title: Discordant cellular response to presurgical letrozole in bilateral synchronous ER+ breast cancers with a KRAS mutation or FGFR1 gene amplification.
abstract: We describe herein a patient presenting with bilateral estrogen-receptor-positive (ER+) breast tumors who was enrolled in a clinical trial exploring molecular aberrations associated with hormone-refractory tumor cell proliferation. Short-term (two week) hormonal therapy with the aromatase inhibitor letrozole substantially reduced proliferation as measured by Ki67 immunohistochemistry in one tumor, whereas the second was essentially unchanged. Extensive molecular and genetic work-up of the two tumors yielded divergent lesions in the two tumors: an activating KRAS mutation in the responsive tumor and an amplification of the fibroblast growth factor receptor-1 (FGFR1) locus in the treatment-refractory tumor. These findings provide an insight to possible mechanisms of resistance to antiestrogen therapy in ER+ breast cancers. First, they illustrate the necessity of clinically approved assays to identify FGFR1 gene amplification, which occur in approximately 5% of breast tumors and have been linked to antiestrogen resistance. It is quite possible that the addition of FGFR inhibitors to ER-targeted therapy will yield a superior antitumor effect and improved patient outcome. Second, they suggest that the role of activating mutations in RAS, although rare in breast cancer, may need to be explored in the context of ER+ breast tumors.
authors.affiliation: Vanderbilt University Medical Center, 2200 Pierce Ave, 777 PRB, Nashville, TN 37232-6307, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: Todd W
authors.initials: TW
authors.lastname: Miller
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kuba
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Meszoely
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D047072:Aromatase Inhibitors; C117307:KRAS protein, human; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins