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Clinical Trial
. 2010 Oct 12;103(8):1201-8.
doi: 10.1038/sj.bjc.6605909. Epub 2010 Sep 28.

Modulation of Plasma Complement by the Initial Dose of Epirubicin/Docetaxel Therapy in Breast Cancer and Its Predictive Value

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Free PMC article
Clinical Trial

Modulation of Plasma Complement by the Initial Dose of Epirubicin/Docetaxel Therapy in Breast Cancer and Its Predictive Value

A Michlmayr et al. Br J Cancer. .
Free PMC article

Abstract

Background: Despite the widespread use of neoadjuvant chemotherapy in breast cancer patients, prediction of individual response to treatment remains an unsolved clinical problem. Particularly, administration of an inefficient chemotherapeutic regimen should be avoided. Therefore, a better understanding of the molecular mechanisms underlying response to neoadjuvant chemotherapy is of particular clinical interest. Aim of the present study was to test whether neoadjuvant chemotherapy with epirubicin/docetaxel induces early changes in the plasma proteome of breast cancer patients and whether such changes correlate with response to therapy.

Methods: Plasma samples of 25 breast cancer patients obtained before and 24 h after initiation of epirubicin/docetaxel-based neoadjuvant chemotherapy were analysed using two-dimensional differential gel electrophoresis (2D-DIGE). Protein spots found to be differentially expressed were identified using mass spectrometry and then correlated with the pathological response after six cycles of therapy. Markers identified in a discovery set of patients (n=12) were confirmed in an independent validation set (n=13).

Results: 2D-DIGE revealed 33 protein spots to be differentially expressed in response to chemotherapy, including the complement factors C1, C3 and C4, inter-α-trypsin inhibitor, α-1-antichymotrypsin and α-2-Heremans-Schmid glycoprotein (AHSG). With respect to cytokines, only interleukin (IL)-6, IL-10 and soluble intracellular adgesion molecule 3 (sICAM3) were minimally modulated. Moreover, two protein spots within the complement component C3 significantly correlated with response to therapy.

Conclusion: We have identified acute phase proteins and the complement system as part of the early host response to epirubicin/docetaxel chemotherapy. As complement C3 cleavage correlates with the efficacy of docetaxel/epirubicin-based chemotherapy, it has the potential as an easily accessible predictive biomarker.

Figures

Figure 1
Figure 1
Two-dimensional gel electrophoresis of the plasma proteome. (A) Position of protein spots most significantly influenced by the initial dose of the therapy on a representative 2D-gel image. Their molecular identity is indicated in Table 2. The underlined numbers represent members of the complement system. (B and C) show 2D-western blot images using antibodies against complement component C3 (B) or C4 (C). The detail displayed in the punctured frame shows the signals obtained by incubation with monoclonal anti-C4d antibody. Only this antibody recognised the upper C4 α-chain. Protein spots indicated in rectangles represent complement isoforms that are significantly differentially influenced by the initial dose between responders and non-responders.

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