17IN - Pharmacogenetics/Genomics (PGX) to optimize endocrine therapy

Date 30 September 2012
Event ESMO Congress 2012
Session Optimizing treatment in luminal breast cancer
Topics Breast Cancer, Early Stage
Pharmacology
Presenter James Ingle
Authors J. Ingle
  • Mayo Clinic, 55905 - Rochester/US

Abstract

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 3rd 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, 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-?B 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.