Indian J Cancer. 2013 Apr-Jun;50(2):115-21. doi: 10.4103/0019-509X.117031.
Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and
response to metronomic chemotherapy using cyclophosphamide and
celecoxib in patients with advanced breast cancer.
Perroud HA, Rico MJ, Alasino CM, Pezzotto SM, Rozados VR, Scharovsky OG.
Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Rosario, Argentina.
Abstract
Background: Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has
therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no
reliable biomarkers of response have been found yet that allow patient selection for treatment.
To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and
evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day.
Materials and Methods: Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble
VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15
patients included in a phase II trial of MCT with Cy+Cel. Results: Serum levels of sVEGFR-2 and
sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C
showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same
patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased
significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant
variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and
VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394,
respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values
lower than the 50 th percentile for both ratios showed longer TTP. Conclusions: We have identified
the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP
treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of
patients.
PMID: 23979202 [PubMed - in process]
^^^^
CURRENT OPINION Crosstalk between HER2 signaling and
angiogenesis in breast cancer: molecular
basis, clinical applications and challenges
Raafat S. Alameddinea, Zaher K. Otrockb, Ahmad Awadac, and
Ali Shamseddinea
Purpose of review
Angiogenesis is an essential hallmark of cancer. Targeting angiogenesis has proven its efficacy in the
modern therapeutic paradigm. HER2 positive breast cancer, in particular, is a challenging disease in
which resistance to standard therapy has been attributed to parallel and downstream signaling cascades
including angiogenesis. This review explores the molecular mechanisms underlying crosstalk between HER2
signaling and angiogenesis. It highlights the role of angiogenesis in the emerging resistance to anti-HER2
therapy. It surveys the current repertoire of clinical trials involving use of combination of anti-HER2 and
antiangiogenic therapies. Finally, it entertains the hopes and challenges posed by this novel therapeutic
approach.
Recent findings
HER2 signaling upregulates angiogenesis at different levels and by different mechanisms. A large number
of clinical trials were conducted in attempt to exploit the potential benefit of the combination. Results of
early phase trials were promising. However, in the late phase clinical trials, the AVEREL trial did not
demonstrate a consistent benefit for bevacizumab in the HER2 positive breast cancer patient population.
The BETH trial is ongoing and recruiting patients. Safety issues regarding cardiovascular toxicity of the
combination have been already raised. Negative experience of dual EGFR and VEGF targeting in colon
cancer cannot be overlooked.
Summary
Angiogenesis and HER2 signaling are closely related at the molecular level. Appraisal of efficacy of
antiangiogenic therapies requires revisit of the current literature as well as following the results of
ongoing trials.
Keywords
angiogenesis, breast cancer, human epidermal growth factor receptor 2, vascular endothelial growth factor
INTRODUCTION
Angiogenesis is implicated in a broad range of
physiological and pathological processes. Besides
wound healing, development and reproduction,
angiogenesis accounts for the capacity of solid
tumors to grow and metastasize [1,2]. Forty years
ago, the bright work of Folkman paved the way for
the exploration of a new field in cancer therapy [3].
For decades, antiangiogenic agents have been developed
and proved benefit in different malignancies.
Interaction among soluble factors, receptors, endothelial
cells and other stroma elements reside at
the core of angiogenic regulation. Among soluble
factors, the family of vascular endothelial growth
factors (VEGF) received a particular attention. The
VEGF family includes seven members with different
structures, receptors and target cells [1]. Alongside
VEGF, fibroblast growth factors (FGF), platelet
derived growth factors (PDGF), transforming growth
factors (TGF), matrix metalloproteases (MMP) and
aDepartment of Internal Medicine, Division of Hematology and Oncology,
American University of Beirut Medical Center, Beirut, Lebanon, bTaussig
Cancer Institute, Cleveland Clinic, Ohio, USA and cJules Bordet Institute,
Free University of Brussels, Belgium
Corresponding to Ali Shamseddine, American Univeristy of Beirut
Medical Center, Beirut, Lebanon. Tel: +961 137 4374; fax: +961 137
0814; e-mail:
as04@aub.edu.lb
Curr Opin Oncol 2013, 25:000–000
DOI:10.1097/CCO.0b013e32835ff362
Role of metronomic scheduled chemotherapy
The efficacy of cytotoxic agents in solid tumors
has been curbed by the capacity of tumor cells to
grow between chemotherapy cycles [67]. Due to
their heterogeneous genomic makeup and genetic
instability, tumor cells do not respond optimally
to antiproliferative agents [68,69]. Metronomic
scheduling, consisting of more frequent dosing in
smaller doses, might offer the advantage of targeting
tumor-associated endothelial cells, demotes angiogenesis
and promotes apoptosis. For more than
a decade, a vast body of preclinical evidence
has culminated in support of metronomic dosing
of chemotherapy [70–73]. Treatment of murine
tumors resistant to trastuzumab with metronomic
cyclophosphamide was effective in delaying
tumor growth and treating acquired trastuzumab
resistance [74]. In 22 patients with advanced
or metastatic breast cancer pretreated with trastuzumab,
the combination of trastuzumab and
metronomic cyclophosphamide and methotrexate
was well tolerated and effective. Median PFS was
6 months. No serious adverse events were observed
[75]. Clinically, one phase II trial has been withdrawn
because of slow accrual, another one is
actively recruiting patients (Table 3).