Abstract P3-13-06: Single nucleotide polymorphisms and mortality after docetaxel-based chemotherapy in premenopausal breast cancer: A population-based cohort study in Denmark
Authors: Hjorth Cathrine F , Damkier Per , Stage Tore B , Feddersen Søren , Ejlertsen Bent , Lash Timothy L , Hamilton-Dutoit Stephen , Ahern Thomas P , Rørth Mikael , Sørensen Henrik T , Cronin-Fenton Deirdre 
Published: March 2022

Abstract
Background Taxane-based chemotherapy is first line treatment in various cancers, including premenopausal breast cancer, but the inter-individual effectiveness is unpredictable. Differences in expression and activity of docetaxel-metabolizing enzymes and transporters (DMETs) may modify docetaxel effectiveness. Although reported data are inconsistent, some findings suggests that variant alleles that reduce the function of 1) SLC-transporters reduce drug influx into hepatocytes; 2) CYP-450 enzymes hamper drug metabolism; and 3) ABC-transporters decrease docetaxel clearance. The net effect is hypothesized to be increased docetaxel exposure and effectiveness. In contrast, GSTP1 variants have been associated with poorer docetaxel effectiveness. We investigated whether single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes and transporters were associated with mortality in premenopausal breast cancer patients. Materials and methods Using the Danish Breast Cancer Group (DBCG) clinical database, we identified data on premenopausal women aged 18–55 years, diagnosed with non–metastatic breast cancer during 2007–2011. All women were recommended epirubicin, cyclophosphamide and docetaxel-based adjuvant chemotherapy, and tamoxifen if the disease was estrogen receptor (ER) positive. From DBCG and other Danish administrative and medical registries we retrieve data on death, emigration, and tumor characteristics. We collected archived formalin-fixed paraffin-embedded primary tumor tissue from Danish pathology departments. We genotyped 17 candidate SNPs using TaqMan SNP genotyping assays and, for each SNP, categorized the women as having two normal alleles (wildtype) or at least one variant allele. We followed the women from six months after breast cancer diagnosis until death, emigration or 30th June 2019, whichever came first. Comparing variant carriers with wildtype, we computed cumulative incidence proportions (CIPs) and used Poisson regression models to calculate unadjusted incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) of all–cause mortality. We stratified by ER status to evaluate interaction. Analyses were repeated for breast cancer specific mortality. Results Our cohort included 2,262 women. During follow–up (median 9.6 years, interquartile range: 8.4–11.0), 250 women died (CIP: 14%); 219 due to breast cancer (CIP: 11%). Genotyping was successful for ≥95% of the study cohort, with exception of two SNPs, which were excluded from analyses. We detected decreased mortality in variant carriers of SLCO1B1 rs2306283 (IRR: 0.75, 95% CI 0.58–0.97), and ABCB1 rs1128503 (IRR: 0.81, 95% CI: 0.63–1.05), ABCB1 rs2032582 (IRR: 0.80, 95% CI: 0.62–1.04) and ABCC2 rs12762549 (IRR: 0.80, 95% CI: 0.62–1.04). In contrast, mortality was increased in carriers of GSTP1 rs1138272 (IRR: 1.28, 95% CI: 0.93–1.76) and, unexpectedly, in carriers of CYP3A rs10273424 (IRR: 1.36, 95% CI: 0.99–1.86) variant carriers. Sensitivity analyses yielded similar findings. ER status did not modify the associations. Conclusions In this study, mortality may be associated with SNPs in ABCB1, ABCC2, SLCO1B1, CYP3A and GSTP1 in premenopausal women with non-metastatic breast cancer receiving docetaxel. The mechanisms underlying our findings remains unclear but may be related to docetaxel pharmacokinetics.
Citation Format: Cathrine F Hjorth, Per Damkier, Tore B Stage, Søren Feddersen, Bent Ejlertsen, Timothy L Lash, Stephen Hamilton-Dutoit, Thomas P Ahern, Mikael Rørth, Henrik T Sørensen, Deirdre Cronin-Fenton. Single nucleotide polymorphisms and mortality after docetaxel-based chemotherapy in premenopausal breast cancer: A population-based cohort study in Denmark [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-06.