Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer.
Tamoxifen treatment of estrogen-dependent breast cancer ultimately loses its effectiveness due to the development of resistance. From a functional screen for identifying genes responsible for tamoxifen resistance in human ZR-75-1 breast cancer cells, fibroblast growth factor (FGF) 17 was recovered. The aim of this exploratory study was to assess the predictive value of FGF17 and the receptors FGFR1-4 for the type of response to tamoxifen treatment (clinical benefit) and the duration of progression-free survival (PFS) in patients with recurrent breast cancer. mRNA levels of FGF17 and FGFR1-4 were quantified by real-time reverse transcriptase PCR in 285 estrogen receptor-positive breast carcinomas with clinical follow-up. All patients had recurrent disease and were treated with tamoxifen as first-line systemic therapy for local or distant relapse. FGF17 and FGFR1-3 mRNA levels had no significant predictive value for this group of patients. However, high FGFR4 mRNA levels analyzed as a continuous log-transformed variable predicted poor clinical benefit (odds ratio=1.22; P=0.009) and shorter PFS (hazard ratio=1.18; P<0.001). In addition, in multivariable analysis, the predictive value of FGFR4 was independent from the traditional predictive factors. Our analyses show that FGFR4 may play a role in the biological response of the tumor to tamoxifen treatment. In addition, as altered expression of FGF17 causes tamoxifen resistance in vitro, the FGF signaling pathway could be a valuable target in the treatment of breast cancer patients resistant to endocrine treatment.
Meijer
Danielle
D
Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
Sieuwerts
Anieta M
AM
Look
Maxime P
MP
van Agthoven
Ton
T
Foekens
John A
JA
Dorssers
Lambert C J
LC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000188:drug therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D017211:Treatment Failure
D018931:Antineoplastic Agents, Hormonal; C484724:FGF17 protein, human; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D005346:Fibroblast Growth Factors; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4