Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download FR by Ovary Histology - the Gynecologic Cancer InterGroup
Document related concepts
Transcript
Pharmacogenomics: Studies in Breast Cancer Lynn C. Hartmann MD Mayo Clinic Cancer Center Major Breast PGx Projects • MA.27 (AIs) GWAS (Replication BIG 198) • Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40) • Anastrozole and phenotypes (MBD, BMD, hormone levels) • P1 and P2 GWAS for BC events Major Breast PGx Projects • AIs and fractures GWAS • Genomics and Randomized Trials Network (SUCCESS A clinical trial) • GARNET • GARNET-Mayo WHI Pharmacogenomics: Large-Scale Collaborations NCI Cooperative Groups RIKEN Center for Genomic Medicine PGRN • Translational Science • Statistical Genomics • Functional Genomics Pharmacogenomic Gene Resequencing Clinical Study Core Relevant Prospective Clinical Trials Genotyping Pharmacogenomics Research Network Functional Pharmacogenomics Statistical Pharmacogenomics Bioinformatics Structural Pharmacogenomics 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 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: the major adverse event leading to discontinuation of aromatase inhibitor therapy on MA.27 NCIC-CTG TBCI* Postmenopausal Breast Cancer Adjuvant Trial MA.27 Study chair: Paul Goss Activated: May 26, 2003 Accrual completed: July 31, 2008 R A N D O M I Z E Anastrozole x 5 years Placebo x 3 years Celecoxib* x 3 years Exemestane x 5 years December 21, 2004: closure of celecoxib:placebo randomization after entry of 1622 patients Placebo x 3 years Celecoxib* x 3 years *400 mg bid *The Breast Cancer Intergroup of North America: NCIC CTG, CALGB, ECOG, NCCTG, SWOG Hypothesis PGRN-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 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 offtreatment for any grade of MS-AE • Genotyping with Illumina Human610-Quad chip Manhattan Plot of 551,395 SNPs Conditional Logistic Regression Analyses* -log10(p-value) 2 SNPs Chromosome Position *adjusted for 8 eigenvectors Chr 14 Peak +/- 200KB* *Conditional Logistic Regression Analyses adjusted for 8 Eigenvectors SNPs with Lowest P-Values SNP Minor Allele Frequency Cases Control s rs11849538* 0.172 0.091 Odds Ratio P-Value 2.21 6.67E-07 rs7158782 0.190 0.110 2.16 7.74E-07 rs7159713 0.190 0.110 2.16 7.74E-07 rs2369049 0.180 0.100 2.08 2.23E-06 *Fine mapping after imputation. (E-07=10-7) Challenges • • • • Determine if SNPs have function Relate SNPs to genes Relate genes to drug effect Determine mechanism of SNP/gene relationship to clinical phenotype 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 Pharmacogenomic Gene Resequencing Clinical Study Core Relevant Prospective Clinical Trials Genotyping Pharmacogenomics Research Network Functional Pharmacogenomics Statistical Pharmacogenomics Bioinformatics Structural Pharmacogenomics 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 Pharmacogenomics Proposal • Collaboration of – NCI PGRN Cooperative groups Ovarian SPOREs
