title: Gene expression profiling of sequential metastatic biopsies for biomarker discovery in breast cancer.
abstract: The feasibility of longitudinal metastatic biopsies for gene expression profiling in breast cancer is unexplored. Dynamic changes in gene expression can potentially predict efficacy of targeted cancer drugs. Patients enrolled in a phase III trial of metastatic breast cancer with docetaxel monotherapy versus combination of docetaxel + sunitinib were offered to participate in a translational substudy comprising longitudinal fine needle aspiration biopsies and Positron Emission Tomography imaging before (T1) and two weeks after start of treatment (T2). Aspirated tumor material was used for microarray analysis, and treatment-induced changes (T2 versus T1) in gene expression and standardized uptake values (SUV) were investigated and correlated to clinical outcome measures. Gene expression profiling yielded high-quality data at both time points in 14/18 patients. Unsupervised clustering revealed specific patterns of changes caused by monotherapy vs. combination therapy (p = 0.021, Fisher's exact test). A therapy-induced reduction of known proliferation and hypoxia metagene scores was prominent in the combination arm. Changes in a previously reported hypoxia metagene score were strongly correlated to the objective responses seen by conventional radiology assessments after 6 weeks in the combination arm, Spearman's ρ = 1 (p = 0.017) but not in monotherapy, ρ = -0.029 (p = 1). Similarly, the Predictor Analysis of Microarrays 50 (PAM50) proliferation metagene correlated to tumor changes merely in the combination arm at 6 and 12 weeks (ρ = 0.900, p = 0.083 and ρ = 1, p = 0.017 respectively). Reductions in mean SUV were a reliable early predictor of objective response in monotherapy, ρ = 0.833 (p = 0.008), but not in the combination arm ρ = -0.029 (p = 1). Gene expression profiling of longitudinal metastatic aspiration biopsies was feasible, demonstrated biological validity and provided predictive information.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden. Electronic address: Theodoros.Foukakis@ki.se.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Foukakis
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Lövrot
authors.affiliation: Department of Radiology and Nuclear Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sandqvist
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Hanjing
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, University of California at San Francisco, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Lindström
authors.affiliation: Pfizer Oncology, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Giorgetti
authors.affiliation: Department of Radiology and Nuclear Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Jacobsson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Elham
authors.initials: E
authors.lastname: Hedayati
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008875:Middle Aged; D064847:Multimodal Imaging; D009362:Neoplasm Metastasis / Q000235:genetics*; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D011758:Pyrroles / Q000627:therapeutic use; D000077210:Sunitinib; D043823:Taxoids / Q000008:administration & dosage; D014057:Tomography, X-Ray Computed
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D000077210:Sunitinib
keywords: Breast cancer; Hypoxia; Positron emission tomography; Relapse biopsy; Sunitinib