Has anyone had a tumor sensitivity test done?

[DeenaH]

I am going to be calling Dr. Robert Nagourney tomorrow to inquire about this. Apparently if they can retrieve a large enough sample (1cm) of live cancer tissue, they can test that sample to see which chemos and chemo combos (including targeted therapies) will and won't work on your cancer. This intrigues me.

I was warned that most private and university oncologists will be against this type of testing, so I am expecting resistance from my doctors. I just want to educate myself as much as I can before I talk to my doctors.

I just found out Friday that my lung mets have grown between 1/3 and 40% in two months while on Herceptin/Tykerb. This after becoming stable after the first 2 months. This cancer is smart and aggressive! Chemo is in my future once again. Drat!

To me it makes so much more sense to take one of my tumors (although I know this is not an easy surgery, I am strong right now) and test it to make sure we aren't just throwing toxic drugs in my body and hoping they will stick. It's just such a guessing game already.

Just wondering if any of you have had experience with tumor sensitivity testing. Pros, cons? I don't want to just buy months on my life. I am still hoping for a cure, or at least long term stability!

[ElaineM]

http://www.precisiontherapeutics.com/
Precision Therapeutics also does this testing.

[chrisy]

Hi Deena

No, I haven't had this done and don't know anyone who has - but I'm a little familiar with the concept and Dr. Nagourney's work. A few years back, ASCO declined to recommend this approach but my opinion is that this was because it was not "proven" to be of benefit, proof only being available after lots of testing. Thus they did not recommend it as it is expensive, not without risk (as you note, getting sufficient sample is no easy task) and not certain to provide any benefit.

Also, cells (even your own cells) behave differently in a test tube than in your body - another reason that sort of testing may be met with skepticism. This in a strange way could also work against you - I wonder if there is danger of a false negative (meaning the test shows something wouldn't work when in reality it might - and you cross it off your list without trying it?)

The impression I got from the ASCO (non) recommendation was that they felt it was just not ready for prime time.

This thinking may begin to shift as more and more focus is placed on individualized treatment based on the characteristics of the person's specific cancer - and more is validated about the testing itself.

Still, it is your life and, although they may not recommend it - it should be your decision. It will be "information" that can be either used or disregarded.

All that said, I too was/am interested in that approach, it made sense to me and I would be open to trying that myself. But of course I'm not a doctor, just a patient!

Let us know what you find out, I'm sure there are others who are interested in knowing!

[chrisy]

Deena,

One other point as I read your signature...

Looks like the only "chemo" you have had is Taxotere in the neoadjuvant setting. You should be aware that many of the chemo agents available to you are less difficult than taxotere, can be very effective and for a long time.


"A few months" is not enough time...I think we all would agree with that! Remember stats are just stats, not what YOU will experience. You have many many options that are available for you - and more are being discovered every day.

[DeenaH]

Chrisy - I did A/C before I did Taxatere. I do know there are quite a few I haven't tried, I just hate the idea that some might not work and I'll be weaker after the toxicity. You make some excellent points to consider though. That's why I posted here! Just trying to get my mental juices flowing about this subject. I like to have my ducks in a row before I speak to a doctor so they know I know what I am talking about. Thanks so much for your input as a fellow patient! I'll definitely post anything I learn.

[kiwigirl]

Is T- DM1 an option for you?

[Jackie07]

More and more insurance companies are requiring these 'sensitivity' tests now. 4 months after I had been reminded by my oncologist of resuming Tamoxifen last summer (because of new report about the benefit of continuing after 5 years?), the insurance company (BCBS) sent me a kit and asked me to send in cell samples (from the two corners inside my mouth) to see if it is an effective medicine for me.

The result must be 'positive', as I am still taking the pill every night.

It does not just save money and time, it spares us from heart damage and other possible side effects of unnecessary treatment.

[Rich66]

Hmm. Cotton swabs in mouth? Never heard of that one. Tried to get a cell sample for mom when it was thought she had ascites fluid in abdomen. By the time of the procedure, the ultrasound tech didn't feel it could be done safely at the time due to decreased fluid. The big hurdle to my mind is access to an adequate sample. I think the folks Nagourney et al work with in CA are more aggressive about getting tissues. If you can't get enough sample for the other tests, a smaller amount might yield results via ChemoFX which can "grow" the samples, the negative there being delays and potentially less accurate results. GDpawel will chime in shortly I suspect. More on various chemosensitivity tests here

[Jackie07]

It's called a 'cheek' swab test:

http://www.healthanddna.com/drug-saf...tamoxifen.html

Not cotton swabs - they were long sticks with sponge-like stuff on the tip.

