any tumor tests to predict which chemos work better?

[sarah]

Hello,
A member of our cancer support group is looking for a way to find which chemos will work for her, she feels she's running out of time and options, has mets to liver and bones, it's a genetic bc. She's looking at a company called Caris Life Science who purports to be able to do that for 5000 euro so I'm just wondering if any of you know of any tests that rule out certain chemos or suggest that others might be more beneficial???? any thoughts? very worried about this person. thanks
Does the oncotype test help? or just for ER status?
health and happiness
sarah

[chrisy]

What you are talking about is a chemo sensitivity test in which a (preferably large) sample of the tumor os taken, and they test actual chemos on it, looking for those chemos(or combinations) which work best against that tumor. There are at least 2 types of assays, measuring proliferation (growth activity) or apoptosis (cell death). The latter is thought to be superior.

Chemo sensitivity testing is not widely accepted in the US, as early versions of these tests had marginal predictive value. But, these tests have continued to evolve and in some cases have worked very well. The most reputable company doing these in the US is called Rational therapeutics", dr. Nagourney.

Although its not widely accepted in the oncology community yet, it is not "snake oil" either, and can be worth looking into.

Gdpawel frequently posts here on this topic.

[sarah]

Thanks Chrisy for this info
Sarah

[gdpawel]

The only thing I can tell you about Caris is that the only truly useful information relates to the common markers which are tested in most pathology laboratories, i.e. ER, PR, Her2, etc. Maybe DHFR (dihydrofolate reductase).

Caris begins with an immunohistochemistry (IHC) analysis. IHC testing examines "dead" tissue. An IHC test measures the level of proteins in cancer cells providing clues about which therapies are likely to have clinical benefit and then what additional tests should be run. It never actually tests your tumor specimen against any drug agents.

If deemed appropriate, they will run additional tests. Fluorescent In-Situ Hybridization (FISH) is used to examine gene copy number variation in the tumor. Polymerase Chain Reaction (PCR) or DNA sequencing is used to determine gene mutations in the DNA of the tumor.

It is a tumor analysis coupled with clinical literature search, which tries to match therapies to patient-specific biomarker information to generate a treatment approach. In other words, information that may help when considering "potential" treatment options (theoretical analysis).

Rational Therapeutics and Weisenthal Cancer Group both use a functional profiling platform. It takes the tumor with the surrounding tissue (intact and live) and then puts chemo on it to see which chemos (actually) kill the cancer cells.

The ability to monitor cell "function" provides clinicians with a vital method to characterize and compare activity of cells. Programmed cell death, or apoptosis, is critical in cancer formation and is often used to determine if cells are functioning properly.

Phenotype (functional profiling) analyses, measure biological signals rather than DNA indicators, provides clinically validated information and plays an important role in cancer drug selection. The data that support phenotype analyses is demonstrably greater and more compelling than any data currently generated from genotype analyses.

Funtional profiling "actually" measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

Caris is testing for mutations, RT and WCG are testing for drugs. Rating the efficacy of population research vs rating the efficacy of drugs actually tested against an individual's cancer cells.

The endpoints (point of termination) of molecular profiling (genotyping analysis) are 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 endpoints of functional profiling (phenotyping analysis) are 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).

Again, the choice is theoretical vs actual analysis.

Greg

[Rich66]

Is the person in France? Does the person have the financial and logistical means to pursue one of the various choices? Out of curiousity, was Caris offered by her oncologist or was it something she discovered?
More on the type of test Greg discussed here

[fullofbeans]

It seems to me that the tumor needs to be live to have chemo-sensitivity test?? so yes i believe it helps i.e. not snake oil, but I believe that you need to keep them live at time of removal/biopsy no?, It would not make sense that frozen sample can be tested on... who does this (take live sample biopsy? and culture it for test commercially, rational therapeutic seems to..but how do you send sample to them.. not very practical unless the centre testing is linked to your hospital tho..

For non solid cancer it is easier because they can simply use blood and it is easy to do (so yes for non solid cancer it should be the norm). But I would love to be wrong but in my opinion unless your sample is live (kept live or cultured straight away), then it is snake oil.

But what they can do it to give you the mutation Her2, PTEN, PI3K... which can help select..

