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prevent cell death. It is anticipated that combinatorial approaches, acting on the
secondary mutations and/or compensatory pathways, may markedly improve on the
effects of targeted agents used alone. 1. Baselga J, Campone M, Piccart M, et al.
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
N Engl J Med 2012;366:520-9.
Disclosure: J. Baselga: Consulting activity with Novartis and Genentech
17IN PHARMACOGENETICS /GENOMICS (PGX) TO OPTIMIZE
ENDOCRINE THERAPY
J. Ingle
Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA
Endocrine therapy of breast cancer is associated with substantial variability between
patients in terms of efficacy, adverse events and end organ effects indicating genetic
variability. This discussion will consider the host (germline) genome and consider
SERMs and 3 rd generation AIs. In of terms of single gene studies, most of the work
has been done with CYP2D6 and tamoxifen efficacy (first reported by our group in
2005) but the results have been mixed, related (in this author’s opinion) to a series of
flawed retrospective studies. Additional studies focusing on tamoxifen have examined
polymorphisms in phase II (conjugating) enzymes (UGTs, SULTs), ESR1 and ESR2,
Annals of Oncology
but results remain preliminary. Our group conducted the largest PGx GWAS to date
in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2 and identified
SNPs associated with development of breast cancer and SNP-dependent mechanisms
underlying SERM and estrogen-dependent regulation of BRCA1 expression.
Considering AIs, substantial research has occurred relating to the aromatase gene
CYP19. Our group has conducted GWAS in postmenopausal women with baseline
hormone levels as the phenotype and identified SNPs related to estradiol levels, that
achieved genome-wide significance, with one SNP creating an estrogen response
element (ERE), and regulation by these SNPs of estrogen-dependent TSPYL5
induction and CYP19 adipose promotors induction. We also identified a
genome-wide significant non-synonymous SNP in SLCO1B1 associated with
estrone-conjugate levels. We have completed a GWAS in women receiving AIs with
musculoskeletal adverse events (MS-AE) as the phenotype and identified a SNP that
created an ERE, was associated with estrogen-dependent TCL1A expression, which in
turn altered interleukin (IL) 17 receptor (R) A expression, IL-17, IL-12, IL-RB2, and
IL-1R2 expression, as well as NF-κB transcriptional activity. These finding provide a
pharmacological explanation for MS-AE in women treated with AIs. To date, PGx
studies have not produced changes in clinical practice of endocrine therapy for breast
cancer. In several instances they have served as discovery tools that provided
direction for research that has led to new knowledge of the biology underlying
endocrine therapy.
Disclosure: The author has declared no conflicts of interest.
ix28 | Abstracts Volume 23 | Supplement 9 | September 2012