Expression of the ATP-Binding Cassette Transporter MRP1 in Hodgkin/Reed-Sternberg Cells Is Associated with Lower Treatment Failure – Free Survival in Classical Hodgkin Lymphoma.
Wesley O Greaves, Beatriz Sanchez-Espiridon, Kranthi Kunkalla, Kunal S Dave, Cynthia S Liang, Elias Drakos, Lianchun Xiao, L Jeffrey Medeiros, Francisco Vega. University of Texas MD Anderson Cancer Center, Houston; Spanish National Cancer Research Centre (CNIO), and Centro Oncológico MD Anderson International España, Madrid, Spain
Background: Approximately 20% of patients with classical Hodgkin lymphoma (CHL) are not cured with conventional chemotherapy regimens and have poor overall survival. The mechanisms responsible for chemoresistance in these tumors are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and overexpression of ABCC1 (MRP1) has been shown to contribute to the drug resistance phenotype of the CHL derived cell line KMH2 (Blood. 2010;116:418). However, the role of ABC transporters has not been explored in CHL tumors. We surveyed a large number of CHL tumors for expression of ABC transporters.
Design: The study group included 103 patients with advanced CHL (Ann Arbor stages III and IV) who received first-line standard chemotherapy with ABVD or ABVD variants. We used immunohistochemistry to assess for expression of MDR1, MRP1, MRP2, MRP3 and ABCG2 in tissue microarrays of pre-treatment, paraffin-embedded CHL tissue samples. Positive cases showed cytoplasmic staining in >10% HRS cells. Fisher's exact test was used to evaluate the association of clinical response with categorical variables. Kaplan-Meier method and the log rank test were used for survival analysis. A multivariate Cox proportional hazards model was fitted to evaluate the association of survival with demographic and clinical factors.
Results: The estimated 3-year overall survival rate was 92.1%. Overall survival was significantly associated with clinical response, relapse and age >45 years. Thirty-three cases (32%) were screened for MDR1, MRP2 and MRP3 expression and were all negative. Due to loss of tissue cores, only a subset of cases was evaluable for ABCG2 and MRP1 expression, present in 9 of 73 (12%) and 23 of 77 (30%) tumors, respectively. MRP1 expression was marginally associated with treatment failure-free survival (p=0.06) which showed an estimated rate of 66.7% and 82.4% for MRP1 positive and negative groups, respectively. There was no significant association between ABC transporter expression and response to therapy.
Conclusions: The ABC transporters ABCG2 and MRP1 are expressed in a subset of advanced stage untreated CHLs. Expression of MRP-1 in HRS cells of untreated CHL is marginally associated with lower treatment failure-free survival. Assessment of MRP-1 expression in CHL at time of presentation may be helpful for stratifying therapy in these patients.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 153, Tuesday Afternoon