The following is a letter from the husband of a breast cancer patient, along with my answers.

Husband's Questions/My Answers:

Question 1,Part 1. Cancer Medicine textbook (1997) 4th edition, concludes that, at best, chemotherapy sensitivity and resistance assays (CSRAs) will tell you what drugs will not work, vs. predicting what will work.

Answer: There are two main classes of CSRA testing methods. The first is based on cell proliferation. The 1997 textbook dealt mainly with data from this (older) methodology. The 2nd type is based on cell death.

If you will read my "FAQ"  , it takes you through a detailed explanation of the type of information provided by this (newer/cell death) methodology. The take home message is that, over a broad range of different types of human tumors, drugs which are active in the cell death assays are 7 to 9 times more likely to work than are drugs which are inactive.

Question 1, Part 2: If the survival curve for metastatic breast cancer [referring to a survival curve shown on my website]  shows 3.75 years mean average vs. 2 years for standard treatment [n.b. this latter number is the result obtained with non-assay directed therapy, see below], how much of success is due to avoiding bad chemotherapy?  If the chart is valid, why can't it be submitted to a peer review publication?

Answer: I can't say how much "success" is attributable to anything, as I have no way of finding out what the patients actually ended up receiving. The only thing I can do is to point out the following:  There has been absolutely no progress in the chemotherapy of metastatic breast cancer since 1970. (n.b. your wife's pulmonary disease is metastatic breast cancer).

Here is Dr. Shulman's (from Harvard's Dana Farber Cancer Institute) quote:

"[over the past 30 years]... We relentlessly combined chemotherapy agents in various regimens, with ever-increasing dose seen in this compilation of data, the survival for patients participating in these studies is exactly the same, less than 2 years. These four studies are a snapshot of hundreds of studies done throughout the world, spanning 30 years, utilizing innumerable combinations of standard dose chemotherapy without a hint of significantly improved survival."

Now, the only thing I can tell you is that, when patients with metastatic breast cancer had their tumors submitted to our laboratory and when the tests "worked" (i.e. when we were able to report out a result) these patients lived a median of almost twice as long as in the case of the "best" treatments ever reported in the literature (which have shown no hint of producing better results than the "standard" treatments of 30 years ago). Coupled with all other information available, the preponderance of data certainly indicate that breast cancer patients are much more likely to be helped than harmed by obtaining information regarding the cell culture drug resistance status of their tumors.

With regard to publishing our data, the problems are (1) lack of specific data concerning what drugs the patients actually received and (2) lack of a control group (although the small group of patients whose assays didn't work does provide at least some form of comparison).

If you review the discussion on my website concerning my ovarian cancer paper (which I think is a very excellent piece of research and data analysis, given the limitations that I face because of the nature of my private, laboratory-based medical practice) and also regarding the recent manuscript which was submitted to and rejected by the Journal of Clinical Oncology, you'll see that getting cancer journal editors to think outside the box has been more than challenging.

Question 2. Are you familiar with Dr. Sampson, retired cancer specialist at Stanford University School of Medicine and article written about EVA method and lack of validity of this test? (at Quackwatch web site)

Answer: I am familiar with this website and with Dr. Sampson's writings. I wrote a detailed, point by point rejoinder several years ago and the website editor refused to publish this rejoinder. Dr. Sampson knows nothing at all about the technologies and does not understand the data. This is not entirely his fault.

One of the confusing features of this area is that most of the laboratories which are active in this field want everyone to think that they have something new and unique and better than anyone else. So they all give their technologies different names. When, in fact, they are all more or less doing the same thing. They obtain a fresh tumor. Chop it up. Isolate tumor cells. Put them into cell culture (in the presence and absence of anti-cancer drugs) for between 2 and 6 days. Then they apply some test at the end to measure whether or not the cell are living or dead. Some laboratories are working with markers for impending cell death which may be measured even earlier than 2 days. But, in the real world of the drugs we have available today, all of these various endpoints are measuring the same thing -- whether the cells are already dead, whether they are dying, or whether they are destined to die. The proof of the pudding that these endpoints are really all the same is the fact that they all give the same results, in most situations (and within the error limits of the tests).

