Personalized Cancer Medicine

[gpawelski]

The genetic analysis of Oncotype DX predicts which women will have a greater chance of breast cancer recurrence. The test looks at 21 genes that influence the behavior of breast cancer cells. Until this test, it had been difficult to pinpoint which women would benefit most from chemotherapy, and those which wouldn’t.

MammaPrint is another genetic test that could help patients with early-stage breast cancer predict their chance of relapse, information that could save many patients from unnecessary chemotherapy. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine.

These new gene expression profiling tests enable the oncologist and breast cancer surgeon to more accurately determine who should be treated and who should not be treated with chemotherapy, but they cannot predict chemo response.

These laboratory tests are a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them (and even less for "targeted" drugs), there should be due consideration to looking at the advantage of molecular and cellular assay tests to the resistance that has been found to chemotherapy drugs.

These tests can enhance the ability to distinguish between "low" risk and "high" risk patients. Patients in the high-risk group, who would benefit from chemotherapy can then be pre-tested with a "functional" bio-marker to see what treatments have the best opportunity of being successful, and offers a better chance of tumor response resulting in progression-free survival, while those in the lower-risk groups can be spared the unnecessary toxicity, particularly associated with ineffective treatment.

These new genetic tests have enormous implications for the short-term future of cancer research in general, and is one of the truly great cancer breakthroughs of our time. These DNA microarray will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through a cell-based assay using an EGFRx™ Anti-Tyrosine Kinase Profile.

New anti-cancer drugs selectively "targets" cells within the body that have a specific molecular defect that is believed to cause dangerous cell behaviors such as uncontrolled proliferative growth and high metastatic potential, behaviors that are associated with aggressive cancer. The defect occurs within the interior of the cell in a region that is called the tyrosine kinase domain and it involves a complicated chemical process called EGFR signaling.

The drugs are called anti-EGFR drugs or tyrosine kinase inhibitors. When the drugs work, they can be highly beneficial, causing tumor shrinkage or promoting stable disease and extending survival. However, targeted therapy drugs like tyrosine kinase inhibitors only work for a small percentage of the patients who receive them. Further, the drugs are expensive and have been associated with toxic side effects. No molecular (gene-based) test has been proven to tell reliably who will benefit from anti-EGFR treatment.

The EGFRx™ Anti-Tyrosine Kinase Profile assay can prospectively report to a physician specifically which chemotherapy agent would benefit a high risk cancer patient by testing that patient's "live" cancer cells. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. Knowing the drug sensitivity profile of a specific cancer patient allows the treating oncologists to prescribe chemotherapy that will be the most effective against the tumor cells of that patient.

Every breast cancer patient should have her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

Presentations: http://weisenthal.org/Weisenthal_ESCIa.pdf

http://weisenthalcancer.com/Shared%20Pages/EGFRTables.htm

[gpawelski]

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. The very idea of "personalized" medicine scares the hell out of the pharmaceuticals. It represents a radical departure in the pharma business model. Thanks to advances in biology and genetics, upcoming and existing technologies for personalizing cancer diagnosis and drug treatments are very real.

The key hurdle for these technologies is overcoming the pharmaceutical industry's prevailing blockbuster economic model of the last twenty years. As one peruses the internet, they can see drug companies and so-called industry experts rush to suggest that personalized medicine and their blockbuster model are incompatible. Tests to identify individuals most likely to benefit from chemotherapy will certainly cut into their old and antiquated model.

The spate of recent blockbuster "miracle" drugs has failed to show statistical survival benefit anywhere close to a majority of patients. These drugs actually did work miracles, in "some" patients. How do the drug companies respond when tests show their drug to be highly effective, but only in 11% of the potential patient population, a fraction of affected patients? Charging significantly more for those therapies will only work to a point. Personalized medicine will take the wind out of the sails of big pharma.

Pharmaceutical companies and their industry shills will try to buck the trend as long as they can, but many realize that personalized treatments are inevitable and are making their way into a new paradigm of cancer treatment. The pharmaceutical industry will need to transform itself as "business as usual," it will no longer be good enough. The old pharma "blockbuster" business model is incompatible with personalized medicine. Diagnostics will almost certainly trump pharmaceutics.

[gpawelski]

In chemotherapy selection, Gene and Protein testing examine a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response.

Whole Cell Functional Profiling tests not only for the presence of genes and proteins but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

Genes create the blueprints for the production of proteins within the cell. A protein is a molecule that makes a cell behave in a certain way. It does so by interacting with other proteins in a complex series of steps.

The goal of Gene testing is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. However, just because a gene is present it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even Protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs.

Gene and Protein testing involve the use of dead, formaldehyde preserved cells that are never exposed to chemotherapy drugs. Gene and Protein tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene and Protein tests cannot discriminate among the activities of different drugs within the same class. Instead, Gene and Protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene and Protein tests tell us anything about drug combinations.

"Whole Cell" Functional Tumor Cell Profiling tests living cancer cells. Functional Tumor Cell Profiling assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. Functional Tumor Cell Profiling can discriminate differing anti-tumor effects of different drugs within the same class. Functional Profiling can also identify synergies in drug combinations.

Gene and Protein tests are better suited for ruling out "inactive" drugs than for identifying "active" drugs. When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect.

Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

Although Gene and Protein testing currently are limited in their reliability as clinical tools, the tests can be important in research settings such as in helping to identify rational targets for development of new anti-cancer drugs.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.