What may limit the effectiveness of Avastin is that 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. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

If you find one or more implicated proteins in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You're not going to accomplish this using genetic tests.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.

PM -- I think you've got it just right -- as squeamish as we all may (rightly) feel about evaluating the marginal utility of such an expensive drug -- to the relatively-short prolongation of the lives of admittedly terminal cancer patients -- it is time to have those conversations.

Our health-care system in America can simply no longer afford NOT to -- many, and perhaps the majority, of our urban hospitals (serving the neediest Americans) are drowning in seas of red ink -- nearly 50 million Americans have no health-care coverage, and 30 million American children don't.

As hard as these discussions will be -- we simply are out of other options -- we must address the idea of "rationing" health care (cancer drugs here plainly included), if we are going to hand a solvent system on hand, to pass-on to our children.

Avastin -- despite all the good it does -- probably ought NOT be prescribed in some of these "lower marginal utility" cases -- it is simply a waste of one precious commodity -- insurance coverage funds -- at the expense of another -- slightly prolonged human lives.

Tough topic -- no easy answers -- but PAST time to start a fact-based inquiry.

Thanks for this!

Namaste

"New rules" -- Rule No. One: Never, ever post from your sundeck, wirelessly, while sipping ice tea, solar ice tea, with fresh lemon, on a long-Holiday weekend -- I mistook this post as being authored by PM -- my mistake, Gooz!

Please accept my apologies.

And, yes, that would mean that my excuse -- as lame as it may sound -- is that "the Sun was in my eyes"!

No -- seriously -- dude. It. was.

Life is not fair. Some people are rich, healthy, smart. Other people are stupid and lazy. Should they have the same rights? No.

Even socialists do not believe in "absolute" equality. Socialist principals are simple: everyone MUST contribute to society well-being and everybody MUST be rewarded/paid based on their contributions. No EQUALITY!

Finally:

- People with and without medical insurance should not have the same rights and cannot have the same benefits.

- People paying for medical insurance by themselves or through their employers are also unwillingly paying for people without insurance. This is the reality. So, the society MUST thanks them a lot!

- Some people think that some companies get excessive profits. This is the free-market system. Without these successful companies, the entire society is doomed. Do Apple, Google, Microsoft, Intel, etc., are making excessive profits? No. They have the right to their profits. The same is true for pharmaceutical and biotech companies. They have the right to charge for their products as much as they think is right. It is up to their customers to buy or not buy their products and services.

- This is why wealthy Canadians are coming to the USA to get medical services they cannot get in Canada. It is that simple.

It amazes me when it comes to the economic issues in cancer care, not only that some private insurance carriers don't like to pay for oncologic in vitro chemoresponse assays but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments. Evidence in support of these tests is more than sufficient to justify them.

Profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the tests, which is to identify efficacious therapies irrespective of drug mark-up rates.

Everyone is scared to death - and rightly so - at what is going to happen to the healthcare economic system with increasingly expensive new drugs that benefit only a small percentage of patients who receive them. Hence the headlong rush to develop companion diagnostic tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

The pressure, in fact, is so great that these molecular companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

I think that in both of these areas - private insurance carriers and the FDA - there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments - everybody wants that - but also, in the "here and now," using currently-available cell-based assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.