CTCs as prognostic and predictive factors for mbc treatments

[Hopeful]

http://breast-cancer-research.com/content/pdf/bcr2907.pdf

Hopeful

[Rich66]

Hmmm....The chart seems to support things I've seen in various research.

Endocrine therapy associated with least CTCs. Looks like Fulvestrant the lowest.

Traditional chemos by itself associated with highest CTCs.

Combining Traditional with alkylating agent (Carboplatin, Gemcitabine) reduces CTCs.

Herceptin (biologic) reduces CTC association a bit..Tykerb reduces it more.

Avastin seeems to reduce CTCs a bit too.

Too bad they don't test chemo + endocrine, bilogic + endocrine, chemo + endocrine + biologic or chemo combo + endocrine + biologic

[gdpawel]

The number of cells discovered in the CTC technique has turned out to be a good prognosticator of how well treatments are working. But CTCs really aren't useful with respect to drug selection. CTCs are free-floating cancer cells that can remain in isolation from a tumor for over twenty years. What is the relationship of such long-lasting cells to the tumor cells that needed to be attacked through tested substances? What if you miscount non-tumor epithelial cells as tumor cells? Also, highly invasive cells may not be detected if you are looking for epithelial antigens because the CTC also goes through a phase called "epithelial to mesenchymal transition", where you will miss locating that tumor cell if you are targeting the antigen. The key is to look for the tumor cell and not something else that "hangs with the tumor cell."

[gdpawel]

Impact of Exploratory Biomarkers on the Treatment Effects of Avastin (bevacizumab) in Metastatic Breast Cancer

Jubb AM, Miller KD, Rugo HS, et al
Clin Cancer Res. 2011;17:372-381

Summary

Results of phase 3 trials evaluating the vascular endothelial growth factor (VEGF) receptor inhibitor bevacizumab in pretreated metastatic breast cancer have indicated that certain patient populations are less likely to benefit from the drug. However, there are no known clinically relevant biomarkers that could identify breast cancers highly likely or highly unlikely to respond to bevacizumab.

Investigators conducted a retrospective analysis of patients treated on a phase 3 randomized trial that compared single-agent capecitabine vs capecitabine plus bevacizumab in women with previously treated metastatic breast cancer. Formalin-fixed, paraffin-embedded tumor tissue was available for analysis in 223 of the 462 patients who were treated in this study. Depending on the specific biomarker in question, investigators used either in situ hybridization or immunohistochemistry to analyze the relationships between the marker's expression and the subsequent progression-free survival (PFS) when treated with or without bevacizumab.

A significant difference in outcome was found in patients treated with capecitabine plus bevacizumab in the presence of low expression of delta-like ligand (P = .01), and a borderline difference was observed in patients with low expression of the VEGF-C component (P =.05) and neurophilin-1 (P =.07). Of note, these differences were no longer "significant" after performing a statistical correction for the fact that multiple hypotheses were tested in this retrospective analysis.

Viewpoint

There has been heighted interest in the discovery of a well-validated biomarker to predict for the clinical utility of bevacizumab in cancer treatment in general and in breast cancer management in particular. Although rather extensive evidence from multiple randomized trials confirmed the "statistically significant" benefits in either PFS or overall survival resulting from the administration of this agent across multiple tumor types, the overall degree of impact associated with this extremely expensive and not nontoxic agent is quite modest. The existence of a reliable biomarker that could assist clinicians in their decision to use this agent would be a major advance in standard cancer management.

The most prominent finding in the current study is that metastatic breast cancer patients with tumors demonstrating low expression of delta-like ligand who are treated with capecitabine plus bevacizumab experience a rather pronounced degree of clinical benefit, with a median PFS improvement of 4.5 months. This is particularly worthy of further exploration in a future prospective clinical trial. Retrospective analyses of previously conducted prospective therapeutic clinical trials, as was done here, are an essential initial step, but prospective trials are still needed to identify potentially promising tissue- or serum-based biomarkers for novel (and expensive) antineoplastic agents that can provide genuine clinical utility in routine cancer management.

http://clincancerres.aacrjournals.org/content/17/2/372.long

[gdpawel]

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood.

2008 Sep;264(3):275-87.
Weisenthal LM, Patel N, Rueff-Weisenthal C.
Weisenthal Cancer Group, Huntington Beach, CA 92647, USA. mail@weisenthal.org

BACKGROUND:

Angiogenesis studies are limited by the clinical relevance of laboratory model systems. We developed a new method for measuring dead microvascular (MV) cells in clinical tissue, fluid and blood specimens, and applied this system to make several potentially novel observations relating to cancer pharmacology.

METHODS:

Dead MV cells tend to have a hyperchromatic, refractile quality, further enhanced during the process of staining with Fast Green and counterstaining with either haematoxylin-eosin or Wright-Giemsa. We used this system to quantify the relative degree of direct antitumour versus anti-MV effects of Cisplatin, erlotinib (Tarceva), imatinib (Gleevec), sorafenib (Nexavar), sunitinib (Sutent), gefitinib (Iressa) and bevacizumab (Avastin).

RESULTS:

Bevacizumab (Avastin) had striking anti-MV effects and minimal antitumour effects; Cisplatin had striking antitumour effects and minimal anti-MV effects. The 'nib' drugs had mixed antitumour and anti-MV effects. Anti-MV effects of erlotinib (Tarceva) and gefitinib (Iressa) were equal to those of sunitinib (Sutent) and sorafenib (Nexavar). There was no detectable VEGF in culture medium without cells; tumour cells secreted copious VEGF, reduced to undetectable levels by bevacizumab (Avastin), greatly reduced by cytotoxic levels of cisplatin + anguidine, and variably reduced by DMSO and/or ethanol. We observed anti-MV additivity between bevacizumab (Avastin) and other drugs on an individual patient basis. Peripheral blood specimens had numerous MV cells which were strikingly visualized for quantification with public domain image analysis software using bevacizumab (Avastin) essentially as an imaging reagent.

CONCLUSIONS:

This system could be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating MV cells in a variety of neoplastic and non-neoplastic conditions, and for drug development and individualized cancer treatment.

Biomarkers of Antiangiogenic Therapy

http://cancerfocus.org/forum/showthread.php?t=3372