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
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
Translational Opportunities for precision
medicine via the “field” Diagnostic Biomarker
• Avoid 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
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
Translational Opportunities for precision
medicine via the “field” Diagnostic Biomarker
• Avoid 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
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”?
