title: Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients.
abstract: Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopsies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant.
authors: Medical Prognosis Institute, Hørsholm, Denmark.
authors: Steen
authors: S
authors: Knudsen
authors: Medical Prognosis Institute, Hørsholm, Denmark.
authors: Thomas
authors: T
authors: Jensen
authors: Medical Prognosis Institute, Hørsholm, Denmark.
authors: Anker
authors: A
authors: Hansen
authors: Medical Prognosis Institute, Hørsholm, Denmark ; Now at the Department of Clinical Epidemiology at Aarhus University Hospital, Aarhus C, Denmark.
authors: Wiktor
authors: W
authors: Mazin
authors: Astrazeneca UK Limited, Oncology iMED, Alderley Park, Cheshire, United Kingdom.
authors: Justin
authors: J
authors: Lindemann
authors: Massachusetts General Hospital, Massachusetts, Boston, United States of America.
authors: Irene
authors: I
authors: Kuter
authors: Astrazeneca R&D Boston, Waltham, United States of America.
authors: Naomi
authors: N
authors: Laing
authors: Astrazeneca UK Limited, Oncology iMED, Alderley Park, Cheshire, United Kingdom ; Now at Boehringer-Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Elizabeth
authors: E
authors: Anderson
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D000077267:Fulvestrant; D004958:Estradiol