Pharmacogenetic (CYP2D6) and gene expression profiles (HOXB13/IL17BR and molecular grade index) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial.

Abstract

#57 Background: ABCSG 8 is the only prospective trial examining the value of switching patients (pts) to an aromatase inhibitor after tamoxifen (Tam) in which randomization occurred prior to therapy. This trial demonstrated that 2 years (yrs) of Tam followed by 3 yrs of anastrozole (TAM to A) was superior to 5 yrs of Tam (Jakesz SABC 2005). Tam is metabolically activated by CYP2D6 to endoxifen and pts with impaired CYP2D6 metabolism have a higher risk of recurrence (Goetz JCO 2005). The HOXB13/IL17BR (H/I) index (Ma Cancer Cell 2004) is associated with Tam resistance while a 5-gene molecular grade index (MGI) distinguishes outcome in grade II tumors. H/I and MGI are complementary prognostic factors that define low (low MGI), intermediate (low H/I, high MGI) and high risk groups (high H/I and MGI) (Ma Clin Cancer Res 2008). We sought to validate these biomarkers in ABCSG Trial 8, and hypothesized that they may predict the benefit of sequencing TAM to A versus Tam alone.
 Methods: From 1996-2004, ABCSG 8 randomized 3,901 pts with ER positive breast cancer. The primary endpoint was event-free survival. Assuming 40% of pts had reduced CYP2D6 metabolism, we designed a nested case control study in which 110 Tam treated cases matched to 2 controls would yield 80% power to detect a relative risk of 2.3 for pts with reduced CYP2D6 metabolism. Additionally, we sought to perform an exploratory analysis of the benefit of switching from Tam to A in pts with impaired vs non-impaired CYP2D6 metabolism. DNA and RNA derived from paraffin embedded sections were used to genotype for CYP2D6 and to obtain H/I and MGI RT-PCR profiles.
 Findings: Thus far, CYP2D6 genotyping is complete in 345 pts corresponding to 53 cases/106 controls (Tam) and 62 cases/124 controls (Tam to A). DNA and RNA yields were excellent with a CYP2D6 genotype call rate of >95%. CYP2D6 allele frequencies were as expected: *3 (.01), *4, (.23), *6 (.01), *10 (.02), *17 (.00), and *41 (.10). 44% of pts had reduced CYP2D6 metabolism (at least one CYP2D6 null allele or intermediate metabolizer) and 8% were CYP2D6 poor metabolizers. For H/I and MGI, 340 pts were profiled with 64%, 20% and 16% in the low, intermediate, and high risk groups, respectively. Tissue sectioning/genotyping for additional cases/controls is ongoing.
 Discussion: This is the first retrospective analysis of a large Tam versus Tam to A trial to evaluate the association between 1) CYP2D6, HOXB13/IL17BR, and MGI with TAM treatment outcome and 2) the predictive benefit of these biomarkers in pts randomized to switch from Tam to AI versus Tam alone. Final results will be presented at the meeting. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 57.

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…21,29 Furthermore, Goetz et al 22 reported that patients with impaired CYP2D6 metabolism have nearly a twofold higher risk of BC recurrence when treated with tamoxifen in the adjuvant setting. Moreover, the subjects' phenotype appeared to result from the combination of the genotype and drugs (or nutrients) that may interact with CYP450, in particular antidepressants and CYP2D6, as reported by Goetz et al, 31 with a fourfold increase of BC relapse in PM subjects.…”

Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials

“…This heterogeneity is well illustrated in the data recently presented from 3 large adjuvant clinical breast cancer trials, wherein no association of CYP2D6 genotype with breast cancer recurrence was observed in the ATAC and BIG 1-98 clinical trials (31, 32). In contrast, within the ABCSG 8 clinical trial, CYP2D6 poor metabolizers were identified to have a statistically significantly increase in the odds of breast cancer recurrence in patients who received tamoxifen monotherapy, but not those who received tamoxifen followed by anastrozole (33). Furthermore, a secondary analysis of tamoxifen pharmacokinetic data from the subgroup of women taking tamoxifen (n=1,370) within the dietary and lifestyle intervention study (WHEL), demonstrated a significantly increased risk for disease recurrence in tamoxifen treated patients with low steady state concentrations of endoxifen (<5.9 ng/ml), as compared to patients with concentrations >5.9 ng/ml (34).…”

Pharmacogenetics of Tamoxifen: Who Should UndergoCYP2D6Genetic Testing?

“…36 Investigators from the Mayo Clinic and the Austrian Breast Cancer Study Group (ABCSG) recently genotyped CYP2D6 in tumor sections obtained from participants in ABCSG Trial 8 in which women received tamoxifen for 2 to 5 years followed by an aromatase inhibitor for 2 to 5 years, or an aromatase inhibitor for 5 years. 37 Although results are not yet available, preliminary reports suggest that poor metabolizers who received 5 years of tamoxifen therapy had a significantly increased relative risk for breast cancer-related events compared with extensive metabolizers undergoing the same therapy.…”