title: Impact of genetic variability and treatment-related factors on outcome in early breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide, and docetaxel.
abstract: To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.
authors.affiliation: Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, Belgium, christof.vulsteke@azmmsj.be.
authors.forename: C
authors.initials: C
authors.lastname: Vulsteke
authors.forename: A M
authors.initials: AM
authors.lastname: Pfeil
authors.forename: M
authors.initials: M
authors.lastname: Schwenkglenks
authors.forename: R
authors.initials: R
authors.lastname: Pettengell
authors.forename: T D
authors.initials: TD
authors.lastname: Szucs
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.forename: M
authors.initials: M
authors.lastname: Peeters
authors.forename: P
authors.initials: P
authors.lastname: van Dam
authors.forename: A S
authors.initials: AS
authors.lastname: Dieudonné
authors.forename: S
authors.initials: S
authors.lastname: Hatse
authors.forename: P
authors.initials: P
authors.lastname: Neven
authors.forename: R
authors.initials: R
authors.lastname: Paridaens
authors.forename: H
authors.initials: H
authors.lastname: Wildiers
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D018572:Disease-Free Survival; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020641:Polymorphism, Single Nucleotide; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D005472:Fluorouracil