[gdpawel]

Her2, PTEN, PI13K, and all genes, are under the direct regulation and control of genetic elements that no one has ever studied. Two percent of the human genome that codes for known proteins (the part that everyone currently studies) represents only 1.20th of the whole story. One of the most important cancer related genes (PTEN) is under the regulation of 250 separate, unrelated genes. Drug selection would still be a guessing game, which a lot of empirical treatment is today.

While (apoptotic) cell death is of importance in hematologic (non-solid) cancers (easy to do with blood), like many leukemias and lymphomas, it does not represent cancer cell death in all circumstances and can be an unreliable parameter in many solid tumors. Labs that measure only one mechanism of cell death miss important cell responses that are critical to accurate prediction of clinical response.

While apoptosis represents an important mechanism of programmed cell death, it is only one of several cell death pathways. Apoptotic cell death occurs with certain mutational events, DNA damage, oxidative stress and withdrawal of some growth factors particularly within the immune system. Non-apoptotic programmed cell death includes: programmed necrosis, para-apoptosis, autophagic cell death, nutrient withdrawal, and subtypes associated with mis-folden protein response, and PARP mediated cell death.

Yes. The tumor needs to be live "fresh" to have "traditional" chemo-sensitivity testing. When it comes to drug selection, investigators can only measure those analytes (substance or chemical constituent) in paraffin wax that they know to measure. If you are not aware of and capable of measuring a biologically relevant event, you cannot seek to detect it. The cell-lines in paraffin-embedded tissue can change over time. These proliferating populations of cell are biologically distinct in their behavior from "fresh" live cells that comprise human tumors.

The functional platform (that Rational Therapeutics and Weisenthal Cancer Group) uses morphologic (structure) and metabolic (cell metabolism) endpoints (point of termination) to gauge cellular response to drugs in human tumor microspheroids (microclusters) isolated from surgical biopsies/specimens. By examining drug-induced cell death events in native-state microclusters, the functional profiling platform has the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, known to be crucial for clinical response prediction. The microclusters recapitulate the human tumor environment.

Newer forms of assays are being provided by private U.S. companies such as Precision Therapeutics (ChemoFx and BioSpeciFx assays), Rational Therapeutics (EVA-PCD and TARxGET assays), DiaTech Oncology (the MiCK "microculture kinetic" assay), and the Weisenthal Cancer Group (CytoRx, EGFRx and AngioRx assays).

Going after a surgical/biopsy specimen has a role in eliminating ineffective agents and avoid unnecessary toxicity and in directing "correct" therapy. Patients benefit both in terms of response and survival from drugs and drug combinations found to be "active" in assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

There would be a huge advantage to the patient to receive a "positive/sensitive" drug, compared to a "negative/resistant" drug. The time and energy required to conduct an excisional biopsy pales in comparison to the time, energy and lost opportunities associated with months of ineffective, toxic therapy. Only your tumor specimen goes to the lab, not the patient.

The choice of a lab is not a geographical consideration, but a technical consideration. All of the labs are experienced and capable of providing very useful information.

However, the labs vary considerably with regard to technologies, approach to testing, what they try to achieve with the testing, and cost. Some labs have been offering these assays as a non-investigational, paid service to cancer patients, in a situation where up to 30 different drugs and combinations are tested, at two drug concentrations in three different assay systems.

The labs will provide you and your physician with in depth information and research on the testing they provide. Absent the assays, the oncologist will perform "trial-and-error" treatment until he/she finds the right chemotherapy regimen. You should have the right chemo in the first-line of treatment.

By investing a little time on the phone speaking with the lab directors, you should have enough knowledge to present the concept to your own physician. At that point, the best thing is to ask the physician, as a courtesy to the patient, to speak on the phone with the director of the laboratory in which you are interested, so that everyone (patient, physician, and laboratory director) understand what is being considered, what is the rationale, and what are the data which support what is being considered.

The two labs that provide the functional profiling platform are Rational Therapeutics and Weisenthal Cancer Group.

http://www.rationaltherapeutics.com/Contact-Us.aspx
http://www.rationaltherapeutics.com/...andidates.aspx

http://weisenthalcancer.com/Contact_Us.html
http://weisenthalcancer.com/Specimens.html

Best wishes!

