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#HCAQofQ Tariq Mughal
1. Tariq Mughal
Vice-President Medical affairs, Foundation Medicine
Professor of Hematology-Oncology
Personalized Cancer Medicine
HCA-SCRI Healthcare Meeting
London; 25 Feb 2016
4. Cancer Core Europe: Sep 2015 Cambridge
Cambridge Cancer Centre, Cambridge
Institute Gustave Roussy, Paris
Karolinska Institute, Stockholm
Netherlands Cancer Institute, Amsterdam
Vall d’Hebron Institute of Oncology, Barcelona
German Cancer Research Center, Heidelberg
7. Personalized Cancer Medicine: Some
Conceptual thoughts
1. A brief history of precision medicine
2. What really is a driver mutation?
3. How can be best identify driver mutations?
4. Some case histories
5. Concluding thoughts
10. Survival for Patients with CML by Treatment Era
Courtesy of Prof H Kantarjian; adapted, with permission, from Harrison’s Principles of Internal Medicine, 2014.
11. EVOLUTION OF GENOME DRIVEN THERAPIES FOR CANCER
• 1970’s ER Testing and Hormonal Therapy for Breast Cancer
• 1990’s Cytogenetics/FISH Testing and Therapy for Heme Malignancies
• 1998 HER2 Testing and Trastuzumab for Breast Cancer
• 2001 BCR-ABL Testing and Imatinib for CML
• 2003 EGFR Mutation Testing and Erlotinib for NSCLC
• 2007 KRAS Mutation Testing and Cetuximab/Panitumumab for CRC
• 2010 EML4-ALK Testing and Crizotinib in NSCLC
• 2011 BRAF Mutation Testing and Vemurafenib in Melanoma
• 2012 ROS1 and RET Fusion Testing for Crizotinib and RET inhibitors in NSLC
• 2013 HER2 mutations in and targeted therapy for NSCLC, Breast Cancer, and MPUC
NTRK1 Fusion Testing and Crizotinib in NSCLC
• 2014 Pembrolizumab, Nivolumab for Melanoma and NSCLC
Olaparib for BRCA-mutated Ovarian Cancer
• 2015 Alectinib for Crizotinib-resistant ALK-mutated tumors
Osimertinib for T790M EGFR
Microsatellite instability indicates immunotherapy responses
• 2016 Tumor mutation burden indicates immunotherapy responses
12. 12
Targeted Therapies: Evolution into a Revolution
1998 to 2000 2000 to 2005 2000 to 2010 2010 to 2015 2015 to 2020
~150 targets in development
~700 compounds evaluated
Coming Soon
Extrapolated from BioCentury Online Intelligence Database
13. Personalized Cancer Medicine: Some
conceptual thoughts
1. A brief history of precision medicine
2. What really is a driver mutation?
3. How can be best identify driver mutations?
4. Some case histories
5. Concluding thoughts
14. What is a driver mutation?
Biological definition: a mutation that directly or indirectly confers a selective growth
advantage to the cell in which it occurs
Clinical definition: a mutation that has significant diagnostic, prognostic, or therapeutic
