insufficient her2 testing--not enough patients given possibility of benefiting from

[Lani]

herceptin? Some receiving herceptin exposed only to possible risks without possible benefit?

Information about the use and accuracy of breast cancer tests is lacking, study finds

A new study finds that there is little information available about the use of new testing technologies and targeted therapies in breast cancer, specifically the anti-cancer drug trastuzumab (Herceptin). Published in the November 15, 2009 issue of Cancer, a peer-reviewed journal of the American Cancer Society, the review suggests that many breast cancer patients who may benefit from trastuzumab are not receiving it, and that some women receiving the drug have never been tested for the receptor it targets.

Standard care now dictates that women with early-stage breast cancer should be tested to see if they have tumors that express the HER2 protein. Those who test positive are candidates for treatment with trastuzumab, which is only effective in HER2-positive cancers.

Researchers at the UCSF Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) and led by Kathryn A. Phillips, PhD, of the University of California-San Francisco, reviewed the medical literature to determine how HER2 testing is being used in routine clinical practice. The studies they found reported that up to two-thirds of patients eligible for HER2 testing had no documentation of a test in their health insurance records. About one in five women who received trastuzumab had no documentation of a positive HER2 test in their health insurance records. The studies also revealed that about one in five HER2 test results may be incorrect.

The authors also found that studies looking at the economic issues associated with prescribing trastuzumab often did not explicitly consider the role of HER2 testing, which can have a substantial impact on the cost-effectiveness of the therapy.

Given the increasing use of targeted therapies like trastuzumab, proper testing will become more important to ensure that medications are directed only to the patients who will benefit from them.

"Our review of the literature suggests that there are important knowledge gaps regarding the real-world use of HER2 testing and trastuzumab," said Dr. Elena Elkin, a researcher at Memorial Sloan-Kettering Cancer Center in New York and one of the study's authors. "Filling these gaps may help optimize limited health care resources and improve care for women with breast cancer," she added.

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Article: "Clinical practice patterns and cost-effectiveness of HER2 testing strategies in breast cancer patients." Kathryn A. Phillips, Deborah A. Marshall, Jennifer S. Haas, Elena B. Elkin, Su-Ying Liang, Michael J. Hassett, Ilia Ferrusi, Jane E. Brock, and Stephanie L Van Bebber. Cancer; Published Online: September 14, 2009 (DOI: 10.1002/cncr.24574); Print Issue Date: November 15, 2009.

[gdpawel]

I've often wondered if the underlying science of Herceptin is sound. Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, a functional assay actually assesses the direct or indirect effect of the drug upon the whole cell, whether it is a tumor cell or an endothelial cell. Her2 just happens to be one molecule which has been implicated in the process but there may be more.

If it were the only protein involved, then one would expect that Her2 expression would correlate with Herceptin activity 100% of the time but it actually does so only about 20% of the time. The functional assay doesn't just focus on Her2 or any one protein or mechanism. Whether it's Her2 alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.

Many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond. And optimal and reproducible Her2 testing continues to evade the diagnositcs of the disease. Numerous other genes, tumor, and patient factors contribute to the risk of the cancer coming back and the effectiveness of chemotherapy for breast cancer.

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

There are many pathways/mechanisms 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 individual trees.

One of the findings I found most amazing in this study was that 20% of people on herceptin had never been tested for HER2. How can that be? It is so expensive, and such a time consuming treatment, how can it be approved for people who have not been tested? If that is true, no wonder medical costs in this country are through the roof. Who is minding the store?

[Lani]

Perhaps they had an OncoDX test which would measure her2 by its RNA. Thus, officially they had neither an IHC nor a FISH test, but were deemed her2+ by the oncodx.Just speculation...

would be interesting to know, but you are the expert, so assume you may have some insight into why this would be reported.
I can't imagine they would give anyone herceptin with all its cost without some kind of definitive test, can you?
The health insurance providers in this country are so careful to not spend money (i.e., make profit), I guess there has to be some kind of explanation as to why herceptin would be given in these circumstances.
Thanks Lani.
I am coming up on my 3 year diagnosis/surgery date within the next 30 days.
I have to say I have started to put it behind me, in the sense that I did what the docs said, all I could do, and all seems to be going okay. I don't think I will get too excited until the herceptin 3 year date until next spring, maybe then I will feel like celebrating.
I was stage 2, 3 cm in left (which they said was DCIS at diagnosis and biopsy), negative nodes, but they found a 1 cm satellite tumor at mastectomy that they didn't see upon diagnosis.

[CLTann]

RLS,

An interesting term, satellite tumor! It really matters not whether or how the second came from the larger tumor they originally found. The important factor is that the tumor cells did not spread to anywhere outside the removed breast. You are perfectly correct that the verdict comes on elapsed time. The longer you waited for the absence of any outward symptoms, the more assurance you are getting "cured" and NED. Good luck to you. Yes, time will tell. Too bad that we cannot detect mets on single cancer cells. Even if we could, either the presence or absence of one cancer cell does not mean bad things are happening.

[gdpawel]

To get the new genetic/molecular tests, the validation standard that all the private health insurance companies is accepting is accuracy. The essential proof is that all they have to do for these tests is that the test has a useful degree of accuracy. The traditional criteria ever used to evaluate laboratory tests has always been the predictive accuracy of the test.

However, the headlong rush to develop companion diagnostics to identify molecular predisposing mechanisms still does not guarantee that a cancer drug will be effective for individual cancer patients. Nor can they discriminate the potential for clinical activity among different cancer agents of the same class.

The drug discovery model has been limited to one gene/protein, one target, one drug. The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyse the systems' response to drug treatments, not just one target or pathway.

Uncovering the genetic differences that determine how a person responds to a drug, and developing tests, or biomarkers, for those differences, is proving more challenging than ever. As a result, patients with cancer are still being prescribed medicines on a trial-and-error basis.

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" diagnostics (is the cell being killed regardless of the mechanism) as opposed to "target" diagnostics (does the cell express a particular target that the drug is supposed to be attacking).

While a "target" diagnostic test tells you whether or not to give "one" drug, a "functional" diagnostic test can find other compounds and combinations and can recommend them from the one test.

The core of functional diagnostics is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. Both genomics and proteomics can identify potential new thereapeutic targets, but these targets require the determination of cellular endpoints.

The cell "function" methodology measures the net effect of all processes within the cancer, acting with and against each other in real-time, and it tests "living" cells "actually exposed" to drugs and drug combinations of interest.

Many hope that molecular tests may hold the key to success, particularly as more specific drugs are designed to hit the molecular changes that are responsible for the uncontrolled growth of cancer cells. However, most drugs cannot be looked at in this way and tests that are now in use have limited predictive accuracy. There is no single gene whose expression accurately predicts therapy outcome.