title: Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.
abstract: Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Sucheston
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: SWOG Statistical Center, Seattle, WA, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Barlow
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zirpoli
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H C F
authors.initials: HC
authors.lastname: Moore
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Thomas Budd
authors.affiliation: Columbia University Medical Center, Columbia University, New York, NY, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Hershman
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Davis
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Ciupak
authors.affiliation: Department of medicine, Baystate Medical Center, Springfield, MA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Stewart
authors.affiliation: Lombardi Comprehensive Cancer Center, Washington, DC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Isaacs
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Hobday
authors.affiliation: Allan Blair Cancer Centre, Regina, SK, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Salim
authors.affiliation: Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Seattle Cancer Care Alliance, Seattle, WA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Gralow
authors.affiliation: College of Medicine, Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Livingston
authors.affiliation: Loyola University Chicago Cardinal Bernardin Cancer Center, Maywood, IL, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Albain
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050697:Retinal Dehydrogenase
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D003520:Cyclophosphamide; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050697:Retinal Dehydrogenase; C513055:ABCB1 protein, human; C510223:ALDH1A1 protein, human; C421109:multidrug resistance-associated protein 1