[ElaineM]

Try http://www.precisiontherapeutics.com/
They can test up to 12 different chemos to see which one might work the best.

[sarah]

greg et al,
many thanks for all this info, so helpful.
yes, she's Dutch living in France.
One of our members discovered Caris in hopes of it helping his wife.
Love this site, you are all so knowledgable and kind, what would I do without you.
just learnt that probably thanks to the heavy radiation I had, I have a blocked artery, cholesterol also involved, think Femara may have added to that also. just back from intense test so my typing and spelling are probably weird. will have angioplasy and stent, I know it's off subject but if you have any info on this - a totally new area for me, I'll welcome it!!
health and happiness
love sarah
I'll pass this info along to our member and friend.

[fullofbeans]

response from rationa therapeutics:

Thank you for your interest in the work of Dr. Robert Nagourney and Rational Therapeutics.

IF chemotherapy is being considered, and IF we can easily obtain a 1-2 cm piece of viable tumor (solid tumor, lymph node, cytologically positive pleural or ascites fluid), received in our laboratory within 24-48 hours of collection, our goal would be to expose the living tumor cells to a wide panel of standard agents and novel combinations. Under this approach, “functional profiling” measures the response of tumor cells when exposed to chemotherapies in the laboratory. By identifying which agents induce the tumor to shut down and die and also which ones do not, we can aid your oncologist in choosing the most effective chemotherapy regimen based on your unique tumor makeup; additionally sparing unnecessary toxicity associated with ineffective treatments.


Functional profiling is not intended to be a scale model of chemotherapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it’s always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient’s cancer cells in the laboratory. Data reveals that our personalized "functional profile" increases response rates 2-3 times that of standard protocols.

We would be happy to discuss specifics or answer any questions. International specimens are do-able although complicated and problematic due to the timeframe in receiving viable tumor tissue. We have worked with World Courier to handle international shipments. They are expert and Customs, etc. but are not inexpensive (I would estimate $1000-$2000 just for transportation). If our program makes sense, please do not hesitate to contact us directly.



Rational Therapeutics
Physician/Patient Relations

[sarah]

Thank you, this is good to know about. I don't think she is having an operation at this time but if she does, this would be a good idea.
thanks again.
sarah

[Rich66]

For what it's worth, some patients have a biopsy specifically for the test.

[sarah]

oh ok so maybe she do that. many thanks Rich.

[Joan M]

A few days ago, a friend recommended Ralph Moss's book, Customized Cancer Treatment, published by Equinox Press, 2010. I have not yet read it. My friend said that Moss discusses chemosensitivity. Diatech (diatech-oncology.com) and Rational Therapeutics (rational-t.com) are two of the labs mentioned by Moss for chemosensitivity testing.

Joan

[gdpawel]

Ralph W. Moss, PhD, is the former science writer at Memorial Sloan-Kettering Cancer Center. For over thirty years, he has independently investigated new and promising cancer treatments around the world. He is the recipient of many awards and the author of twelve books and three films, including the PBS documentary, The Cancer War.

Dr. Robert Nagourney, one of the pioneers along with Dr. Larry Weisenthal of functional profiling analysis, says the new book talks about the functional profile platform. He previously penned Cancer Therapy, Herbs Against Cancer, Questioning Chemotherapy and The Cancer Industry, which took another look at what's working and what isn't with today's treatments.

Moss' new book makes a very good case for drug sensitivity tests to see which drugs will work best. He does a tremendous job in turning over every single stone why The Test (as he calls it in the book) has struggled to gain acceptance in the billion dollar cancer medicine industry.

Also intriguing is Moss' association of cell culture assays and complementary and alternative medicine (CAM) in the final conclusions of the book. He feels that there are many treatments of natural origin that have been proposed as candidates for cancer therapy. Some of these may have great value.

[Mandamoo]

I have been following this thread with interest.
I live in Australia and currently have tumor tissue from my initial surgery being tested. It is being tested by a government laboratory and the testing is in R&D phase - I understand that initial testing is chemosentivity of which we have preliminary results after a few months. The additional testing is various types of assays?
I have to admit to finding the above discussion confusing - can anyone explain perhaps in more lay terms the types of testing.

