title: The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy.
abstract: To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
authors.affiliation: Service d'anatomie et cytologie pathologiques, CHU Rangueil, Toulouse, France 50032.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Guellec
authors.forename: Elizabeth Cohen-Jonathan
authors.initials: EC
authors.lastname: Moyal
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Hervé
authors.initials: H
authors.lastname: Rubie
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Castex
authors.forename: Jerome Sales
authors.initials: JS
authors.lastname: de Gauzy
authors.forename: Paul
authors.initials: P
authors.lastname: Bonnevialle
authors.forename: Anne
authors.initials: A
authors.lastname: Gomez-Brouchet
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D001859:Bone Neoplasms / Q000201:enzymology / Q000401:mortality / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D002648:Child; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012516:Osteosarcoma / Q000201:enzymology / Q000401:mortality / Q000628:therapy*; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D039641:Integrin beta Chains; C084344:integrin beta5; D051418:Focal Adhesion Kinase 2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Biomarker; Immunohistochemistry; Integrin pathway; Osteosarcoma