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)MA.27 (AIs) GWAS (Replication BIG 1- 98) Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40)Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40) Anastrozole and phenotypes (MBD, BMD, hormone levels)Anastrozole and phenotypes (MBD, BMD, hormone levels) P1 and P2 GWAS for BC eventsP1 and P2 GWAS for BC events

AIs and fractures GWASAIs and fractures GWAS Genomics and Randomized Trials Network (SUCCESS A clinical trial)Genomics and Randomized Trials Network (SUCCESS A clinical trial) GARNETGARNET GARNET-Mayo WHIGARNET-Mayo WHI Major Breast PGx Projects

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

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

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 patientsAIs: 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)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 studiesMA.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.27Musculoskeletal 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 Anastrozole x 5 years x 5 years Celecoxib* x 3 years Celecoxib* Exemestane x 5 years x 5 years Placebo Placebo x 3 years Placebo Placebo x 3 years Activated: May 26, 2003 Accrual completed: July 31, 2008 RANDOMIZERANDOMIZE * The Breast Cancer Intergroup of North America: NCIC CTG, CALGB, ECOG, NCCTG, SWOG December 21, 2004: closure of celecoxib:placebo randomization after entry of 1622 patients *400 mg bid Study chair: Paul Goss

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

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

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

SNPs with Lowest P-Values SNP Minor Allele Frequency Odds Ratio P-Value Cases Control s rs * E-07 rs E-07 rs E-07 rs E-06 * Fine mapping after imputation. (E-07=10 -7 )

Challenges Determine if SNPs have functionDetermine if SNPs have function Relate SNPs to genesRelate SNPs to genes Relate genes to drug effectRelate genes to drug effect Determine mechanism of SNP/gene relationship to clinical phenotypeDetermine 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 ERαWomen 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 deprivationThese women may be more sensitive to estrogen deprivation The relevance of TCL1A to these symptoms is under investigationThe relevance of TCL1A to these symptoms is under investigation A replication study is in development and further functional studies are in progressA replication study is in development and further functional studies are in progress

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

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

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