Genomic Medicine The Future of Cancer Care - Shayma Master Kazmi, M.D. Medical Oncology/Hematology Cancer Treatment Centers of America
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Genomic Medicine
The Future of Cancer Care
Shayma Master Kazmi, M.D.
Medical Oncology/Hematology
Cancer Treatment Centers of America
Personalized Medicine • Personalized health care is a broad term for interventions that are targeted to individuals based on their risk in order to provide a more coherent and focused approach to health care • Personalized health care includes preventive, diagnostic and therapeutic interventions, with risk defined through genetics as well as clinical and family histories • More technology-focused definition relies on use of molecular testing to define risk, e.g., genetics, genomics, etc. • Goals include greater effectiveness and efficiency of health care delivery as well as improved health outcomes and quality of life
PRESENTATION OUTLINE
• Define Personalized Medicine/Genomics
progress to date in cancer care
• Limitations/Challenges
• Current & future strategies at CTCA to
incorporate Personalized Medicine into cancer
care
© 2014 Rising Tide 3
Definitions
• Genetic testing
– Testing germline mutations for possible presence
of genetic diseases or variability in metabolism of
drugs
• Genomic testing
– Usually testing somatic mutations in cancer cells
to assess for drug targets
© 2014 Rising Tide 5
© 2014 Rising Tide 6
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Benefits of Personalized Medicine
• Better matching patients to drugs instead of
‘trial and error’
• Customized pharmaceuticals may eliminate
life-threatening adverse reactions
• Improved efficacy of drugs
• Reduce costs of clinical trials by
– Quickly identifying total failures
– Favorable responses for particular backgrounds
© 2014 Rising Tide 8“Targeted”, “Personalized”, or
“Precision” therapy
• Not a new concept
• Hormonal therapy of breast/prostate cancer:
Earliest systemic anti-neoplastic strategy ER
receptor discovered 40 years ago
• HER-2 over-expression in breast cancer
• CML/GIST (profoundly different pathology but
similar molecular abnormalities resulting in
essentially identical highly effective therapy)
• Resulting over-simplification of complex biology
© 2014 Rising Tide 9EGFR (Epidermal Growth Factor
Receptor)
• Major research efforts to develop EGFR receptor
inhibitors, known in pre-clinical systems to be
relevant in tumor progression
• Majority of lung cancer patients over-express
EGFR receptor
• 10% of patients with metastatic lung cancer have
major response (over 80%) to one EGFR inhibitor
• Phase 3 randomized trials with this agent
(combined with chemotherapy) negative
© 2014 Rising Tide 10EGFR Receptor
• Evidence that over-expression of receptor in lung
cancer is not clinically relevant, but the presence
of particular EGFR mutations predict for clinical
activity (approximately 20-25% of patients - more
commonly observed in non-smokers, Asian
population, women)
• Definitive evidence in that lung cancer patients
with a mutation experience a superior outcome
when treated with EGFR inhibitor alone, rather
than chemotherapy (Lancet Oncology 2012;
13:239)
© 2014 Rising Tide 11Other Examples of Effective
“Precision” Therapy
• ALK rearrangement (4-5% of lung cancer)
– Crizotinib - FDA approved 8/2011, other ALK inhibitor
approved since, more in development
• BRAF mutation (50% patients with melanoma)
– Vemurafinib – FDA approved 8/2011, more in
development
• Hedgehog pathway inhibitor (basal cell carcinoma
– locally advanced/metastatic)
– Vismodegib – FDA approved 1/2012
• Her-2 antibody drug conjugate
– Ado-trastuzumab emtansine – FDA approved 2/2013
© 2014 Rising Tide 12Issues for Future “Precision Medicine”
Drug Development
• Small subsets of patients: How to prove clinical
benefit? Is a phase 3 trial always required? How
does a drug achieve FDA approval?
• Quality of evidence for clinical utility of
molecular/biological markers (e.g., individual/
institutional financial conflict-of-interest)
• Insurers willingness to pay for anti-neoplastic
therapy based on molecular test results, rather
than on data from phase 3 randomized trials?
