any tumor tests to predict which chemos work better?

[gdpawel]

Rich

Based on the little amount of information given, it doesn't seem like chemosensitivity testing. In order to do drug sensitivity testing, you need to actually measure drugs against any tumor specimen. Genetic testing never measures drugs against your actual cancer cells. It is "theoretical" analysis. Receiving results of that theoretical analysis a few months later tells me it is genetic testing. Drug sensitivity tests are usually given within a week.

If Amanda's understanding of "cores" is correct, an core biopsy (tru-cut) takes a sample of tissue with preservation of the histological architecture of the tissue cells. It takes an entire lump or suspicious area and removes it. They do use this "minimum" amount of biopsy to do drug sensitivity testing. If it is kept "fresh" live for analysis, it could be used for drug sensitivity testing. But after a few days, they are "dead" cells, which is what genetic testing does.

Donating tissue for research purposes is cell-lines (what I described previously). They immortalize the tumor cells. But this is not chemosensitivity testing.

If the key findings so far are that the cancer was/is "resistant" to anthracyclines and taxotere, it seems like a "cell-growth" assay. The old "cell-growth" assay is excellent at identifying drugs most likely "not" to work. They assay is not as good at identifying drugs which are "more likely" to work or to identify the disease-specific activity patterns of targeted drugs (like Tykerb). The results of this type of testing are to be used only for the purpose of drug "de-selection" and not for drug "selection."

"In Australia, the government funds it but you need to qualify and to qualify, I have to have had 3 taxotere treatments." Sounds more like a clinical trial. Simon says you can't do this or that unless Simon Says. So no. I still have no idea what Amanda's actual tests were.

As for "massive release of cells into the circulation" thought to happen during surgery, if the chemotherapy given was effective (sensitive to the cancer cells), it would have taken care of these cells. Don't forget, the Pachmann, et al research, quantifying circulating tumor cells, found that neoadjuvant chemotherapy with paclitaxel (Taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor, explaining the fact that complete pathologic responses (tumor shrinkage) do not correlate well with improvements in survival.

Greg

[Emelie B]

Greg,
I sent the information that you have been so kindly providing Sarah and asked if we could consider chemo sensitivity testing and this is his response, "ASCO, the group that supervises breast cancer care in the US and world has looked at these chemosensitivity studies. Their recommendation is that they don’t work and per their April 2011 Guideline Update, they specifically recommend not running them. We can talk and still try to run it on a fresh biopsy if you want, and if your insurance co agrees to pay for the test. "
I read the 2011 Guidelines and it stated there have not been enough studies conducted to consider these viable tests.
I hope things change soon so we don't have to continue with the shotgun method of choosing a treatment.
Thank you for all you do to provide us with valuable information.
Emelie

[gdpawel]

Emelie

Thanks for bringing this up. It needs to be pointed out why ASCO had done this. Some have told me, "I never heard that ASCO had been knighted a regulatory agency."

What is it that ASCO was saying? Chemotherapy sensitivity and resistance assays (CSRAs) should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are dependent upon mega-trials 100% funded by pharmaceutical companies (that, plus fees from speeches they give for these coompanies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

I go into detail here: http://cancerfocus.org/forum/showthread.php?t=3442

Again, thanks for bringing this up. They whole story needs to be told. I agree with you about hoping things change soon so that patients don't have to continue with the shotgun method of choosing a treatment.

Greg

[Mandamoo]

Ok - I have more information on the type of testing that has been done on my tissue for your information. It is not chemosensitivity testing as far as I understand it.

I don't understand what this means so I will type directly from the report:
Ion Toerren AmpliSeq Analysis of DNA on Formalin Fixed Paraffin Embedded Tissue.
Methodology:
Ion Torrent AmpliSeq (then there a whole lot of other jargin) and Ion Torren TargetSeq (more stuff I don't understand :-) )

The results were:
Somatic Mutations detected:
Gene - TP53
Accession Number X16416
Cosmic ID 10662[1]
cds Mutation Syntax c.743G>A
aa Mutation Syntax p.R248Q
Hg19 Coordinates 17:7577538-7577538
Effect Missense, non-functional
Therapeutics - this mutation confers resistance to doxorubicin and taxanes, in vitro testing shows sensitivity to PRIM-1 but there is no in vivo sensitivity and no induced reactivation with PRIMA-1. pCR was not demonstrated with neoadjucant anthracycline + cyclophosphamide followed by taxane in IDE.

Comments:
a TP53 somatic mutation was identified by both methodologies with a frequency of approximately 28% in the primary tumour and 54% in the lumpy node metastasis. This mutation introduced both contact and structural changes in the L2 and L3 loop and enhances in vitro invasiveness of human lung cancer cells. This mutation has been reported in 874 tumours and 19 families with LiFraumeni syndrome. TP53 mutations have been reported in 23% of breast cancers with this mutation reported 0.69%. An extensive literature search shows low level evidence for resistance to antrhracycline/cyclophospahmide and paclitaxel with increased activity of multiple drug resistance gene product, P=glycoprotein. Preclinical evidence shows the R248Q mutation is not responsive to an experimental drug PRIMA-1 in vivo. Preclinical evidence indicates the possibility of cyclotherapy, combining p53 activators and mitotic inhibitor but these are not available for patient treatment.

The lower limit of detection is estimated to be -5% and this is dependent on the proportion of tumour present in the sample.

Exome sequencing is being performed and additional report will be issued.
This testing methodology is for research use only and is not NATA accredited.

