Review of Anti-angiogenic Therapy in Breast Cancer
Tumors need sustained blood and nutrition supply in their growth and achieved by vascular endothelial growth factor(VEGF) families, so the anti-angiogenic therapy(AAGT), which aims at stopping the VEGF route to inhibit the overexpression of VEGF ligand family, have huge potential in curing tumors. But in breast cancer treatment, this kind of treatment did not show great efficiency and efficacy, that means AAGT is not as good as scientists believed initially. But there still be great potential to improve this therapy by combining to other treatment like chemotherapy or gene-target therapy to inhibit its toxicity and tumor cell resistance.
This opinion paper helps to understand the mechanism of anti-angiogenic therapy(AAGT), its promises, and pitfalls surrounding usage of breast cancer, discuss the present perspective, and explore future direction of both applications of AAGT and treatment of breast cancer.
Tumor growth needs a sustained purveyance of nutrients including oxygen to maintain the expansive proliferation of tumor cells. Therefore, the tumor could induce the germination of new vessels from the surrounding vascular [fig1]with several types of cytokines and growth factors especially VEGF-A. Plus, VEGF usually over-express in most solid cancers .
Plus, several preclinical research shows that inhibition VEGF works in animal models for suppressing tumor growth[2,3]. Therefore, inhibition of sprouting angiogenesis by blocking the VEGF signaling pathway exists in suppressing tumor in human beings. (Fig 2) .
Breast cancer is a malignant tumor arising from the cells of the breast, which is the most common cancer among American women. Breast cancer has more than five different types, including Ductal carcinoma in situ, Invasive ductal carcinoma, Invasive lobular carcinoma and some other much less in common ones. In breast cancer, the level of angiogenesis is relevant to survival, that is, high levels of VEGF and other angiogenic factors indicate high-risk disease correlating with a poor prognosis.
I gained all the information from current years’ journal paper in both AAGT and breast cancer treatment. Went through those data, analyzed all information provided in recent journals, discussed both advantage and disadvantage of this therapy and came out with the personal presentation of the future usage of AAGT and breast cancer treatment as well.
According to those literatures, I could get the conclusion that 1) the basic mechanism of tumor vessels is thinner the wall of vessel cell owing to lacking pricytes, this diminish changed the permeability within both same and different tumors, that abnormal vascularity could increase the tumor resistant to chemotherapeutic agents; 2) VEGF inhibitors cannot provide long-lasting clinical response in all patients , where the VEGF-target therapy resistance could be explained with two mechanisms: tumor will not respond with an outset of treatment, that is, they have intrinsic resistance, or they do respond the treatment at very beginning, but receiving the ability to withstand treatment during growth, which means they developed the acquired resistance. preclinical tests also show that VEGF- target therapy has less effective stopping the establishment of tumor vessels.3)in breast cancer part, Phase 3 clinical trials of VEGF routes inhibitors shows partially sensitive answered in AAGT this conclusion could be verified by randomized trials in breast cancer, including four agents: metastatic 1st line, metastatic 2nd line and beyond, adjuvant and neo-adjuvant. studies show that there is no significant improvement in overall survival(OS) and partially improved the progression-free survival(PFS), Bear HD et al. and von Minckwitz G et al. found that Doxorubicin/docetaxel/ cyclophosphamide ±bevacizumab and Epirubicin/docetaxel/Cyclophosphamide ± bevacizumab ) treatment in HER-2 negative population can improve the complete response rate in pathology at the primary endpoint.
From what have been showed before, we can see that the AAGT does not works as effectively as we thought initially. But we can also find out that single agent given treatments are all failed, but the joint of the addition of bevacizumab agent to chemotherapy in HER2-negative transferred breast cancer(AVADO, RIBBON-1, and RIBBON-2) showed no improvement in OS, but PFS does, than chemotherapy. It results from the limitations of AAGT showed in fig 3. And these failures and limitation give us a new direction of anti-angiogenic remedy in breast cancer rather than laying into the non-effective situation at present.
On the other hand, in the last ten years, HER2-directed therapy has already been a mature remedy of curing HER-2-positive breast cancer which is the most common type. And new delivery of chemotherapeutic agent choosing such as monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates are also an aspect of improving the efficacy and effectiveness of drugs no matter in which type of treatment including AAGT.
By addition to some herbal medicine or other kinds of drugs, AAGT may also show the huge potential in curing breast cancer in the future, for reducing the toxicity and resistance of present drugs. In my opinion, even the AAGT shows almost nothing in present preclinical trials, and some studies found herbal medicine could help reduce the toxicity during the treatment, Chinese traditional treatment including traditional Chinese medicine, acupuncture etc could be used as an Adjuvant, or the combination of chemotherapy, that is, all the limitation could help to search the really useful and effective treatment not only in breast cancer but also changing AAGT into an available, operative and profitable remedy.