© 2014 Rising Tide 13Aspirin use and survival after the
diagnosis of colon cancer (NEJM)
• Two populations (121,000, Nurses Health Study
[1976]; 51,000, Health Professionals Follow-up
Study [1986]) - detailed health information
• 964 pts. developed colon cancer; tumor tested
• 17% patients PIK3CA mutation
• In patients with PIK3CA mutations in the tumor –
82% reduction in risk of death if took aspirin
compared to patients who did not take aspirin
• No impact of aspirin if “normal” PIK3CA
© 2014 Rising Tide 14But …
• The future is here
• It is possible (today or within less than a year) to
sequence the entire genome of a tumor and the
corresponding normal genome of an individual
cancer patient for < $5,000 (12-15 years ago this
would have cost $6,000,000,000)
• So, the issue is not whether the data will be
available to patients, but rather how to optimally
convert this massive quantity of raw data into
information of genuine value in individual patient
management
© 2014 Rising Tide 15Declining Cost of
Sequencing a Human Genome
© 2014 Rising Tide 16Proposed future research strategy
• Web-based national/international registry of
outcomes (history, validated treatment
results) from therapy based on molecular-
based management – (“N-of-1” research)
• Results made available to all interested parties
(public, patients, regulatory agencies, 3rd party
payers, employers, research community)
• When robust data available, publication in
peer-reviewed literature
© 2014 Rising Tide 17Targeted Cancer Therapy
• The best oncology drugs introduced during the
last 15 years have been targeted agents, with
activity dependent on identification of the
appropriate population
• Assessment of tumors for specific molecular
abnormalities (mutations, overexpression, etc) is
now a standard part of clinical practice
• The large majority of drugs in development are
targeted, and many are being developed with
companion diagnostic tests
© 2014 Rising Tide 18Molecular Tumor Profiling-Current
status in clinical practice
• Limited practical application
• Expensive-not consistently reimbursed
• Considered a research tool
© 2014 Rising Tide 19Targeted Therapeutics in Cancer. McDermott U et al. N Engl J Med 2011;364:340-350
Targeted Cancer Therapy
21New Frontiers in Genomics at CTCA
**Signature Trial Program-Novartis
Phase II, pipeline drugs
**My Pathway Trial-Genentech
Phase II, 5 available drugs for broader
application
© 2014 Rising Tide 22Signature Trial
• FGFR-BGJ398
• RAS/RAF/MEK-Binimetinib(MEK162)
• PI3K/PTEN-Buparlisib(BKM120)
• ALK/ROS1-Ceritinib(LDK378)
• RTK-Dovitinib(TKI258)
• BRAFV600-Encorafenib(LGX818)
• CDK4/6, Cyclin D1/3 or p16-LEE011
• PTCHI/SMO- Sonidegib(LDE225)
© 2014 Rising Tide 23My Pathway
• An open label phase IIA study evaluating
Trastuzumab/Pertuzumab, Erlotinib,
Vemurafenib, and Vismodegib in patients who
have advanced solid tumors with mutations or
gene expression abnormalities predictive of
response to one of these agents
© 2014 Rising Tide 24PRO 02 My Pathway Study – Main Schema
25• Rapidly accumulating data on the heterogeneity and molecular complexity of the tumor • As new markers are validated in clinical trials, they will need progressive integration into routine practice with the help of decision making algorithm • On going debate about the tumor sample for mutation analysis, primary versus metastatic tumor versus circulating tumor cells • On going debate on FDA approved test vs. laboratory developed test • Single test (KRAS, EGFR, HER2) with reflex vs. multiplex testing (panels) (exomes, genomes) • Technology advancing at incredible rate, regulatory agencies, government and payers working hard to keep up
Targeting Treatment to a Specific Variant in the Melanoma Gene. McDermott U et al. N Engl J Med 2011;364:340-350
Thank you
Contact information:
Dr. Shayma Kazmi
Shayma.Kazmi@ctca-hope.comYou can also read
