[gdpawel]

Rich

There are no guarantees that physician's choice will prove true if used to choose treatment. The widespread and inappropriate use of chemotherapy is an obstacle to controlling cancer growth and metastasis in patients. Patients would certainly have a better chance of success had their cancer been "chemo-sensitive" rather than "chemo-resistant," where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most "effective" chemotherapy would be more likely to improve survival.

It would seem more prudent to invest the time in using diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize, and match the most "effective" therapeutics to your "individual" cancer cells.

Going after a surgical/biopsy specimen has a role in eliminating ineffective agents and avoid unnecessary toxicity and in directing "correct" therapy. Data has shown that patients benefit both in terms of response and survival from drugs and drug combinations found to be "active" in assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

There would be a huge advantage to the patient to receive a "positive/sensitive" drug, compared to a "negative/resistant" drug. As I stated before, the time and energy required to conduct an excisional biopsy pales in comparison to the time, energy and lost opportunities associated with months of ineffective, toxic therapy.

There is no consistent associations between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy. Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective.

New analyses of data from 2 large trials have found no association between the CYP2D6 genotype and the effectiveness of tamoxifen in preventing breast cancer recurrence, in contrast to several previous positive studies. So CYP2D6 testing not be used routinely to decide whether or not to prescribe tamoxifen. Physicians should not routinely test for CYP2D6 status before deciding whether to prescribe tamoxifen or an aromatase inhibitor.

Although the functional profiling platform usually does not give strong cell-death signals for tamoxifen exposure in most tumors, sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

A functional profiling assay is conducted on human tumor samples utilizing native microspheroids (fresh, live cells) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment. This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Tamoxifen at concentrations of 2.5 micromolar (concentration of one millionth of a mole per litre) or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

Joan

Cancer is many things, but simple is not one of them.

Greg