Abstract
Background: Proteasome inhibitors (PI) affect a variety of intracellular processes, including the cell cycle, NF-kB and other signal transduction pathways, and the balance of bcl-2-related proteins, yet it remains unknown which of these targets are most crucial in determining response to PI treatment in non-Hodgkin Lymphoma (NHL). Responses to bortezomib (btz) have been seen in different NHL subtypes in several phase 2 studies. The consistency of response suggests that there may be biological characteristics that determine individual tumor responses to PIs. We used tissue microarray (TMA) technology to determine if pre-treatment tumor characteristics can predict outcome of btz treatment in NHL.
Methods: TMAs were constructed using paraffin-embedded blocks of pre-treatment tissue from patients enrolled in a phase 2, CTEP-NCI sponsored trial of btz in NHL. Microsections were stained for 18 proteins with reported relevance to proteasome function and/or lymphoma prognosis. All stains were evaluated and scored by a central pathologist. Staining was correlated with quality and duration of response (DOR) or time to treatment failure (TTF). The best response was treated as a binary outcome (PR/CR vs SD/POD). Correlation between each marker and response was assessed by univariate analysis. The exact Wilcoxon rank-sum test was used to compare DOR and TTF with respect to the binary marker scores.
Results: This analysis includes 35 of 75 patients treated with btz between 11/6/01 and 2/23/07 for whom pre-treatment tissue blocks could be obtained. Response data were available for 32 of these patients. Diagnoses include: FL (N=10), SLL (N=4), MCL (N=14) and MZL (N=4). Expression of the cell-cycle inhibitor p27 was more common in responding vs non-responding pts (p=0.024), and was also significantly associated with longer DOR (p=0.020) and longer TTF (p=0.021; figure). Presence of Bcl-6 was significantly associated with shorter DOR (p=0.049) and shorter TTF (p=0.048; figure), but not response.
Conclusions: Using TMA analysis, we have shown that NHL patients with pre-treatment p27 staining were more likely to respond to btz, and had a longer DOR and TTF than those without baseline staining. Conversely, patients with baseline Bcl-6 expression had a shorter DOR and TTF than those without. Although the number of patients in this analysis is small, the data will help us generate hypotheses about disease and treatment biology that can be tested in larger studies. We are currently collecting samples from a broader pool of patients treated with btz at MSKCC to verify these results. TTF with bortezomib by (A) p27 and (B) Bcl-6 status.
Figure.
