title: High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.
abstract: Chemotherapy and rituximab (R) is current standard therapy in diffuse large B-cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R-CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p-AKT), bcl-2, MCL1, bcl-xL, Bax and Bak. High p-AKT expression (>108 cells/mm2, highest quartile, n=27) predicted worse progression-free (PFS) (P=0.02) and overall (OS) (P=0.01) survival, independent of International Prognostic Index and sex. Also bcl-2+ (cut-off 50%) predicted worse PFS (P=0.005) and OS (P=0.05) but after adjustment for clinical factors only the influence on PFS (P=0.03) remained significant. The prognostic impact of p-AKT overexpression was independent of bcl-2 status. MCL1, bcl-xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p-AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl-2 status could have prognostic importance also in the era of immunochemotherapy.
authors.affiliation: Section of Haematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden. sverker.hasselblom@vgregion.se
authors.forename: Sverker
authors.initials: S
authors.lastname: Hasselblom
authors.forename: Ulrika
authors.initials: U
authors.lastname: Hansson
authors.forename: Markus
authors.initials: M
authors.lastname: Olsson
authors.forename: Leif
authors.initials: L
authors.lastname: Torén
authors.forename: Anders
authors.initials: A
authors.lastname: Bergström
authors.forename: Herman
authors.initials: H
authors.lastname: Nilsson-Ehle
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012189:Retrospective Studies; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000069283:Rituximab; D051057:Proto-Oncogene Proteins c-akt