I tried to get samples of the lung mets this week with biopsy but was only able to get 2 cores and that was only enough for the lab to do the standard tests - we may get a bit of tissue for the R&D testing. The pathologist working on my tissue talks about developing testing for individualised cancer treatments. The reason I am so interesting is I went from a stage 2b to stage 4 while receiving, FEC, Taxotere and Herceptin. Quite obviously FEC was completely useless in fighting the cells in my bloodstream and so far Herceptin has done little either.

[Joan M]

gdpawel,

Thanks for the information about Moss.

It seems that testing which drugs would work best contradicts the trend lately to cut back on medical tests. Also, testing patients upfront is not in the best interest of pharmaceutical companies. That is, fewer patients would be getting treated with particular drugs. For example, several years ago one of my oncologists and I were discussing what was then a new drug for lung cancer, Tarceva, which as it turned out only works if a patient's cancer is genetically compatible, or has a specific genetic mutation. The oncologist noted that compatibility is not tested clinically: that is, the drug either works or doesn't work, and that indicates whether the cancer was genetically compatible. As a result, patients who are not compatible get the drug anyway. A waste of the drug. A waste of money. And unnecessary stress to a patient hoping for a good result and suffering from side effects. Seems kind of a backward process. Unless, of course, that's changed lately, and oncs are now able to test whether a person would benefit from Tarceva.

As more cancer drugs become targeted therapies -- which seems like the direction it's going -- upfront testing would have to become the rule.

Joan

[sarah]

Wow this whole discussion is so interesting and informative. The future looks so promising; we may have ways to tell what will work and what won't. I'm overwhelmed by all this fantastic and exciting information. Again, many, many thanks to all of you and to this site for creating the place for all this information to be exchanged. Despite being in my 12th year of cancer i feel like such an idiot about so much and still have trouble with many of the medical reports but thanks to all of you, I know I have a great resource to count on and by helping me, you also help our little group of expats in living in the south of France who find themselves with a deadly disease and dealing it with a language that is in some cases they don't understand well and in others is their 2nd or 3rd. Grand merci as they say here.
love sarah

[sarah]

I just wanted to add that I think of all of you who are struggling with mets and I know in my heart that solutions are coming and with all my heart I hope they are coming today. Keep up the fight. I do understand that fight, 7 years ago, I was sure I was a goner but I have 7 years of reprieve and I have enjoyed at least 5 of them and still am. This testing thing seems to have such great potential.
hugs and love and good health to all of you - you are such kind and knoweldgeable people. I would be lost without you. excuse my mushiness but it is sincere.
love sarah

[gdpawel]

Amanda

The pathologist establishes a cell-line (immortalizes it) with your tumor cells. A cell-line is a product of immortal cells that are used for biological research. Cell lines can perpetuate division indefinitely. Regular cells can only divide approximately 50 times.

Cell lines are useful for experimentation in labs as they are always available to researchers as a product and do not require harvesting (acquiring of tissue from a host) every time cells are needed in the lab. They can clone cells from a cell line (HeLa cells). However, this is not what is called "chemosensitivity" testing.

Problem is (and why it will be hard for the pathologist to develop testing for individualized cancer treatments), cell lines don't recapitulate drug response patterns which exist in the body. For "drug selection," it is better to directly remove tumor microclusters straight from the body and immediately test them, before they change, as what US functional profiling labs like Rational Therapeutics and Weisenthal Cancer Group do.

Cells are taken fresh "live" in their three dimensional, floating clusters, cultured in conical polypropylene microwells for 96 hours to increase the proportion of tumor cells, relative to normal cells.

Polypropylene is a slippery material which prevents the attachment of fibroblasts and epithelial cells and encourages the tumor cells to remain in the form of three dimensional (3D), floating clusters. Our body is 3D, not 2D in form, undoubtedly, making this novel step better replicate that of the human body.

When allowed to grow in vitro, "living" cancer cells develop into these tiny microspheroid clusters that form a complex biosystem in which each malignant cell reacts upon its fellow colonists in subtle but important ways.

Analysis of microspheroids (microclusters) with cell-death assays, provides a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic. There is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

I've been studying cell function analysis for the last ten years.

Greg

Greg