title: Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC).
abstract: BACKGROUND
  To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy.
  
  
  METHODS
  Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points).
  
  
  RESULTS
  Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38).
  
  
  CONCLUSIONS
  Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.
authors: Department of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven, Belgium.
authors: C
authors: C
authors: Vulsteke
authors: D
authors: D
authors: Lambrechts
authors: A
authors: A
authors: Dieudonné
authors: S
authors: S
authors: Hatse
authors: B
authors: B
authors: Brouwers
authors: T
authors: T
authors: van Brussel
authors: P
authors: P
authors: Neven
authors: A
authors: A
authors: Belmans
authors: P
authors: P
authors: Schöffski
authors: R
authors: R
authors: Paridaens
authors: H
authors: H
authors: Wildiers
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D006402:Hematologic Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020360:Neoadjuvant Therapy / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1
keywords: aBCC1; breast cancer; fEC chemotherapy; febrile neutropenia; mRP1; single-nucleotide polymorphisms