[gdpawel]

Treating breast cancer with a combination of chemotherapy and Avastin is not clinically meaningful, according a document published by the FDA. The FDA said the level of improvement in women treated with chemotherapy and Avastin was not significantly better than in women who received chemotherapy alone. In addition, women who took Avastin experienced more serious side effects, such as bleeding.

Avastin received "accelerated approval" in 2008 for the treatment of breast cancer in combination with Taxol. Accelerated approval is granted to drugs based on initial positive studies and drugmakers must submit additional data for full approval. The drug's manufacturer submitted two follow-up studies for full approval of Avastin. The FDA said the follow-up research failed to confirm the magnitude of the benefits observed in the initial study used for accelerated approval.

Investigators of a randomized, phase III trial of Avastin with Taxol in patients with metastatic breast cancer discussed the lack of an overall survival benefit in light of a significant and clinically meaningful improvement in progression free survival. The authors noted the possibility of accelerated tumor regrowth (tumor rebound) compared with chemotherapy alone. It was speculated whether increased in VEGF levels upon discontinuation of Avatin might have resulted in more aggressive disease (Miller K, Wang M, Gralow J, et al. Taxol plus bevacizumab versus Taxol alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676).

Serum from Avastin treated patients actually support endothelial cell growth in cell culture better than serum from control patients, without Avastin treatment. When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.

However, there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen. Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry.

Actual results in patients count and theory doesn't matter as much as the evidence that it does what we want it to do. It would be more advantegeous to sort out what's the best profile in terms of which patients benefit from this drug.

Some scientists are not sure whether Avastin or any other anti-angiogenic agents are working primarily by pruning new blood vessels, increasing the delivery of another anti-cancer therapy, or potentially another mechanism.

Clinical oncologists involved with functional tumor cell profiling analysis, can actually examine this. They have a method for testing anti-angiogenic/anti-microvascular agents, such as Avastin and testing for synergy between different anti-microvascular agents on an individual patient, individual tumor basis. Avastin appears to better deliver the effects of other classes of drugs.

Avastin facilitates vascular access of cytotoxics to tumors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.

As for Avastin's side effects. Evidence in the Journal of Clinical Oncology shows that many of the highly expensive targeted drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. Avastin is one example. The dose being used is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.

In any case the issue with all these targeted drugs is we need better biomarkers to pick which patients are more likely to benefit from them to get the most for our buck. The new targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased. Given the technical and conceptual advantages of cell-based functional profiling assays, together with their performance and modest efficacy of therapy prediction based on analysis of genome expression, there is reason for renewed interest in them for optimized use of medical treatment of malignant disease.

Cell culture assays are a "functional" biomarker. A functional biomarker providing information about the biomarker uptake rate in tumor cells or on tumor cell surfaces through fluorescence intensity changes. In vitro apoptosis for choosing drugs is not different than a marker like estrogen receptor or CD20 or a gene expression pattern. They are all markers. One is a structural marker, the other is a functional marker. There is no conceptual difference regarding the sort of study and data which is required to "validate" any of them.

Over the past few years, gene expression profiling has been suggested as the best way of determing ex vivo drug sensitivity. However due to most patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of "functional profiling" cell culture assays, which can integrate all the gene expression into one convenient test result.

Sources:
J Clin Oncol 18:2245-2249
Current Treatment Options in Oncology 2006, 7:103-110 Current Science Inc. ISSN 1527-2729
Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms ASCO 2008 Breast Cancer Symposium Abstract No: 166