[DeenaH]

I do know Dr. Nagourney is more aggressive with getting tissue samples. If I were to go forward with trying this (after much research and consideration, of course), I would likely have it done by a surgeon he works with for best chance of getting a proper sample, and less chance of it dying in transport. Rather, it would just be handed off directly to Nagourney's team to start testing.

I think for me, the biggest question will be, how hard are my tumors to get to, and how hard is the recovery. If they are fairly easy to get, and I won't be wasting too much time recovering from that to start chemo, I can't see a huge reason not to do it. More research will tell. I'll post again after I talk to Nagourney's office today.

Thanks for any and all info!

Kiwigirl - I am not a candidate for TDM-1 until after I try at least one more chemo and progress on that. It is on my radar though!

[Deb33]

My oncologist said it is his standard protocol to sensitivity test any recurring tumors. He uses a lab in AZ that he feels is more thorough than the CA labs. Since I'm fairly new (diagnosed 1/11 and going through chemo), I don't have the specifics. Just that he feels its critical to test.

[radiant]

Wow Deb33 - that's encouraging. Can you find out what lab in az he uses for this?
thx,

Kim

[gdpawel]

Hi Rich! Your suspicions were correct about the proper understanding of tumor sensitivity testing.

The cell-based assay judged by the infamous ASCO tech assessment in 2004 was a direct descendent of the old original Salmon/Von Hoff Human Tumor Stem Cell or Clonogenic assay of the late '70s/early '80s. Over twenty year old material that had been discredited twenty years ago. The so-called ASCO expert panel who did this tech assessment included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger and a German named Hanauske who worked with Von Hoff in San Antonio. All three were old-line "Human Tumor Stem Cell" (clonogenic) assay workers.

What ASCO said was cell culture assays 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 utterly dependent upon mega-trials funded by pharmaceutical companies, that, plus fees from speeches they give for these companies, 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 techology tested under the clinical trial setting?

Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.

Opponents of cell culture assays are insesently confused with the old "clonogenic" chemosensitivity assays, the one that Dan Von Hoff had been discredited long ago. When most academic oncologists refer to "chemosensitivity testing," they are virtually always referring to and thinking about the "human tumor stem cell" assay or "clonogenic" assay. Yet this technology hasn't been used by any private sector laboratory, like Rational Therapeutics or Weisenthal Cancer Group) for more than twenty years. Nor has it ever been advocated the clonogenic assay as the best cell culture assay. But Von Hoff had tried to sell it, not within the confines of a clinical trial, but as a service to patients.

The previous CMS administrator for Medicare in Southern California (NHIC) spent almost the entire 2006 doing a extensive, transparent tech assessment of chemoresponse assays and made the decision that the assays were a perfectly appropriate medical service, worthy of coverage on a “non-investigational” basis. It was a local coverage decision (LCD) and not a national coverage decision (NCD) because Medicare has only about 20 doctors and 40 total clinicians working in its coverage office. Also, Medicare doesn't have a single oncologist on staff, yet since the year 2000, they issued 165 restrictions and directives on the use of cancer drugs and diagnostic tools.

Private insurers like NHIC, on the other hand, employ thousands of doctors and nurses to do this. Last year, an insurance company called Palmetto GBA was awarded the contract to administer Medicare services for California. Palmetto made an arbitrary decision to discontinue Medicare payment for chemoresponse assays in California, with doing any transparent tech assessment.

In regards to the discussion whether the in vivo response to a drug may be different in the body than in the petri dish. Rational Therapeutics and Weisenthal Cancer Group work with three-dimensional (3D) tumor cell clusters. Real life 3D analysis makes functional profiling indicative of what will happen in the body. It tests fresh "live" cells in their three dimensional (3D), floating clusters (in their natural state). Even researchers at Johns Hopkins and Washington University at St. Louis had recently found out, our body is 3D, not 2D in form, undoubtedly, making this novel step better replicate that of the human body.

Traditionally, in-vitro (in lab) cell-lines have been studied in 2 dimensions (2D) which has inherent limitations in applicability to real life 3D in-vivo (in body) states. Recently, other researchers have pointed to the limitations of 2D cell line study and chemotherapy to more correctly reflect the human body.
And other recent studies have shown that three-dimensional (3D) tissue culture models have an invaluable role in tumor biology today providing some very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model.

Due to their enormous potential 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.

Blood assays ususally proliferate (grow) cancer cells from a small sample and subject those cells to chemo. Cells 'grown' in the lab will not behave the same way as the actual cancer cells do in your body's own environment. Because they test on subcultured cells (as opposed to fresh tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cell grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.

Older technology assay tests failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth endpoint), not which chemotherapies actively killed the tumor cells (cell-death endpoint). Cancer wasn't growing faster than other cells, it's just dying slower. The newer assay testing technology connects drugs to patients by what 'kills' their cells, not by what 'slows' them down.

