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Applications of comprehensive clinical genomic analysis in solid tumors: obstacles and opportunities
Vincent A. Miller, M.D.
Foundation Medicine, Inc.
AACR Annual Meeting 2012
Current Concepts session NC005
Comprehensive tumor clinical genomic analysis for treatment selection in clinical oncology
Disclosure information
DISCLOSURE INFORMATION
AACR 2012
Vincent A. Miller M.D.
I have the following financial relationships to disclose:
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Stockholder in Foundation Medicine
•
Employee of Foundation Medicine
I will discuss the following off label use and/or investigational use in my presentation:
•
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Potential for investigational targeted therapy selection based on comprehensive clinical genomic profiling Applications of comprehensive clinical genomic analysis in solid tumors: obstacles and opportunities
• What does a practicing oncologist needs to know about clinical grade NGS?
• What are the advantages of clinical grade NGS for oncologists, pathologists and pharma?
• What novel challenges does clinical grade NGS present for physicians and pharma?
• How can a clinical grade NGS analysis help more cancer patients more quickly everywhere?
• How do we make this happen routinely?
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Current challenges of clinical genomic analysis in the clinical setting
Sample
• Limited tissue amounts (e.g., small biopsies)
• DNA damage by routine fixation (FFPE)
• Stromal admixture/low tumor purity
Assay
• Heterogeneity of relevant alterations (point mutations, copy changes, fusion genes)
• Compounding costs of single‐analyte tests
Process
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• Logistics of routing samples to many labs/tests
• Clinically relevant turn‐around times
• Integration and interpretation of results
Genomic diversity and complexity of cancer implies relevance of comprehensive view
Various genes are mutated in each individual tumor, and cancer cells often contain combinations of mutations driving uncontrolled growth …It is therefore critical to understand entire pathways which incorporate many genes
Example pathways
Ding et al. Nature, 2008; Thomas et al. Nature Genetics, 2007
Example genes
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Challenges of sequencing clinical cancer samples
• Low purity – cancerous cells may only be a minor fraction of total sample
• Heterogeneity – multiple sub‐clones of cancer may be present in one tumor sample
– Mutation of interest (e.g., a resistance mutation) may be present in a low abundance sub‐clone
• Aneuploidy – chromosomal gains and losses may modify mutation abundance Relevant mutations may be
rare in the pool of sequenced DNA
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Clinical samples commonly contain biologically relevant
mutations at low mutant allele frequencies
Tumor Purity
Clonal Heterozygous Substitution
Equal Sub‐Clones
100%
50%
25%
50%
25%
12.5%
20%
10%
5%
10%
5%
2.5%
A Typical Lung Cancer Sample
Clinical grade performance: 99%+ sensitivity to detect a mutation with allele
frequency of >10%, with no false positive mutation calls. Deep coverage (>500x) is
necessary for thorough analysis of clinical grade samples.
Case Report: EGFR mutant lung adenocarcinoma
2nd gen. EGFR TKI, possibly with cetuximab PARP inhib./Plat‐based chemo
Nutlins/MDM2 inhib.
Genomic alterations detected in acquired resistance to EGFR-TKIs are
diverse and may explain the largely disappointing results seen to date
with second generation agents
Use of clinical grade NGS may identify one or more tumor specific
treatment options
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Case Report: Adenocarcinoma of the pancreas
BRAF inhib. (Vemurafenib)
CDK4/6 inhib.
BRAF V600E mutations are not routinely tested for in
pancreatic adenocarcinoma
Use of clinical grade NGS may detect this and other actionable
alterations in some cases
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Case Report: Adenocarcinoma of the pancreas
FGFR inhib.
KRAS mutations are detected in most pancreatic adenocarcinomas but
targeted therapies have been largely ineffective
Knowledge of coexistent actionable genomic alterations may expand
potential treatment options
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Case Report: Non‐mucinous adenocarcinoma of the appendix
PKC inhib.
Genomic profiling may reveal actionable alterations in rare and
neglected tumor types where there is limited genomic knowledge
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Case Report: Breast cancer
Trastuzumab
PI3K inhib.
Trastuzumab is effective in a subset of ERBB2 amplified breast cancer
Coexistent genomic alterations can provide explanations for resistance
and rationale for study of select combinations
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Case Report: Transitional carcinoma of the bladder
CDK4/6 inhib.
Nutlins / MDM2 inhib.
BCL‐2 inhib.
Genomic analysis of even a chemosensitive tumor type often
reveals multiple actionable alterations
Findings may suggest targeted therapeutic options if systemic
therapy fails
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Case Report: Cholangiocarcinoma
PI3K inhib.
NF‐κB inhib.
Genomic profiling may reveal actionable alterations in tumor types in
which there is limited genomic knowledge and for which no approved
therapy exists
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Case Report: Salivary gland adenocarcinoma
PI3K inhib.
Nutlins / MDM2 inhib.
CDK 4/6 inhib.
Uncommon tumor type with no approved or effective systemic therapies if
inoperable; multiple rational targets may be identified
Case Report: Ovarian cancer
Aurora kinase inhib.
CDK4/6 inhib.
IGF1R inhib.
Nutlins /MDM2 inhib.
Although no genomic testing is routinely undertaken in ovarian cancer,
actionable alterations were identified that suggest multiple targeted therapy
options either alone, sequentially or in combination
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Response to crizotinib in patients with “ALK‐Positive” NSCLC
©2010 New England Journal of Medicine.
Kwak EL, et al. N Engl J Med. 2010;363:1693-1703.
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Case Report: Non‐small cell lung cancer
crizotinib/ALK inhib.
CDK4/6 inhib.
Although crizotinib is efficacious in ALK rearranged NSCLC, little is
known to explain variability in response magnitude and duration
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“Long tail” of clinical genomic alterations highlights potential benefits of comprehensive profiling (CRC)
*
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The future of oncology….
Cancer will no longer be identified primarily by the location in the body where it begins, but also by its panomic characteristics — the complex combination of patient‐specific molecular characteristics that drive the development and behavior of each cancer. Specifically, over the next decade… Researchers and clinicians will have the tools to quickly conduct a panomic analysis for every patient with cancer. This analysis will include an examination of the patient’s genomic makeup and a complete molecular characterization of their cancer cells.
‐ ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research
ACCELERATING PROGRESS AGAINST CANCER: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research
November 2011
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CONFIDENTIAL
Applications of comprehensive clinical genomic analysis in
solid tumors: obstacles and opportunities
• Cancer genomics are reasonably well annotated in many common tumor types BUT translation of that knowledge to patients is lagging.
• Many studies across multiple cancer types suggest single marker analysis and single type of analysis are inadequate.
• Integrated clinical genomic profiling is feasible and necessary in clinical care and research setting.
• This prospective “alliance” of clinical genomic profiling and targeted therapies beginning in phase I and with genotype‐
phenotype correlation will accelerate progress, lead to better outcomes and might well save money by generating more powerful unambiguous go‐no‐go signals.
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Acknowledgements
Foundation Medicine
John Curran
Matthew Hawryluk
Mary Pat Lancelotta
Doron Lipson
Jacquelyn Miller
Gary Palmer
Jeff Ross
Phil Stephens
Roman Yelensky
and many more
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DFCI
Nikhil Wagle
Most Importantly
Physicians across the US and around the world
and all THE PATIENTS