Pharmacogenomics: Pharmacogenomics: Studies in Breast Cancer Studies in Breast Cancer

Lynn C. Hartmann MDLynn C. Hartmann MD

Mayo Clinic Cancer CenterMayo Clinic Cancer Center

Major Breast PGx ProjectsMajor Breast PGx Projects

• MA.27 (AIs) GWAS (Replication BIG 1-MA.27 (AIs) GWAS (Replication BIG 1-98)98)

• Neoadjuvant chemo (Gepar Quinto; Neoadjuvant chemo (Gepar Quinto; Replication NSABP B-40)Replication NSABP B-40)

• Anastrozole and phenotypes (MBD, Anastrozole and phenotypes (MBD, BMD, hormone levels)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 Genomics and Randomized Trials Network (SUCCESS A clinical trial)Network (SUCCESS A clinical trial)

• GARNETGARNET

• GARNET-Mayo WHIGARNET-Mayo WHI

Major Breast PGx ProjectsMajor Breast PGx Projects

Pharmacogenomics: Large-Scale Collaborations

NCICooperative

Groups

RIKENCenter 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 A GWAS for musculoskeletal adverse events on aromatase adverse events on aromatase

inhibitors as adjuvant therapy in early inhibitors as adjuvant therapy in early breast cancer (NCIC CTG Trial breast cancer (NCIC CTG Trial

MA.27)MA.27)

A Collaboration of A Collaboration of Pharmacogenetics Research Network Pharmacogenetics Research Network

RIKEN Center for Genomic Medicine RIKEN Center for Genomic Medicine NCIC Clinical Trials NCIC Clinical Trials

Group Group

Mayo Clinic Breast Cancer SPORE Mayo Clinic Breast Cancer SPORE Breast Cancer Intergroup of North America Breast Cancer Intergroup of North America

Background Background

• AIs: integralAIs: integral part of optimal therapy in part of optimal therapy in postmenopausal patientspostmenopausal patients

• Almost one-half of patients have new or worsening Almost one-half of patients have new or worsening joint-related complaintsjoint-related complaints with AI therapy with AI therapy (Crew, JCO, (Crew, JCO, 2007; 25:3877)2007; 25:3877)

• MA.27: MA.27: Large trial (n=7,576) examining AIs as Large trial (n=7,576) examining AIs as adjuvant therapy with majority of patients adjuvant therapy with majority of patients consented to collection and use of consented to collection and use of DNA for genetic DNA for genetic studiesstudies

• Musculoskeletal adverse events: Musculoskeletal adverse events: thethe major major adverse eventadverse event leading to discontinuation of leading to discontinuation of aromatase inhibitor therapy on aromatase inhibitor therapy on MA.27MA.27

NCIC-CTG TBCINCIC-CTG TBCI**Postmenopausal Breast Cancer Adjuvant TrialPostmenopausal Breast Cancer Adjuvant Trial

MA.27MA.27

Anastrozole Anastrozole x 5 yearsx 5 years

Celecoxib*Celecoxib*x 3 yearsx 3 years

Celecoxib* Celecoxib* x 3 yearsx 3 years

Exemestane Exemestane x 5 yearsx 5 years

Placebo Placebo x 3 yearsx 3 years

Placebo Placebo x 3 yearsx 3 years

Activated: May 26, 2003

Accrual completed:July 31, 2008

RANDOMIZE

*The Breast Cancer Intergroup of North America: NCIC CTG, CALGB, ECOG, NCCTG, SWOG

December 21, 2004: closure of celecoxib:placeborandomization after entry of 1622 patients

*400 mg bid

Study chair: Study chair: Paul GossPaul Goss

HypothesisHypothesisPGRN-RIKEN-MA.27 StudyPGRN-RIKEN-MA.27 Study

A A genome-wide association case control genome-wide association case control studystudy (GWAS) will identify single (GWAS) will identify single nucleotide polymorphisms (SNPs) nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse associated with musculoskeletal adverse events (MS-AEs) in women receiving events (MS-AEs) in women receiving aromatase inhibitor adjuvant therapy for aromatase inhibitor adjuvant therapy for early breast cancerearly breast cancer

DesignDesign• A nested matched case-control study with two A nested matched case-control study with two

controls for each case. Matching on: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-Case definition: grade 3-4 MS-AE or go off-

treatment for treatment for any any grade of MS-AEgrade of MS-AE

• Genotyping with Illumina Human610-Quad chip Genotyping with Illumina Human610-Quad chip

-log

10

(p-v

alu

e)

Manhattan Plot of 551,395 SNPsConditional Logistic Regression Analyses*

2 SNPs

*adjusted for 8 eigenvectors

Chromosome Position

Chr 14 Peak +/- 200KB*

*Conditional Logistic Regression Analysesadjusted for 8 Eigenvectors

SNPs with Lowest P-Values

SNPSNP Minor AlleleMinor Allele

FrequencyFrequency

Odds Odds RatioRatio

P-ValueP-Value

CasesCases ControlControlss

rs11849538rs11849538**

0.1720.172 0.0910.091 2.212.21 6.67E-076.67E-07

rs7158782rs7158782 0.1900.190 0.1100.110 2.162.16 7.74E-077.74E-07

rs7159713rs7159713 0.1900.190 0.1100.110 2.162.16 7.74E-077.74E-07

rs2369049rs2369049 0.1800.180 0.1000.100 2.082.08 2.23E-062.23E-06

*Fine mapping after imputation. (E-07=10 -7)

ChallengesChallenges

• 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 Determine mechanism of SNP/gene relationship to clinical phenotyperelationship to clinical phenotype

Conclusions Conclusions

• Women with a MS-AE after AI therapy are more Women with a MS-AE after AI therapy are more likely to have a variant on Chr 14 that creates an likely to have a variant on Chr 14 that creates an ERE for ERERE for ERαα

• These women may be more sensitive to These women may be more sensitive to estrogen deprivationestrogen deprivation

• The relevance of The relevance of TCL1ATCL1A to these symptoms is to these symptoms is under investigationunder investigation

• A replication study is in development and further A replication study is in development and further functional studies are in progressfunctional 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 – Pharmacogenomics Proposal – Ovarian CAOvarian CA

• Rationale: Rationale:

Variability in treatment responseVariability in treatment response

Variability in toxicity, esp neuropathyVariability in toxicity, esp neuropathy

• Primary goalsPrimary goals

Identify genes (SNPs) that are Identify genes (SNPs) that are associated with TTR and neuropathyassociated with TTR and neuropathy

Pharmacogenomics ProposalPharmacogenomics Proposal

• Collaboration of –Collaboration of –

NCI NCI

PGRNPGRN

Cooperative groupsCooperative groups

Ovarian SPOREsOvarian SPOREs