1. 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

2. Definition Pharmacogenomics (PGx) Personalized Medicine
Influence of Individual Genomic Polymorphisms on Drug Response
Personalized Medicine
Identify Risk for Toxicities
Identify Predictive Markers of Efficacy

3. Pharmacogenomics in Drug Development
Efficacy ‘Pgx for Group’
No increased risk of serious adverse event
Predict
increased response
Safety ‘Pgx for Individual’
Increased risk of serious adverse event
reduced response
Using genes
to predict
response
to medicines
Pharmacogenomics in Drug Development

4. Context Rising concern about safety HHS Recommendations 2008
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

5. Context Rapid Increase in Newly Approved Drugs and Biologics
Increasing New Approvals Including PGx Language in Labeling Indication

6. Currently Approved Oncology Drugs

7. Percentage of Labels with PG Information

8. 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

9. Free of hematologic toxicity (Probability)
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:

10. 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)

11. 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

12. 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