scholarly journals Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review

2020 ◽  
Vol 21 (11) ◽  
pp. 4154 ◽  
Author(s):  
Julian Matthias Metzler ◽  
Laurin Burla ◽  
Daniel Fink ◽  
Patrick Imesch
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Drug Effects ◽  
Suppressor Cells ◽  
T Cell Response ◽  
Target Drug ◽  
Gynecological Malignancies ◽  
Programmed Death ◽  
Cancer Studies

Ibrutinib is an orally available, small-molecule tyrosine kinase inhibitor. Its main purpose is to inhibit Bruton’s tyrosine kinase (BTK), an enzyme that is crucial in B cell development. It is FDA approved for the treatment of certain hematological malignancies. Several promising off-target drug effects have led to multiple, mostly preclinical investigations regarding its use in solid tumors. Unfortunately, data on its effectiveness in gynecological malignancies are limited, and (systematic) reviews are missing. The objective of this review was to summarize the existing literature and to analyze the evidence of ibrutinib as a treatment option in gynecological malignancies, including breast cancer. Studies were identified in MEDLINE and EMBASE using a defined search strategy, and preclinical or clinical research projects investigating ibrutinib in connection with these malignancies were considered eligible for inclusion. Our findings showed that preclinical studies generally confirm ibrutinib’s efficacy in cell lines and animal models of ovarian, breast, and endometrial cancer. Ibrutinib exerts multiple antineoplastic effects, such as on-target BTK inhibition, off-target kinase inhibition, and immunomodulation by interference with myeloid-derived suppressor cells (MDSCs), programmed death-ligand 1 (PD-L1), and T cell response. These mechanisms were elaborated and discussed in the context of the evidence available. Further research is needed in order to transfer the preclinical results to a broader clinical appliance.

Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 578-578 ◽  
Author(s):  
S. E. Deprimo ◽  
C. Friece ◽  
X. Huang ◽  
J. Smeraglia ◽  
L. Sherman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Plasma Levels ◽  
Kinase Inhibitor ◽  
Metastatic Breast ◽  
Response Analysis ◽  
Sunitinib Malate ◽  
Multitargeted Tyrosine Kinase Inhibitor

578 Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET and FLT3. In a phase II trial of 64 patients with refractory, metastatic breast cancer, sunitinib treatment resulted in an ∼11% objective response rate (Miller et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 62 patients were obtained on days 1, 14, and 28 of the first cycle and days 1 and 28 of subsequent cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), soluble KIT (sKIT), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were modulated in most patients during the course of treatment. At the end of the first cycle, VEGF levels were increased more than 3-fold relative to baseline in 73% of cases, while sVEGFR-2 levels decreased by at least 30% in 88% of cases, and by >20% in all but 4 cases. In addition, levels of sVEGFR-3 were decreased by >30% in 82% of cases during the first cycle. For each of these markers, levels tended to return to near-baseline after 2 weeks off treatment. Longitudinal decreases in sKIT were also observed; decreases >50% by the end of cycle 2 were correlated with treatment outcomes for time-to-progression (P < 0.001) and survival (P = 0.03). Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Sunitinib therapy is associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of sunitinib activity in patients with metastatic breast cancer. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib, while sKIT may be correlated with clinical response. Analysis of these and other biomarkers in larger studies of sunitinib in breast cancer may be warranted. [Table: see text]

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