Integrating Pharmacogenomic Questions Into GCIG Ovarian Cancer Clinical Trials Lori Minasian, MD Chief, Community Oncology and Prevention Trials Research.

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Presentation transcript:

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) Personalized Medicine Influence of Individual Genomic Polymorphisms on Drug Response Personalized Medicine Identify Risk for Toxicities Identify Predictive Markers of Efficacy

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

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

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

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

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;13:3269-3275

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