Adding to the confusion is that different laboratories, all working with virtually the exact same assay endpoint, tend to want to give the assay, as done by them, its own unique name. Thus Dr. Nagourney's "EVA" assay is virtually identical to what Dr. Bosanquet and I used to refer to as the "DISC" assay (I still do; Dr. Bosanquet has changed the endpoint ever so slightly and has also changed the name). So poor Dr. Sampson goes hunting through the literature and can find only a couple or so papers on the "EVA" assay and concludes that it is "unproven."

What Dr. Sampson should have done is to review the entire literature dealing with these types of assays (cell death assays), as I have done in a paper which was also rejected when I submitted it for publication, but which appears on my website, along with copies of all correspondence with the journal which rejected it and with the peer review from the journal which rejected it.

Go to my website and scroll down to:

"Invited review prepared for publication in the journal ONCOLOGY 7/19/2002" (or just click here to view the paper without all of the background correspondence).

Let me summarize, in a nutshell, the arguments against doing this testing and the arguments in favor of doing this testing.

Argument against doing the testing:

It has never been shown that patients do better when treated on the basis of assay-directed therapy in prospective, randomized trials, in which patients are randomized to treatment on the basis of test information versus treatment without the benefit of test information.

Larry's comment:   It is hereby stipulated that the above is a true statement.

Arguments in favor of doing the testing:

1. The tests have been extensively validated for accuracy, without any controversy whatsoever. In more than 40 peer-reviewed publications, in a wide range of human tumors, ranging from acute and chronic leukemia to ovarian and breast cancer (data shown in the above-cited review),  patients treated with drugs which were active in the assays were more likely to respond to treatment than the group as a whole and dramatically more likely to respond to treatment than patients treated with drugs which were not active in the assays, with there being a 7 to 9 fold advantage to treatment with assay "positive" drugs, compared to assay "negative" drugs. In a number of studies, patients treated with assay "positive" drugs enjoyed significant survival advantages, as well.

2. In virtually all forms of cancer, there are a few to many equally acceptable treatment choices, if chosen literally on the basis of a coin flip. In most cases, it is helpful to know that one or more of these choices is 7 to 9 times more likely to work than other of these choices.

3. The criteria always used to evaluate medical tests is the accuracy of the tests and not the "efficacy" of the tests. I am unaware of a single test (laboratory or radiographic or anything else) used in cancer which has been proven to be "efficacious," in prospective randomized trials, where patients are managed with and without the benefit of the information provided by the tests, and treatment outcomes compared. The only information which has ever been obtain is how accurate are the tests and, in general, the accuracy of the cell culture drug resistance tests compares favorably with that of other similar tests used in cancer medicine. So critics such as Dr. Sampson are demanding a standard of proof which is truly unprecedented, and which has not been met by all of the other tests used in cancer medicine.

4. Most of the cancer treatments used have not met the standard of proof demanded of cell culture drug resistance testing, which is, again, a test and not a treatment. The degree to which "standard" cancer chemotherapy has been "proven" to be more efficacious than other forms of treatment has been overstated, overassumed, and over-sold. I provide some examples of this in my rejoinder letter to the Journal of Clinical Oncology.

5. Both I and Dr. Nagourney have made major efforts to get clinical trials done to prove the utility of cell culture drug resistance testing. I recently spent 12 years getting the best data that anyone's ever been able to get with CSRAs in ovarian cancer (hugely significant correlations with assay results and long term patient survival; median survivals in platinum-resistant disease more than twice as good as reported anywhere else in the literature; anecdotes such as 4 year CRs to gentle, outpatient, third line therapy in a patient with primary resistant disease, who failed tandem marrow transplants at a cost of $250,000 at UCLA; 7 1/2 year ongoing remission and survival in a patient with adenocarcinoma of the pancreas, metastatic to spleen, kidneys, and liver; many, many more). As in the case of the other matters discussed in my present letter to you, documentation for all of this is provide on my website.

Anyway, the Gynecologic Oncology Group turned Robert Nagourney and me down cold when we came to them with a trial and a protocol in 1991. I then spent 12 years getting the world's greatest data to support another clinical trial. And no one wants to hear about it or consider it. I can't even get an abstract accepted for publication at an SGO meeting Because I can't offer anything beyond "free" assays. While Big Pharma can offer millions to show that there is a 1% advantage to platinum/Taxotere over platinum/Taxol. Because Taxotere is a patented drug, and what I do is public domain and non-proprietary. So they can offer millions, while I can only offer "free" assays.

