive pre-cancer lesions

Opportunity to develop precision diagnostics: bronchial airway

gene-expression as a biomarker of smoking and lung cancer

RNA-Whole genome gene-

expression profiling

Smoking impacts airway and microRNA

gene expression

PNAS 2004; NAR 2005; PNAS 2009

Subset of changes are irreversible upon

cessation Genome Biology 2007

Airway gene expression can serve as an early

diagnostic biomarker for lung cancer

Nature Medicine 2007; CaPR 2008; NEJM 2015

The elevator pitch!

Silvestri et al. NEJM 2015;373:243-251

The elevator pitch!

Silvestri et al. NEJM 2015;373:243-251

Sensitivity ~90%

Specificity ~ 50%

NPV > 90%

Clinical Utility of this test:

41% of noncancer patients with non-diagnostic

bronchoscopies underwent invasive procedures (TTNA or

surgery) post-bronchoscopy

34% (37/110) of surgical lung biopsies were performed for

benign lesions

50% of unnecessary invasive procedures could have

been avoided based on a negative biomarker

Vachani et al. In press.

PerceptaTM launched by Veracyte, April 2015

The challenge in overcoming “the valley of death”: moving

from clinical validation to clinical utility

• Avoid unnecessary invasive procedures in those with benign disease

Extending the “field” to the nasal epithelium

Clinical ModelClinico-

genomic

AUC* 0.76 0.80

Sens* 0.85 0.94

Spec 0.42 0.44

NPV* 0.73 0.88

PPV 0.60 0.63

Validation of a clinical model vs. clinical model +

30 gene nasal marker (n=132)

Funded by EDRN; Perez-Rogers et al. submitted

Potential clinical applications: moving to screening

The Detection of

Early Lung Cancer

Among Military

Personnel

(DECAMP)

Consortium

The challenge in developing and validating a screening biomarker:

longitudinal study of the “field” in high-risk individuals

Funded by DoD;

Janssen

DECAMP1 (nodule) study

DECAMP2 (screening) study

• Avoid unnecessary invasive procedures in those with benign disease

Opportunities for the “field” to impact the premalignant setting

Companion Dx PrognosticCampbell et al. CaPR 2016

The Airway “field of injury” as a potential companion diagnostic and

intermediate marker for therapeutic efficacy in chemoprevention setting

Genes that are highly

expressed when PI3K is

activated

Activity of PI3K gene-expression pathway is significantly reduced post-treatment

with myo-inositol in those smokers who had regression of their dysplastic lesions :

potential marker for selecting patients likely to respond? Science

Translational

Medicine. 2010

The Validation Challenge: Phase-2b clinical trial: ~75

subjects with dysplasia randomized to placebo vs.

myoinositol

-Lam et. al. Under revision

Eva Szabo, Stephen Lam,

Paul Limburg

Results: Gene expression/Presence of Premalignant LesionsGene expression alterations in the “field” associated with

presence of premalignant lesions: Prognostic markers?

This gene signature

overlaps with genomic

alterations in the

premalignant lesion itself

Smokers with

Premalignant lesion

Smokers without

Premalignant lesion

Challenge in establishing longitudinal study of premalignant disease where

“field” collected: The PCGA for Squamous Cell Lung CancerFunded by Janssen in collaboration with Mary Reid, Roswell Park

Potential biomarker for stratifying high-risk subjects into

chemoprevention trials and monitoring efficacy of intervention

Overarching challenge: heterogeneity in the “field”

Immune cells??

Can single cell sequencing provide us with insight into molecular heterogeneity ?

Summary and Future Directions:

The molecular “field of injury” provides a temporal and spatial window for precision detection

and prevention of many tumor types

• Measuring an individual’s physiologic response to cancer-causing agents that precedes cancer

development and is relatively accessible to sample

NEEDS:

• Longitudinal high-risk cohorts (PCGA) with field sampled including in chemoprevention trial

setting

• High-throughput cost-effective single cell approaches to study heterogeneity. How deep ??

• High-throughput in vitro and in vivo premalignant systems to screen candidate genes

• Role of immune system, microbiome, epigenome etc…in the “field”

• Explore whether neoantigens in the field could be targets for immunoprevention

• Platform for evaluating the “exposome”?

Leveraging the “field effect” for precision molecular ...collaboration.aacr.org/sites/CPS/Shared...

Documents