implications in subsets of cancer patients and for specific therapies
17. Personalized Cancer Medicine: Some
conceptual thoughts
1. A brief history of precision medicine
2. What really is a driver mutation?
3. How can be best identify driver mutations?
4. Some case histories
5. Concluding thoughts
19. NGS: Various Approaches
• Whole Genome Sequencing (WGS)
– Determines the complete DNA sequence of an organism's
genome at a single time
• Whole Exome Sequencing (WES)
– Selectively sequences only the coding areas of the genome
• Comprehensive Genomic Profiling
– Massively parallel sequencing of the entire coding region in a
defined subset of genes of interest and detects all four
classes of alterations
• Targeted Sequencing (Hot spot)
– Sequences only the hot spots of a subset of genes of
interest
20. Founding Team Of Foundation Medicine
Eric Lander, PhD
• Cancer genomics innovator and creator
of OncoMap project
• Medical Oncology, Dana Farber Cancer
Institute, Broad Institute
• NIH “New Innovator”
Levi Garraway, MD, PhD
• Recognized leader in cancer
genomics, targeted therapeutics
• Founding director of Broad Institute
Cancer Program
• Dana Farber, HHMI, NCI advisor
Todd Golub, MD
• Principal Investigator of The Cancer
Genome Atlas program
• Clinical Pathology, Dana Farber
Cancer Institute, Broad Institute
• Co-discoverer of EGFR mutations in
lung cancer
Matthew Meyerson, MD, PhD
• Recognized driving force in genomics
• Founding Director of the Broad Institute
• MIT, Harvard Medical School
• Founder Millennium Pharmaceuticals
• Successful biotechnology entrepreneur
• Founder, CEO of CombinatoRx, $750M, public
listing
• TR Innovator of the Year
• Boards of BIO, Forma Therapeutics, Science
Museum
Alexis Borisy
2010
23. Drilon A, Clin Cancer Res, 2015
MSKCC vs FoundationOne Comparison: In 65% of
patients, a targeted therapy was identified
Targeted agent
on or off
clinical trial
Targeted therapy
in NCCN guidelines
No genomic
alteration identified
Genomic
alterations
identified, but
no targeted
therapy options
available
24. Why FoundationONEHemeTM Test was
Developed
• Detects all clinically relevant classes of genomic alterations in
hematologic and soft tissue tumors
• DNAseq of the entire coding region of 405 genes and select intronic
regions in 31 genes known to be clinically & biologically relevant in
cancer
• RNAseq of 265 genes recurrently rearranged in cancer
• Validated high accuracy achieved by high, uniform coverage: at
median exon depth of 250x, >99.5% of exons covered >100X
• Requires only small amounts of fresh (peripheral blood/bone marrow
aspirate) or FFPE clinical specimens (≥50ng of DNA, lesional tissue >20%
of nucleated elements)
• Customized computational biology algorithms validated for high
accuracy in clinical samples with high stromal contamination
He, et al, in press, Blood, 2016
26. Mutations detectable by first-generation vs NGS
Y253H
M343V
T315I
L248Q
M351V
Lower detection limit
of Sanger Sequencing
27. Personalized Cancer Medicine: Some
conceptual thoughts
1. A brief history of precision medicine
2. What really is a driver mutation?
3. How can be best identify driver mutations?
4. Some case histories
5. Concluding thoughts
28. • 57 year old patient with triple negative inflammatory breast cancer
• ER/PR/HER2 negative
• Extensive prior chemotherapy with multiple regimens
• Widespread metastatic disease with extensive skin involvement
• Patient was started on HER-2 targeted therapies with chemotherapy:
• Lapatinib/Oral capecitabine 4/12-5/12->SD (difficulty swallowing)
• Lapatinib/Trastuzumab-Albumin bound paclitaxel 5/12-6/12 *
• Lapatinib/Trastuzumab-Vinorelbine 6/12-7/12- PR; she continues
treatment off steroids
ERBB2 Mutated Inflammatory Breast Cancer
Cristofanilli M et al., SABCS, 2012/Ali SM et al., J
Clin Oncol. In press May 2012
29. Inflammatory Breast Cancer (ILC) With ERBB2
Mutation Response to anti-HER Targeted Therapy
5/15/12 8/14/12
Images provided by Dr. M Cristofanilli, Jefferson U, Philadelphia, PA
30. Response to Anti-HER2 Targeted Therapy
Pre-therapy: extensive
active disease
Post-therapy: good response
with lower/less activity
Cristofanilli M et al., SABCS, 2012/Ali SM et al., J Clin Oncol. In press May 2012
31. Cervix Squamous Cell Carcinoma with FBXW7 Mutation
Responds to Everolimus
Before targeted therapy On Everolimus x 2 mo
33. Personalized Cancer Medicine: Some
conceptual thoughts
1. A brief history of precision medicine
2. What really is a driver mutation?
3. How can be best identify driver mutations?
4. Some case histories
5. Concluding thoughts
34. Complexity of Cancer Genome
• Cancer evolves & adapts (in a Darwinian fashion) to both host
defenses and to therapy - driven by clonal heterogeneity
• Clonal evolution contributes to resistance to therapy; treatment
may hasten the evolutionary process
• Functionality: Lineage specificity of genomic abn: BRAF V600E
no response to vemurafenib in colorectal cancer; HER2
amplification no benefit to trastuzumab in endometrial cancer
• Different areas of the genome may have different rates of
mutation acquistion and indeed the order
Hyman et al, NEJM 2015
35. Concluding thoughts
• Hybrid-capture NGS technology is enabling us
to deliver evidence-based precision cancer
medicine
• In the near future, comprehensive genomic
profiling will incorporate predictive
biomarkers for immunotherapy enabling even
greater clinical application