My GOG experience was on top of an ECOG experience, in which we accrued 6 patients in 8 months and the study was closed, because none of the 50+ ECOG hospitals wanted to go through the trouble of biopsying tumors and sending tissue, when they could just do the mindless Pepsi vs Coke trials and get more money and more publications out of it.

And this was on top of a VA study in multiple myeloma, which took me three years of work to get funded and organized and which closed in about 6 months because of poor accrual and because of protocol violations in a STANDARD (non-assay directed) treatment group.

And the ASCO-affiliated breast cancer trialists spent decades trying to show truly minuscule advantages of CAF over CMF and AC/Taxol over AC, and where the median survival in metastatic disease hasn't improved in 30 years.

In 1982 Dana Farber's Emil Frei won the Karnofsky Award. In his acceptance speech at ASCO, he decried the demise of the "discoverer" (risk taker, not so well organized, high failure rate, but big payoff when successful) because of the ascendancy of the "investigator" culture (no risk taking, well organized, exhaustive analysis of trivial hypotheses, minuscule payoff when successful). Dr. Frei didn't say so, but it's not certain that the ability to do innovative science and the ability to organize and fund clinical trials are skills inherited on the same chromosome.

Recently, the Executive Editor of Fortune Magazine came to the same conclusion about the gross inadequacy of the cancer clinical trials system in the USA in a well-researched expose which could have only come from outside the academic clinical trials system, as it was an indictment of the entire NCI/American University cancer clinical trials culture (which is, not incidentally, dominated by ASCO).

To review:

1. Argument against using the tests: No prospective randomized trials showing that using the assays makes a difference with respect to treatment outcome.

2. Argument in favor of using the tests: The tests have been proven to be accurate and preponderance of best available evidence indicates that patients are likely to be helped by obtaining the information provided by the tests, and there is little likelihood that patients would ever be harmed, if the tests are used to help decide between treatments which would be equally likely to work, absent any information from the tests.

Getting back to your questions:

Question 3. Is your lab accredited by the US government? Which accreditation does it meet?

Answer: Yes, we are fully licensed and accredited. PDF file of licensure documents is attached. At the US government level, we are licensed by the applicable regulatory agency, which is the Centers for Medicare and Medicaid Services, Clinical Laboratory Improvement Amendments ("CLIA"). Our CLIA ID number is 05D0662326, Expiration Date 08/28/2005. We are also licensed by the State of California Department of Health Services (Clinical Laboratory License CLF 10209, Expiration Date December 30, 2004; License renewed on an annual basis).

Question 4. Recently, there is a new test, CellSearch, that identifies cancer cells in blood and can be used to give more rapid determination if a particular chemo is working or not. Do you have any results using this test to show your results correlate with lower cell counts in the patient's blood or use of other markers to show that your test is better than the standard protocol being used by oncologists.

Answer: No.

Question 5. Dr. Grace at St. Vincent's hospital uses this test but are there other oncologists in New York city using this method and if so, who are they. I have not been able to reach Dr. Grace by phone.

Answer: Dr. Grace's office number is 212-675-6826. He would be the one tell you about his own experience with utilizing our test information in the management of his cancer patients, although I'm sure he's much too busy to answer as many questions as you are asking me here (I am hoping that this detailed response can spare him this burden). I can't give you the name of other New York oncologists who may utilize these tests in the management of their patients.

Test results produce problems for oncologists. Oncologist make an important part of their revenue not by being doctors, but by being retail pharmacists, in which the profits come from the "spread" between wholesale acquisition costs of the anti-cancer drugs and the reimbursement they receive for these drugs. In the absence of our test results, oncologists are free to choose from between a number of different treatments, with a vast difference in profit margins. Use of our tests severely constrains this choice and may even lead to the identification of "best" treatments which lose the oncologists money. Dr. Grace does not have this inherent conflict of interest, and he is only interested in treating his patients with the therapy which is most likely to help them, and not in the treatment with a favorable profit margin.

Question 6. As my wife has metastastic ductal carcinoma and is ER negative and HER2/neu positive, she will be taking Herceptin. What is the interaction of herceptin with the chemos you will test? How would you run or validate hormone therapy with chemo?