My take on this - correct me please is that this is not chemosensitivity testing but DNA analysis which has determined that the cancer in me has a particular genetic mutation which has previously been shown to be resistant to anthracylcines and taxanes and that currently there are no other suggested effective alternatives (though there are many other cytotoxics to try that are not mentioned).
We hope to redo the lung biopsy and get live tissue for further testing of the metastasis.
Interested in your comments on this type of testing.
Amanda

[gdpawel]

Amanda

It's what I most suspected, "theoretical" analysis. All DNA or RNA-type tests are based on "population" research (not individuals). They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may "tend" to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data. If you are okay with that, go for it!

Best wishes!

Greg

[Mandamoo]

I guess I see it as anOther piece of the puzzle. Maybe if can get some live tissue we could do some chemosensitivity testing.

[sarah]

Greg, you state: "
The only problem I see is that these assays are labor intensive, non-proprietary (public domain) and there is absolutely no support from either private sector investors or clinical trialists (who receive generous support from pharmaceutical sponsors but who can be given absolutely no support from the particular laboratory). This has always been the problem. It's an orphan technology."
Well that's the crux of the problem, can't make money off it, why do it. If all the fundraisers for different cancers (such as Komen, etc) could be persuaded to fund such a trial, that would be great.
How could we go about it? Still it does have benefit to the insurance companies so they should be for it also.
Sarah

[gdpawel]

Amanda

The measurement of molecular profiling (called genotyping analysis) is gene expression, examining a single process (pathway) within the cell or a relatively small number of processes (pathways) to test for "theoretical" candidates for targeted therapy.

The measurement of functional profiling (called phenotyping analysis) is expression of cell-death, both tumor cell death and tumor associated endothelial (capillary) cell-death (tumor and vascular death), and examines not only for the presence of the molecular profile but also for their functionality, for their interaction with other genes, proteins and other processes occuring within the cell, and for their "actual" response to anti-cancer drugs (not theoretical susceptibility).

Phenotype (functional profiling) analyses, which measure biological signals rather than DNA indicators, provides clinically validated information and plays an important role in cancer drug selection. A more highly productive direction would be to investigate the targeting agents in each individual patient's tissue culture, alone and in combination with other drugs, to guage the likelihood that the targeting will favorably influence each patient's outcome.

Sarah

I sincerely believe you're correct in saying this. Since the late 1980's, the NCI, aided by study sections, effectively closed down research into fresh human tumor cell culture methods for testing and optimizing chemotherapy. The proof of this is the complete lack of NIH-funded studies relating to this topic appearing in PubMed for the last twenty years. Thanks for private researchers in keeping it alive.

As one clinician has put it, we have put all of our clinical trials resources into trying to identify the best treatment for the "average" patient, in a disease notorious for heterogeneity. Drug screening (including therapy screening) belongs in the laboratory, not in the clinic.

In the last few years, there is a belated recognition that "personalized" therapy is a worthy goal, yet 100% of the effort is going into static profiling of molecular markers, as opposed to dynamic, functional profiling of tumor response ex vivo. Clinicians are now being forced into looking at "combined" targeted therapy ("FDA to alter rules for cancer drug cocktails").

How in the world are they going to accomplish this with "static" profiling? Examining a patient's DNA can give physician's a lot of information, but as the NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. They just test for theoretical candidates for targeted therapy.

[sarah]

So Greg, any way to get them to restart the program? and does it really cost about $6000 per patient to do a test?
It would seem that it would still be worth it to health insurers and countries with universal health systems to offer this.
well sometime it will happen
sarah

[gdpawel]

Sarah

Every test does not cost about $6,000 per patient. The cost varies anywhere from $2,500 to even $6,000, depending on the amount of drugs being tested. It is the cost of the drugs that are the real expense in doing this testing. But the cost pales in comparison to ineffective trial-and-error treatment.

The "standard" of care is to give the drug(s) with the least resistance and/or the drug(s) with the most sensitivity. By having additional support of drug patient-specific activity, as determined by extensive laboratory pre-tests to improve patient outcomes, could very well bolster a doctor's argument for using some these drugs (even if it would show some less expensive drugs).

It does amaze me not only that some private insurance carriers do not like to pay for these tests but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments. Even the "profit" motive of private insurers is entirely consistent with the goal of the tests, which is to identify efficacious therapies.

It really annoys me that the validation standard that private insurance companies are accepting from molecular (genetic) profiling tests is accuracy and not efficacy. No longer is it essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these molecular profiling tests is prove that the test has a useful degree of accuracy. Accuracy is the exact same standard functional profiling is judged on (no different). They have the same entitlement to be judged by the same validation standard. It must be noted that all types of diagnostic tests in cancer medicine are just that, "tests" and not treatment.

In the first head-to-head clinical trial comparing molecular profiling with functional profiling, functional profiling was found to be substantially more accurate (Arienti et al. Journal of Translational Medicine 2011, 9:94 doi:10.1186/1479-5876-9-94). It is hoped that some form of clinical trial like this would happen here in the US this year. Perhaps a good three-armed clinical trial: physician's choice vs molecular profiling vs functional profiling?

Greg

[sarah]

Greg, I think it would be great.
Could you succinctly write the importance of doing this? Then I could translate that into French and give it to the doctors at the Hospital here and a friend of mine who writes articles for the French equivalent of ASCO so maybe we could get more interest.
Think about.
I go to a meeting at the hospital the first Wednesday of every month. Next Wednesday is a meeting but it could be another month.
Sarah

[gdpawel]

An email is on its way to you.

Thanks Sarah!

Greg

[sarah]

Many thanks Greg.
Sarah