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题目:: Monitoring bortezomib therapy in multiple myeloma: Screening of cyclin D1 overexpression as a potential prognostic marker for response to treatment.
作者:: Ngo(T B),Felthaus(J),Ihorst(G),Engelhardt(M),Wäsch(R)
状态:: 发布时间2016-12-12 , 更新时间 2016-12-12
期刊:: J Clin Oncol
摘要:: 8614 Background: Cyclin D1 (CCND1), 2 (CCND2) and 3 (CCND3) are overexpressed in almost all MM and their deregulation has prognostic value. As cyclins are substrates of the proteasome, proteasome inhibition by bortezomib may stabilize the cell cycle and facilitate the induction of apoptosis, as it has been recently shown for breast cancer (Ishii et al, J Nat Canc Inst 2006).,In a clinical approach, our objective was to define the expression levels of D-type cyclins in MM pts treated with bortezomib at our medical center between 1/2003 and 3/2006, aiming to define cyclins D as prognostic markers for monitoring treatment efficacy. We analyzed CCND1, CCND2 and CCND3 by real-time PCR in bone marrow specimens of 20 pts and correlated the expression with clinical features and other prognostic markers such as BM infiltration (BMI), ß2-microglobulin (ß2-MG) levels, 13q14 status and light chain-secretion.,The median number of bortezomib cycles in all pts was three and the best response to therapy was CR in one, PR in 11, SD in five and PD in 3/20. All pts who responded to bortezomib showed overexpression (OE) of CCND1. Pts not responding to bortezomib had very low or negative CCND1 cDNA levels. By 3/2007, 50% of all pts in CR, PR or SD had eventually relapsed. Of those pts, three relapsed, despite CCND1 OE prior to therapy. Six pts (66%) with CCND1 OE remained in response. Four pts displaying very high cyclin D1 expression levels were in either PR or SD, even after a follow-up of up to six years. Pts with CCND2 and CCND3 OE responded to bortezomib, but showed a relatively higher relapse rate (50% and 75% respectively). The amplification of the cyclin D genes was not found to correlate with BMI, ß2-MG, light chain secretion or del 13q14. The risk for progression after bortezomib treatment was significantly decreased in pts with cyclin D1 OE (HR 0.102, 95%CI 0.021-0.498, p=0.0048). Consequently, the progression free survival was significantly prolonged with cyclin D1 OE compared to those pts with low or negative cyclin D1 cDNA levels (p=0.0011).,Our findings raise the possibility that CCND1 is a specific marker for predicting a lasting response after bortezomib treatment in MM, warranting a prospective study with a larger patient cohort. No significant financial relationships to disclose.
语言:: eng
DOI:

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