p53 Expression Predicts Poor Prognosis in R-CHOP Treated De Novo Diffuse Large B-Cell Lymphoma
Graham W Slack, King L Tan, David W Scott, Laurie H Sehn, Joseph M Connors, Randy D Gascoyne. BC Cancer Agency, Vancovuer, BC, Canada
Background: De novo diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a variable clinical course. The addition of rituximab (R) to CHOP combination chemotherapy has improved overall (OS) and progression free survival (PFS) but some patients progress despite treatment. Identifying biomarkers that predict poor response to R-CHOP therapy may be useful in guiding patient management. p53 is a nuclear protein with tumor suppressor activity that negatively regulates cell cycle progression by inducing expression of its downstream effector protein p21. The utility of p53 expression as a biomarker of poor prognosis in some solid tumours has been established but the significance of p53 expression in R-CHOP treated de novo DLBCL is unknown.
Design: 184 cases of formalin-fixed paraffin-embedded R-CHOP treated de novo DLBCL in a tissue microarray were independently evaluated by two pathologists for expression of p53, p21, CD10, BCL6, MUM1, GCET1, FOXP1 and LMO2 by immunohistochemistry. p53 expression was correlated with cell of origin (COO) immunophenotype, the International Prognostic Index (IPI) score, OS and PFS. The threshold for positive p53 expression was determined using X-Tile software. The COO immunophenotype was determined using Hans, Choi, and Tally algorithms.
Results: The patient population consisted of 115 males and 69 females ranging from 16-90 years in age (median 65 years). Using a threshold cut-off of ≥ 50% 25 cases were positive for p53. p21 expression was absent in most of these cases (21/25) indicating altered p53 function. p53 positivity was significantly associated with a non-germinal center COO immunophenotype by Tally criteria (p=0.016). Kaplan-Meier univariate analysis showed positive expression of p53 significantly correlated with an inferior 5-year OS (48% vs. 70%, p=0.002) and PFS (44% vs. 61%, p=0.005). Cox regression multivariate analysis showed positive p53 expression maintained prognostic significance in OS (p=0.006) and PFS (p=0.025), independent of IPI and COO immunophenotype by Tally criteria.
Conclusions: p53 expression in ≥ 50% of cells in R-CHOP treated de novo DLBCL independently predicts inferior OS and PFS and is a biomarker of poor prognosis. The absence of p21 expression seen in most p53-positive cases suggests this effect may be due to altered p53 function and loss of tumor suppressor activity.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 196, Tuesday Afternoon