More Related Content Similar to HNSCC Biomarker Expression According To p53 (20) HNSCC Biomarker Expression According To p532. Overview
• Part I
– Head and Neck Cancer
• Background
• Standard of Care
– Molecular Subtypes
– Target Now Study
• Results
• Clinical Implications
• Part II
– Head and Neck Cancer – Opportunities for R&D
• Current Diagnostic Approaches
• Current Research in area of exosomes
• Companies actively researching diagnostic platforms
©2012 Caris Life Sciences, Ltd. and Affiliates 2
3. Head and Neck Cancer
• 6th most common cancer worldwide
• 95% are head and neck squamous cell carcinoma (HNSCC)
©2012 Caris Life Sciences, Ltd. and Affiliates 3
4. Standard of Care
• Treatment Modalities
– Surgery
– Radiotherapy
– Chemotherapy
• Treatment Goals
– Organ preservation
– Quality of Life
• Recent Improvements
– Targeted therapy
©2012 Caris Life Sciences, Ltd. and Affiliates 4
5. HNSCC – Two molecular Subtypes
Carcinogenic Viral
Risk Factors
HPV-16
Tobacco & Alcohol
Molecular Etiology
P53 Pathway TP53 Genetic Mutations E6-mediated degradation of p53
Clinical Characteristics
Survival Poor Good
Response to Rx Poor Good
Tumor Recurrence Higher Risk Lower Risk
6. Genesis of Project Idea
• Biological basis of the difference in prognosis remains unknown
• Target Now profiles ~150 HNSCC patients/year
– analyses on a wide range of clinically relevant biomarkers
– Specimens are often left unused after profiling, stored
• Only hurdle is to delineate our cohort into the two subtypes
• HPV positive patients are usually P53 wildtype and HPV negative patients are P53 mutated
• Teamed up with Caris’ Pharmaceutical Services who had resources to perform p53
mutation analysis on cases we have leftover tissue sample
• Compare biomarker expression profiles between p53 wildtype (HPV +) and p53 mutated
(HPV -) cases with the goal of identifying molecular differences between the two
subgroups which may explain differences in prognosis
©2012 Caris Life Sciences, Ltd. and Affiliates 6
7. Delineate the Cohort - Amplichip p53 Assay
163 HNSCC profiled in 2011
61 cases w/leftover specimen
52 specimens provided
Sufficient quality DNA
For mutation testing
p53 Wildtype n=39
©2012 Caris Life Sciences, Ltd. and Affiliates
p53 Mutated n=13 7
8. IHC Results
***
Observations:
97% of p53 wildtype patients
Were HER-2 negative
***P<0.001
©2012 Caris Life Sciences, Ltd. and Affiliates 8
9. FISH Results
*
***
Observations:
72% of p53 wildtype patients
Were EGFR FISH negative.
*** P<0.001
©2012 Caris Life Sciences, Ltd. and Affiliates 9
10. p53 mutated - Subgroup Analysis
Observations:
Subgroup Analysis according to
Sub-classification of p53 Mutation Type
30 80%
mutations revealed a slight
% mutated subgroup (n=10)
60%
tendency towards EGFR EGFR FISH
FISH positivity in HNSCC number of cases (N)
Negative
40%
20
patients with disruptive Positive 20%
p53 mutations. 0%
Disruptive Nondisruptive
10
0
Wildtype Mutated
©2012 Caris Life Sciences, Ltd. and Affiliates 10
11. Clinical Implications
1. HER2 down-regulation in p53 WT (HPV+)
– more genetically stable tumor cell population
– lack of oncogene addiction in the tumor cell
• Clinical Implications = better prognosis, EGFR targeted
agents likely not suitable, more likely to benefit from
standard chemo- and radiation- therapies
2. EGFR positivity in disruptive p53 mutated (HPV-)
– Genetic instability
– Oncogene addition
• Clinical Implications = worse prognosis, likely benefit
from EGFR-targeted agents
**Recent updates on SPECTRUM trial comparing efficacy of
panitumumab in HPV + and HPV – patients showed that
only HPV – patients achieved improved benefit with Rx
©2012 Caris Life Sciences, Ltd. and Affiliates 11
12. Part II
• Important Take Home Messages
– Early Detection is Key to Improving Survival
• overall 5-year survival rate is 50% and has not improved in past decade
• 2/3 are diagnosed at advanced stage
– Molecular subtyping impacts Treatment Approaches
• HPV + / p53 WT - overall better prognosis, Rx can be scaled down
• HPV - / p53 mutated - worse prognosis, aggressive treatment
approach, targeted therapy
• Head and Neck Cancer – Opportunities for R&D?
• Current Diagnostic Approaches
• Research in area of Exosomes
• Companies actively researching diagnostic platforms
©2012 Caris Life Sciences, Ltd. and Affiliates 12
13. Current Diagnostic Approaches
Visualization and/or Palpation
Imaging Techniques
• Endoscopy, CT or PET scans, MRI, X-rays
Biopsy w/ Pathology Report
• H&E
Laboratory-based techniques
• Loss of Heterozygosity (LOH)
• P53 mutation testing or IHC expression
• HPV testing (CISH, RT-PCR)
©2012 Caris Life Sciences, Ltd. and Affiliates 13
14. Current Research
Adapted from Lee, K.-D., et al 2012 “Body Fluid Biomarkers for Early Detection of Head
©2012 Caris Life Sciences, Ltd. and Affiliates 14
And Neck Squamous Cell Carcinomas.” Anticancer Res 31: 1161-1168.
15. Exosome-related Research
Whiteside Lab – University of Pittsburgh Cancer Institute in collaboration with Ludwig-
Maximilians-University, Munich, Germany (Exosome Dx collaborator) “Tumor derived
microvesicles in sera of patients with headand neck cancer and their role in tumor
progression”
• Microvesicles isolated from sera of 60 HNSCC patients and 25 controls. MV from patients
with active disease expressed higher FasL levels than MV from patients with no evident
disease or normal controls.
Taylor Lab - University of Louisville “Exosomal-miRNA profiles as diagnostic and
prognostic biomarkers in head and neck squamous cell carcinoma” ASCO 2011
• Thirty HNSCC patients (19M, 11F), stage II (n=3), III (n=7), IVa (n=20) entered in the study.
Fifteen were considered for analysis since at least one follow-up sample was collected post
treatment. Of the 84 miRNAs analyzed and 12 detected, miR148b and miR222 appeared to
be uniquely expressed in HNSCC. miR16 was present in exosomes on patients with SCC. In
patients responding to initial therapy, the levels of most exosomal-miRNAs were
suppressed; in patients failing to respond, no decrease in the exosomal miRNAs were
observed.
©2012 Caris Life Sciences, Ltd. and Affiliates 15
16. Potential Market
• Vigilant Biosciences - University of Miami spinoff
– Salivary CD44 oral rinses; 80% sensitivity; 88% specificity
• mAbDx Immunodiagnostics
– identified a “new biomarker” of HNSCC and are evaluating utility of prototype
immunoassays using non-invasive sampling of oral and throat tissues
• NIH (Dental and Craniofacial Research) – office of technology transfer
– Detection of mutations in TGFbetaR1 and PTEN genes associates with devt of
HNSCC.
• Trovagene –
– Diagnostic test for presence of HPV from urine specimens (78% sensitivity;
86% specificity)
©2012 Caris Life Sciences, Ltd. and Affiliates 16