title: Development and blind clinical validation of a microRNA based predictor of response to treatment with R-CHO(E)P in DLBCL.
abstract: MicroRNAs (miRNA) are a group of short noncoding RNAs that regulate gene expression at the posttranscriptional level. It has been shown that microRNAs are independent predictors of outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with the drug combination R-CHOP. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of doxorubicine, cyclophosphamide, vincristine and etoposide as well as the baseline microRNA expression of the 60 cell lines, a microRNA based response predictor to CHOP was developed. The response predictor consisting of 20 microRNAs was blindly validated in a cohort of 116 de novo DLBCL patients treated with R-CHOP or R-CHOEP as first line treatment. The predicted sensitivity based on diagnostic FFPE samples matched the clinical response, with decreasing sensitivity in poor responders (P = 0.03). When the International Prognostic Index (IPI) was included in the prediction analysis, the separation between responders and non-responders improved (P = 0.001). Thirteen patients developed relapse, and five patients predicted sensitive to their second and third line treatment survived a median 1194 days, while eight patients predicted not sensitive to their second and third line treatment survived a median 187 days (90% CI: 485 days versus 227 days). Among the latter group it was predicted that four would have been sensitive to another second line treatment than the one they received. The predictions were almost the same when diagnostic biopsies were used as when relapse biopsies were used. These preliminary findings warrant testing in a larger cohort of relapse patients to confirm whether the miRNA based predictor can select the optimal second line treatment and increase survival.
authors.affiliation: Medical Prognosis Institute, Hørsholm, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Knudsen
authors.affiliation: Rigshospitalet, Department of Hematology, Copenhagen, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Hother
authors.affiliation: Rigshospitalet, Department of Hematology, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbæk
authors.affiliation: Medical Prognosis Institute, Hørsholm, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jensen
authors.affiliation: Medical Prognosis Institute, Hørsholm, Denmark.
authors.forename: Anker
authors.initials: A
authors.lastname: Hansen
authors.affiliation: Medical Prognosis Institute, Hørsholm, Denmark.
authors.forename: Wiktor
authors.initials: W
authors.lastname: Mazin
authors.affiliation: Medical Prognosis Institute, Hørsholm, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Dahlgaard
authors.affiliation: Odense University Hospital, Department of Pathology, Odense, Denmark.
authors.forename: Michael Boe
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Rigshospitalet, Department of Pathology, Copenhagen, Denmark.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ralfkiær
authors.affiliation: Rigshospitalet, Department of Hematology, Copenhagen, Denmark.
authors.forename: Peter de Nully
authors.initials: Pde N
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D012372:ROC Curve; D012008:Recurrence; D015203:Reproducibility of Results; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D035683:MicroRNAs; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone