Transcript FR by Ovary Histology - the Gynecologic Cancer InterGroup

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