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

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Annabel Park
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1 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

2 Disclosures Founder of Allegro Diagnostics Inc. (acquired by Veracyte Inc. on Sept 4, 2014) Sponsored Research Agreements with Janssen (PCGA and DECAMP)

The field effect impacts most cancers Most cancers arise in a field of molecular alterations from exposure to cancer-causing agents Measuring the

3 The field effect impacts most cancers 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

4 There is more than one field : field cancerization vs. field of injury Modern Pathology 2015

5 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

airway and microrna gene expression PNAS 2004; NAR 2005; PNAS 2009 Subset

gene expression can serve as an early diagnostic biomarker for lung

6 Opportunity to develop precision diagnostics: bronchial airway gene-expression as a biomarker of smoking and lung cancer 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 RNA-Whole genome geneexpression profiling

7 The elevator pitch! Silvestri et al. NEJM 2015;373:

8 The elevator pitch! Silvestri et al. NEJM 2015;373:

9 The challenge in overcoming the valley of death : moving from clinical validation to clinical utility 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. Percepta TM launched by Veracyte, April 2015

10 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

80 Sens* 0.85 0.94 Spec 0.42 0.44 NPV* 0.73 0.

11 Extending the field to the nasal epithelium Validation of a clinical model vs. clinical model + 30 gene nasal marker (n=132) Clinical Model Clinicogenomic AUC* Sens* Spec NPV* PPV Funded by EDRN; Perez-Rogers et al. submitted

12 Potential clinical applications: moving to screening

13 The challenge in developing and validating a screening biomarker: longitudinal study of the field in high-risk individuals The Detection of Early Lung Cancer Among Military Personnel (DECAMP) Consortium Funded by DoD; Janssen

14 DECAMP1 (nodule) study DECAMP2 (screening) study

15 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

16 Opportunities for the field to impact the premalignant setting Companion Dx Prognostic Campbell et al. CaPR 2016

The Airway field of injury as a potential companion diagnostic and intermediate marker for therapeutic efficacy in chemoprevention setting Eva Szabo, Stephen Lam, Paul Limburg The Validation

17 The Airway field of injury as a potential companion diagnostic and intermediate marker for therapeutic efficacy in chemoprevention setting Eva Szabo, Stephen Lam, Paul Limburg The Validation Challenge: Phase-2b clinical trial: ~75 subjects with dysplasia randomized to placebo vs. myoinositol -Lam et. al. Under revision 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

Results: Gene Gene expression expression/presence alterations of in Premalignant the field Lesions associated with presence of premalignant lesions: Prognostic

18 Results: Gene Gene expression expression/presence alterations of in Premalignant the field Lesions associated with presence of premalignant lesions: Prognostic markers? Smokers with Premalignant lesion Smokers without Premalignant lesion This gene signature overlaps with genomic alterations in the premalignant lesion itself

19 Challenge in establishing longitudinal study of premalignant disease where field collected: The PCGA for Squamous Cell Lung Cancer Funded by Janssen in collaboration with Mary Reid, Roswell Park Potential biomarker for stratifying high-risk subjects into chemoprevention trials and monitoring efficacy of intervention

20 Overarching challenge: heterogeneity in the field Can single cell sequencing provide us with insight into molecular heterogeneity? Immune cells??

21 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?

Signatures (of Response) to Environmental Exposures

Gene-expression Profiles as Signatures (of Response) to Environmental Exposures Smoking and the airway field of injury as a novel paradigm for the exposome Avrum Spira, M.D., M.Sc. Section of Computational