All of the work in the past twenty years in the cell culture field has been carried out largely on three dimensional clusters of cells (not monolayers). Work is done exclusively with three dimensional, floating, tumor spheroids. When you test the cells as three dimensional spheroids, they are many-fold resistant in vitro, just as they are in vivo (multicellular resistance).

What is not ready for prime-time is molecular profiling in light of the recent findings about the limitation of genetic testing, gene-guided chemotherapy research being questioned, and gene-expression signatures not ready for prime-time. Examining a patient's DNA can give physicians a lot of information, but as the NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. For truly personalized cancer care, patients can only rely on functional profiling assays.

http://her2support.org/vbulletin/showthread.php?t=46200

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 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, your, physician, and laboratory director) understand what is being considered, what is the rationale, and what are the data which support what is being considered.

Some molecular tests (like the AZ lab) do utilize living cells, but generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from circulating tumor cells. This was tried with the human clonogenic assay, which had been discredited long ago. Again, traditionally, in-vitro (in lab) "cell-lines" have been studied in 2 dimensions (2D) which has inherent limitations iin applicability to real life 3D in-vivo (in body) states.

The cell-block technique (which is used for genetic testing) is useful for special stains and immunohistochemistry (IHC) and can give morphological (structural) details by preserving (in paraffin wax) the architectural patterns. However, 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.

Cell-blocks are paraffin-embedded, and parffin-embedded tissue can change over time. These proliferating populations of cells are biologically distinct in their behavior from "fresh" live cells that comprise human tumors. Established cell-line is not reflective of the behavior of "fresh" live tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cell-lines compared to primary, fresh tumors. You can't use cell-blocks at a later date.

Greg

[Chelee]

Deena,
Back in Dec. I went for a 2nd opinion at another center. The onc ordered a PET scan for me which showed increased uptake in my ilium. (It had been a stable bone met for a long time.) Due to the increased uptake of bone mets this onc wanted a bone biopsy 1st before going forward. He told me he was going to have the biopsy sent out to two different places and have the RNA and DNA checked and go from there.

The report was much more extensive then I thought it would be. I had no idea it would have that much information because it wasn't explained to me. The worse part was waiting for the report to get back...it took almost a month. I was told it would take about two or three wks at the most. (So if you have it done it can take a while.) I think the only reason this test was ran was because I was asking about a clinical trial they were running? I've spoken to a few other onc's since then and it seems most centers do not want to run these tests. I'm sure one reason is they are expensive. You may have problems with your insurance company giving approval for this? The testing for my biopsy was done by "Caris Life Sciences". I have what they call a "Target Now" report. Here is the link to their website if you want to read about them and see what's in the report? Good luck to you.

http://www.carislifesciences.com/oncology-target-now

Chelee

[Rich66]

Just so it's a clear, the swab test noted previously tests for an enzyme that turns Tamoxifen into endoxifen, the active anticancer drug. Although this issue has been around a while and has garnered support, it seems to currently be questioned regarding usefulness.
A molecular analysis like Caris gleans info of a more hypothetical nature (this biology suggests) whereas a functional profile chemosensitivity (like Rational Therapeutics or Chemo FX) test assumes minimal knowledge of how cancer might respond, simply tests drugs against the tumor sample to see how it actually does respond in a lab simulated treatment scenario. At least that's my understanding...

[gdpawel]

What Chelle had was a molecular profiling assay. It is not considered a cellular profiling assay.

Target Now uses molecular profiling techniques, including both DNA microarray and immunohistochemical (IHC) analysis, to provide individualized information about a patient's tumor as an aid to the treating oncologist.

It uses IHC analysis with a patient's frozen tissue sample. it may also run a gene expression analysis by microarray which looks for genes in the tumor that are associated with specific treatment options.

Sometimes they utilize living cells, but generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from CTCs. This was tried with the old human clonogenic assay, which had been discredited long ago.

The endpoints (point of termination) of molecular profiling 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.

All DNA/RNA-type tests are based on "population" research (not individuals). It bases 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 personalized medicine but a refinement of statistical data.

There is a problem with growing or manipulating tumor cells in any way. When looking for cell-death-related events, which mirror the effect of drugs on living tumors, cells are generally not grown or amplified in any way. The object is occurrence of programmed cell death in cells that come into contact with therapeutic agents.

Detectable tumor cells in peripheral blood are present only in extremely small numbers. This precludes allowing a sufficient number of cells to incubate for a few days in the presence of chemotherapeutic agents. Analysis of a relatively small number of isolated cancer cells cannot yield the same quality information as subjecting living cells to chemotherapeutic agents, begging the question of whether or not it can accurately predict which drugs will work and which will not.

The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.

The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. This view is not shared by all molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism's functioning.

