title: Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer.
abstract: In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.
authors.affiliation: 1] University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA [2] UMRS-775 "Bases moléculaires de la réponse aux xénobiotiques", University Paris Descartes, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Benhaim
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wakatsuki
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gerger
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bohanes
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Paez
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: LaBonte
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ning
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: El-Khoueiry
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ladner
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wilson
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Giamas
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Division of Medical Oncology, Los Angeles, CA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008198:Lymph Nodes / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D020413:3' Untranslated Regions; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C097199:KSR-1 protein kinase; C560359:LMTK3 protein, human