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Pharmacogenomics: Studies in Breast Cancer

Pharmacogenomics: Studies in Breast Cancer . Lynn C. Hartmann MD Mayo Clinic Cancer Center. Major Breast PGx Projects. MA.27 (AIs) GWAS (Replication BIG 1-98) Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40) Anastrozole and phenotypes (MBD, BMD, hormone levels)

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Pharmacogenomics: Studies in Breast Cancer

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  1. Pharmacogenomics: Studies in Breast Cancer Lynn C. Hartmann MD Mayo Clinic Cancer Center

  2. Major Breast PGx Projects • MA.27 (AIs) GWAS (Replication BIG 1-98) • Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40) • Anastrozole and phenotypes (MBD, BMD, hormone levels) • P1 and P2 GWAS for BC events

  3. Major Breast PGx Projects • AIs and fractures GWAS • Genomics and Randomized Trials Network (SUCCESS A clinical trial) • GARNET • GARNET-Mayo WHI

  4. Pharmacogenomics: Large-Scale Collaborations NCI Cooperative Groups RIKEN Center for Genomic Medicine • PGRN • Translational Science • Statistical Genomics • Functional Genomics

  5. Pharmacogenomic Gene Resequencing Clinical Study Core Genotyping Structural Pharmacogenomics Statistical Pharmacogenomics Relevant Prospective Clinical Trials Pharmacogenomics Research Network Functional Pharmacogenomics Bioinformatics

  6. A GWAS for musculoskeletal adverse events on aromatase inhibitors as adjuvant therapy in early breast cancer (NCIC CTG Trial MA.27) A Collaboration of Pharmacogenetics Research Network RIKEN Center for Genomic Medicine NCIC Clinical Trials Group Mayo Clinic Breast Cancer SPORE Breast Cancer Intergroup of North America

  7. Background AIs: integral part of optimal therapy in postmenopausal patients Almost one-half of patients have new or worsening joint-related complaints with AI therapy (Crew, JCO, 2007; 25:3877) MA.27: Large trial (n=7,576) examining AIs as adjuvant therapy with majority of patients consented to collection and use of DNA for genetic studies Musculoskeletal adverse events: themajor adverse event leading to discontinuation of aromatase inhibitor therapy on MA.27

  8. NCIC-CTG TBCI* Postmenopausal Breast Cancer Adjuvant Trial MA.27 Study chair: Paul Goss Placebo x 3 years R A N D O M I Z E Anastrozole x 5 years Celecoxib* x 3 years Activated: May 26, 2003 Accrual completed: July 31, 2008 Placebo x 3 years Exemestane x 5 years Celecoxib* x 3 years December 21, 2004: closure of celecoxib:placebo randomization after entry of 1622 patients *400 mg bid *The Breast Cancer Intergroup of North America: NCIC CTG, CALGB, ECOG,NCCTG, SWOG

  9. HypothesisPGRN-RIKEN-MA.27 Study A genome-wide association case control study (GWAS) will identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women receiving aromatase inhibitor adjuvant therapy for early breast cancer

  10. Design A nested matched case-control study with two controls for each case. Matching on: Treatment arm (blinded) Prior chemotherapy (yes/no) Age at treatment (+/- 5 years) Case definition: grade 3-4 MS-AE or go off-treatment for any grade of MS-AE Genotyping with Illumina Human610-Quad chip

  11. Manhattan Plot of 551,395 SNPs Conditional Logistic Regression Analyses* 2 SNPs -log10(p-value) Chromosome Position *adjusted for 8 eigenvectors

  12. Chr 14 Peak +/- 200KB* *Conditional Logistic Regression Analyses adjusted for 8 Eigenvectors

  13. SNPs with Lowest P-Values *Fine mapping after imputation. (E-07=10-7)

  14. Challenges Determine if SNPs have function Relate SNPs to genes Relate genes to drug effect Determine mechanism of SNP/gene relationship to clinical phenotype

  15. Conclusions • Women with a MS-AE after AI therapy are more likely to have a variant on Chr 14 that creates an ERE for ERα • These women may be more sensitive to estrogen deprivation • The relevance of TCL1A to these symptoms is under investigation • A replication study is in development and further functional studies are in progress

  16. Pharmacogenomic Gene Resequencing Clinical Study Core Genotyping Structural Pharmacogenomics Statistical Pharmacogenomics Relevant Prospective Clinical Trials Pharmacogenomics Research Network Functional Pharmacogenomics Bioinformatics

  17. Pharmacogenomics Proposal – Ovarian CA • Rationale:  Variability in treatment response  Variability in toxicity, esp neuropathy • Primary goals  Identify genes (SNPs) that are associated with TTR and neuropathy

  18. Pharmacogenomics Proposal • Collaboration of –  NCI  PGRN  Cooperative groups  Ovarian SPOREs

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