[ZGatalica]

Chelee,

The medical staff at Caris Life Sciences is available to discuss your report with your oncologist. Staff members are available Monday through Friday and the company will also triage calls after hours, in which case, someone will return your oncologist’s call the next business day. The Caris phone number is 800.901.5177.

The Caris Target Now report can seem complex at first read and the responses you received from your oncologists are not unusual. In some cases, although rare, the report doesn’t reveal treatment options that the physician hadn’t already considered. However, with the depth of information in the report, this is not the rule. Encouraging your doctor to walk through the report with someone on the Caris medical staff would be a good way to be certain.

The report is designed to highlight the therapies that might work against the biomarkers found in the tissue sample your physician submitted. It also has a lot of information about biomarkers your tissue expressed (or did not express) and this can get complex for even experienced oncologists, who are adept at getting you the best therapy. There are many good therapies from which oncologists can choose and not all of them require the latest diagnostic methods to select.

I hope you find this information helpful.

[gdpawel]

In regards to the Caris Target Now, it is a tumor analysis coupled with clinical literature search, which matches therapies to patient-specific biomarker information to generate a treatment approach. Caris Target Now testing provides information that may help when considering "potential" treatment options.

Caris Target Now begins with an immunohistochemistry (IHC) analysis. 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." They never actually test your tumor specimen against any drug agents.

If there is access to a frozen sample of patient tissue available, Caris Life Sciences may also run a gene expression analysis by microarray. The microarray test looks for genes in the tumor that are associated with treatment options. IHC testing examines "dead" tissue. One gets more accurate information when using intact RNA isolated from "live" fresh tissue than from using degraded RNA, which is present in paraffin-fixed tissue.

As deemed appropriate based on each patient, Caris 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 tumor.

Caris takes the results from each test and applies the published findings from thousands of clinical trials. Based on this analysis, Caris Target Now identifies "potential" therapies for patients and their treating physicians to discuss. Again, never measuring any of the therapies against your individual cancer cells.

Caris Target Now was developed and its performance characteristics were determined by Caris Life Sciences, a medical laboratory CLIA-certified in compliance with the U.S. Clinical Laboratory Amendment Act of 1988 and all relevant U.S. state regulations. It has not been approved by the United States Food and Drug Administration. It says it right on the report.

Their molecular profiling need only obtain a small biopsy of tissue to identify the targets "most likely" to respond to available agents. However, their investigators invented a criterion of response: 1.3 fold improvement in time to progression. Patients who receive an ineffective therapy and showed disease progression, need only improve upon that short response by a mere 30% to be counted among the responders. No wonder none of the molecular assay results make sense.

A patient who fails a therapy after 10 days could theoretically be counted among the successes if their subsequent response to directed therapy was a meager 13 days in duration (J Clin Oncol 28:4877-4883. 2010). The NCI has concluded (J Natl Cancer Inst. March 16, 2010), molecular tests cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for "theoretical" candidates for targeted therapy.

In regards to Rational Therapeutics and Weisenthal Cancer Group, both use the functional profiling platform (just call it differently), It takes the tumor with the surrounding tissue intack and then puts chemo on it to see which chemos (actually) kill the cancer cells.

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

There is much research devoted to measuring gene expression. A key challenge is differentiating changes in gene expression caused by changes in primary DNA sequence, versus those caused principally by modifications to histones and methylation of DNA.

Understanding the structural and functional relationships of cells and tissues is critical to advancements in key research disciplines, including molecular biology, genetics, reproductive function, immunology, cancer and neurobiology.

Now that the human genome has more or less been sequenced and the technologies developed to analyze numerous genes and gene products simultaneously (microarray technologies), the focus of scientific query will switch from simply identifying the gene/protein to investigating the function(s) and inter-relationships between specific gene products and specific cellular activities (drug selection).

No technology is more well suited to the investigation and simultaneous analysis of the relationships between specific target molecules, cell functions and cell sub-populations than cytometry and cytometric analysis of cell phenotype and function provides a very comprehensive overview of this ever-broadening field (function cytometric profiling).

And some inside information. Precision Therapeutics has a complement assay to their ChemoFx, which is run on a "population" of tumors. They identify the responsive, intermediately responsive, and nonresponsive patients. Then take the molecular markers and find out what these patients have in common with respect to 150 different genes.

Then they work on eliminating the genes that are irrelavent. What they get is a multi-gene predictor. It can't work without ChemoFx working. ChemoFx is the backbone of BioSpeciFx. The thing that is unique about BioSpeciFx is that the oncologist can pick and choose which markers he/she want to see. An ala carte selection if you will.

Caris' Target Now does not do this. In fact, they are running 100-120 different markers and charging for each one, with relatively no clinical relevancy to justify this.