Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

Cathrine Fonnesbech Hjorth, Per Damkier, Tore Bjerregaard Stage, Søren Feddersen, Stephen Hamilton-Dutoit, Mikael Rørth, Bent Ejlertsen, Timothy Lee Lash, Thomas Patrick Ahern, Henrik Toft Sørensen, Deirdre Cronin-Fenton

Abstract

PURPOSE: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.

METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.

RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98).

CONCLUSION: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Original languageEnglish
JournalBreast Cancer Research and Treatment
Volume194
Issue number2
Pages (from-to)353-363
Number of pages11
ISSN0167-6806
DOIs
Publication statusPublished - Jul 2022

Keywords

  • Breast Neoplasms/drug therapy
  • Bridged-Ring Compounds
  • Chemotherapy, Adjuvant
  • Cohort Studies
  • Cytochrome P-450 CYP3A/therapeutic use
  • Denmark/epidemiology
  • Docetaxel/therapeutic use
  • Female
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Recurrence, Local/drug therapy
  • Nucleotides/therapeutic use
  • Polymorphism, Single Nucleotide
  • Taxoids/therapeutic use

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