title: pAKT Expression and Response to Sorafenib in Differentiated Thyroid Cancer.
abstract: Sorafenib has an antitumor activity in patients with radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC). Prior research has implicated signaling through the MAPK and AKT/PI3K pathways in the progression of DTC. To assess whether the activity of these pathways is predictive of response to sorafenib, we retrospectively studied molecular tumor markers from these two pathways from a phase 2 study of sorafenib in RAIR-DTC. Tumor samples from 40 of 53 DTC subjects obtained prior to initiation of sorafenib were immunostained with DAB-labeled antibodies to phospho-AKT (pAKT), phospho-ERK (pERK), and phospho-S6 (pS6). BRAFV600E genetic mutation analysis was performed on all samples. Expression levels and mutational status were compared to response and progression-free survival (PFS) for each patient. Low tumor expression of nuclear pAKT was associated with partial response to sorafenib (p < 0.01). Patients with nuclear pAKT expression that was below the median for our sample were more than three times as likely to have a partial response as patients with equal to or above median expression. There was no correlation between tumor expression of nuclear pERK or pS6 and response. Endothelial cell and pericyte expression of pERK, pAKT, and pS6 were not predictive of response. There was no correlation between BRAFV600E mutation status and partial response. No correlation was observed between either the expression of pAKT, pERK, or pS6, or the presence of the BRAFV600E mutation, and PFS. In conclusion, lower tumor expression of nuclear pAKT was associated with higher rate of response to sorafenib. This observation justifies evaluation of combination therapy with sorafenib and an inhibitor of the PI3K/AKT signaling pathway in RAIR-DTC.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Yarchoan
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Changqing
authors.initials: C
authors.lastname: Ma
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Stopenski
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Waixing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Cohen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pappas-Paxinos
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Burles A
authors.initials: BA
authors.lastname: Johnson
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Emerson Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. brosem@mail.med.upenn.edu.|Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA. brosem@mail.med.upenn.edu.|Stellar-Chance Laboratories, Mezzanine, 422 Curie Blvd., Philadelphia, PA, 19104, USA. brosem@mail.med.upenn.edu.
authors.forename: Marcia S
authors.initials: MS
authors.lastname: Brose
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases