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.
Bibliografisk noteFunding Information:
TBS has received consultancy fees from Pfizer and teaching fees from Orifarm, Eisai, Novartis, and Astellas Pharma. TLL participates in the Amgen Methods Advisory Council, for which he receives consulting fees and travel support. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from EMA and from companies in the form of research grants to (and administered by) Aarhus University. BE has received institutional grants from AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, Roche, and Samsung Bioepis. None of these disclosures have any relation to the present study.
This project received funding from the Danish Cancer Society [R167-A11045-17-S2] to DCF, from Aarhus University to CFH, from the Danish Cancer Research Foundation [PLESNER-FAST-Active.FID1839672] to CFH, and from the Lundbeck Foundation [R167–2013–15861] to DCF. The ProBe CaRe cohort infrastructure was supported by grant R01CA166825 to TLL from the US National Cancer Institute.
© 2022, The Author(s).