Answer: The tests have limitations. They are not a scale model of chemotherapy in the patient. We are unable to run complex "models" of the combined effects of chemotherapy, hormonal therapy, and Herceptin. I will say that there is little or no convincing evidence of anything other than an additive effect between hormonal therapy, chemotherapy, and Herceptin. In other words, I would not want my own wife, mother, or sister to receive drugs which were not active in the assays, simply on the undocumented hope that they might be more likely to be active inside the patient's body, with the concurrent treatment with hormones, anti-hormones, and/or Herceptin. But this is simply my own personal opinion, as neither I nor anyone else has persuasive data on which to argue this point.

By the way, the fact that your wife is hormone receptor positive indicates that there is an above-average probability that she will benefit from hormonal therapy, and such benefit can be long-lasting in some patients. And this remains true despite lack of proof from prospective randomized trials that performing estrogen and progesterone receptor assays actually makes a difference in treatment outcome.  These tests have only been validated for accuracy, and not for efficacy, precisely as in the case of chemotherapy sensitivity and resistance assays.

Question 7. The tumor that would be removed and sent to you would be from the lung as it has metastases from the breast but it is only 9 mm large. As we need to characterize the tumor tissue to make sure it is the same ductal tumor, there may not be enough tissue left. What is the minimum amount you need?

Answer: We do the best with what we get. Assuming that we got half of the 9 mm lesion, I doubt that we'd be able to test more than 3 drugs, and we might not be able to test any drugs at all. We can do a much better job with a larger piece of tumor (10 mm or larger).

Question 8. I understand that you took exception to ASCO panel but what peer review studies did they not consider when they did their evaluation. Please cite them other than August study you named in your rebuttal letter.

Answer: The ASCO paper completely excluded all studies describing test accuracy and only included studies purporting to relate to test efficacy. As argued above, the only criteria ever before used to evaluate laboratory tests has been test accuracy. It is unfathomable that the Journal of Clinical Oncology would have accepted for publication a paper on the Estrogen Receptor or on Her2/neu (target for Herceptin) which excluded all publications relating to test accuracy.

For example, you said that your wife's tumor was hormone receptor positive and Her2/neu positive, and that her oncologists are going to base their treatment on these test results. Are you aware that there has never been so much as a single clinical trial published to show that breast cancer patients who are managed on the basis of hormone receptor test results and Her2/neu test results do better than patients who are managed without benefit of the information provided by these tests? By the criteria demanded of our tests by ASCO, there would be no justification for basing your wife's treatment on the basis of these "unproven" hormone receptor and Herceptin receptor test results!

The peer-review publications documenting accuracy of the cell culture drug resistance tests are detailed and referenced specifically in the review paper on my website:

There are more than 40 of these publications, including published clinical correlations in more than 2,000 patients. You might also want to view a streaming video of me explaining these data to a Medicare technology evaluation committee (note: the link below should work if accessed from Explorer running under a Windows operating system, but may not initialize properly from Netscape or Mozilla).

Question 9. Since Dr. Grace has run a number of these studies, why wouldn't he be in a position to publish a study of his patients treated with your assay as to survivorship vs. survivorship studies in general using standard protocol?

Answer: Dr. Grace is a private practitioner. The most he could do is to write a paper describing his own results, which wouldn't be more than a series of case reports. I personally wish that he'd try and do something like this, but, in the end, it wouldn't convince ASCO, because it wouldn't be a prospective, randomized trial. But what he chooses to do is obviously entirely up to him. He is a private practitioner and he's not looking for tenure, grants, more patient referrals, or income from doing the testing (he has no equity or investments or affiliation or association whatsoever with my laboratory or with any other laboratory which provides these tests); so I can understand if he's just content to take care of his own patients in the best way he can and enjoy the rest of his private life without trying to be a missionary and change the cancer world.

Question 10. As my wife is most concerned with side effects of drugs, particularly hair loss, I would like to get recommendation not only of most effective but the drug or combination that has least side effects such as hair loss, but is still effective.

Answer: The tests only provide information relating to anti-cancer activity. They provide no additional information relating to toxicity. It's perhaps easy for me to say (although my own sister recently lost all her hair to chemotherapy, and it did grow back just fine, after her treatment was finished), but I wouldn't focus too much on things like hair loss in making your final treatment decisions.

>>Thank you<<  [name redacted]

You're welcome. Best wishes to you and your wife.

Larry Weisenthal