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Integrating Pharmacogenomic
Questions Into GCIG Ovarian
Cancer Clinical Trials
Lori Minasian, MD
Chief, Community Oncology and Prevention Trials Research
Group, Division of Cancer Prevention, NCI, NIH, HHS
Definition
• Pharmacogenomics (PGx)
– Influence of Individual Genomic
Polymorphisms on Drug Response
• Personalized Medicine
– Identify Risk for Toxicities
– Identify Predictive Markers of
Efficacy
Pharmacogenomics in Drug
Development
Safety
Efficacy
‘Pgx for Individual’
‘Pgx for Group’
Increased risk of
serious adverse
event
No increased
risk of serious
adverse event
Predict
increased response
Using genes
to predict
response
to medicines
Predict
reduced response
Context
• Rising concern about safety
– media reports, Congress, IOM
• HHS Recommendations 2008
• Enhanced Research in PGx
• Enhanced Research on Clinical Decision
Making Tools, esp PGx
• Direct Agencies to Work with Stakeholders
to Enhance incorporation of PGx findings
into routine healthcare delivery
Context
• Rapid Increase in Newly
Approved Drugs and Biologics
• Increasing New Approvals
Including PGx Language in
Labeling Indication
Currently Approved Oncology Drugs
Percentage of Labels with PG
Information
Approved FDA Drugs from 1945-2005
FDA approved Drug Labels
PGx Inf ormative Drug Labels (~10%)
Pharmacogenomics: Tailoring
Cancer Treatment
• Identify specific epidemiologic,
clinical and genetic profiles that could
enhance optimal response to cancer
therapy and minimize toxicity
• Selected examples:
– Irinotecan and UGT1A1 gene for CRC
– 6-MP and TMPT gene for ALL
– Tamoxifen and CYP2D6 for BC
Irinotecan and UGT1A1
Free of hematologic toxicity
(Probability)
Wild-type
Mutant
Cote, JF et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated
with irinotecan. Clin Cancer Res 2007;13:3269-3275
Pharmacogenomics in Ovarian
Cancer (Review by Paige & Brown 2009)
• Drug Response:
– Transport (ABCB1)
– Metabolism (P450, GST)
– DNA Repair (ERCC1)
– Markers of Tumor Response (eg p53)
Pharmacogenomics in Scottish
RT Ovarian Cancer (March 2007)
• Pts randomized to
– Docetaxel + Carboplatin vs
– Paclitaxel + Carboplatin
• Germline DNA from whole blood on 914
or 1077 patients
• Genotyping for 27 polymorphisms in 16
genes
• No clear candidates for taxane/platinum
PGx markers found
Pharmacogenomics
• Better understanding of regulation of
chemotherapy mechanisms of action
• Need large collections of well annotated
specimens in conjunction with clinical
trials
– NCI moving towards collecting blood on
patients in phase III trials
– GCIC offers the possibility of looking at PGx
specific to ethnic populations, esp if achieve
goal of common control arms on phase III
trials