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Moving up a new post on 'functional profiling' posted on the LONG long long 'UPSC' post that loads so slow...

lindaprocopio's picture
Posts: 2022
Joined: Oct 2008

The original UPSC super-long thread is so lengthy that it takes FOREVER to load. And although I think it is EXTREMELY valuable for anyone newly-diagnosed with UPSC to read, new posts can get lost in that crazy-long thread. S000000, I am 'moving up' a recent post there to this new thread.

Daisy366 posted such an interesting post on March 8th in response to some research I'd done and posted on functional profiling. Daisy366 posted:

from DAISY366:
"I have been reading your posts - boy there are alot! and very interesting and informative - but had to respond to this one immediately. Lucky for me I had the functional profiling done after surgery - I guess I thought this was a standard procedure. It showed the Taxol/Carboplatin to have the best response of all the combinations tested. Others included Carboplatin/Gemcitabine which was also responsive, carbo/docetaxel (still responsive), and doxorubicin (not responsive). The staging process is also interesting to me. After surgery I was told I was stage IIIc - all lymph nodes tested from surgery were negative. But subsequent PET scan showed metastasis in several distant areas - which I assumed changed my stage to IV, though my doctor has never foramlly told me this. I thought he was trying not to scare me. I guess it's time I came out at asked him to explain."

This was in response to this old post from me:
"The info I wanted to post is a new diagnostic procedure that is really what we should ALL be fighting to get if any of us has to have any further surgery for cancer recurrence (God Forbid!!). This new technique involves taking the LIVE tumor cells harvested from the surgery and TESTING them with various chemo drugs to see which chemo drugs work best SPECIFICALLY for your INDIVIDUAL cancer! That way they already know BEFORE you start chemo exactly what drugs are most apt to be effective in killing your specific uniquely individual cancer. Isn't that amazing?!

The reason why this is so important to all of us is something that Peggy emailed to me from a very complicated medical report about endometrial adenocarcinomas (that's us, right?). It said: "In the serous papillary and clear cell category, EGFR positively decreased survival from 86 to 27%. EGFR strongly correlates with tumor metastasis and patient survival in endometrial cancer. Altered expression of this oncoprotein may serve as a guide to prognosis and treatment in these patients." and "Seventy-seven percent of patients with metastatic disease were EGFR-positive versus 36% positively in patients with no evidence of metastases."
This scary EGFR "epidermal growth factor receptor" is a protein on the cancer cell that causes it to reproduce and grow at a CRAZY-fast rate, and unless someone tests the live tumor cells with the chemo drugs that are so effective on EGFR, they don't know who has it and who doesn't. That's why it's so deadly, because EGFR goes untreated during chemo even though there are several very effective chemo drugs being used for other cancers that do a really effective job of suppressing EGFR, and that give the taxol/platin chemo drugs time to kill the cancer cells with EGFR before they reproduce too quickly to be dealt with. I'm not explaining it as well as I should, but if you are interested, you can put "EGFR" in the SEARCH box at the top of this page and there has been a LOT of discussion about this on other Discussion Boards here, and a lot of information about the various drugs that have worked so well to address this for people with other cancers. I know I would be afraid to learn that my survival rate had dropped from 86% to 27%, but I would be glad to know that I could still save myself by taking the newer EGFR-suppressing drugs. And that's why knowledge is power in this battle. I don't know that there is any other way to test for it except with live tumor cancer cells at the time of surgery, which is why it isn't commonly done, I'm guessing. But it seems important for women with UPSC to know, since there are drugs that really negate the power of it, and if our cancer cells have this EGFR mutation, we want those drugs!

This is from another post on this same website we are on, really good stuff!:
Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden, April 18, 2007, concluded that "functional profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity of Iressa, Tarceva, Sutent, Nexavar, and Avastin in primary cultures of "fresh" human tumors).

Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.

Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell culture assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

"Functional profiling" 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.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.

The "functional profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

Author/Speaker/Performer :Larry Weisenthal, M.D., Ph.D.;
Contact information: phone: (714) 596-2100.
Link: http://weisenthal.org/Weisenthal_ESCIa.pdf Source : Eur J Clin Invest 37 (suppl. 1):60, 2007

california_artist's picture
Posts: 865
Joined: Jan 2009

I've only commented on this to bring it to the forefront again, as many people here have never heard any of this information.

With so many stage lll and lV's, we need all the informaiton we can get. Thanks, Linda.


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gdpawel's picture
Posts: 538
Joined: May 2001

One of the reasons why testing live tumor cancer cells at the time of surgery are not commonly done becasue pathology on cell-lines is cheap. However, one gets more accurate information when using intact RNA isolated from "fresh" live tissue than from using degraded RNA, which is present in paraffin-fixed tissue.

The "cell-line" (cell-block) technique is useful for special stains and immunohistochemistry 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.

For a cell-based functional profiling assay to be done you would need "fresh" live tumor specimens to be able to distinguish between susceptbility of the cancer cells to different drugs in the same class and the susceptibility to combinations (in other words, which combinations are best and in what sequence would they be most effective).

Funtional tumor cell profiling assays will test your "fresh" live tumor specimens, transported via polyporpylene media, to be able to distinguish between susceptibility of the cancer cells to different drugs in the same class and the susceptibility to combinations. In some cases, they may test as much as 20-30 drugs (the "drugs" are expensive). They test additional drug concentrations for the "targeted" agents, some of which have very steep dose response relationships. Specimens are tested using at least three of five available cell-death endpoints.

A combination of a morphologic endpoint and at least two metabolic endpoints (whole cell profiling). Interpretation is highly labor-intensive, requiring an average of three hours of physician/lab work. Analysis is not treated lightly. It must be realized that these types of assays are complex procedures. The results are meaningful to the extent that the laboratory is experienced and diligent in its quality assurance practices.

Tumor screening in a cell-based assay profiles the function of cancer cells (is the whole cell being killed regardless of the targeted mechanism or pathway). The oncologist can have this test performed by sending any live "fresh" tumor specimen that can be secured via a polyporpylene transport bottle and/or vial for collecting a solid tumor specimen, via FedEx to the lab in question.

This is generally done in 5-7 days (depending on the situation). A lymph node has been an excellent specimen so that they can collect enough "live" tissue to more reliably determine the histologic and molecular features of a cancer. Imaging technologies cannot substitute for the biologists thorough examination of the features of a cancer cell. Again, only the tumor specimen travels to California, not you.

california_artist's picture
Posts: 865
Joined: Jan 2009

May be of use to someone.

Posts: 130
Joined: Mar 2011

who didn't know of this possibility BEFORE we had our surgery (and had a chance to insist on it).

I suppose that there's another option for me, potentially--if my lung nodules don't shrink, that is--which would be to harvest some cancerous tissue from the lungs or lymph nodes to do this testing. I guess I could lobby for that, although neither one of the oncologists I've seen in Michigan seem at all inclined to think this technique produces useful information.

I am VERY interested in knowing whether anyone on this board has been able to persuade their oncologists to do this testing, or to have it done themselves if their doctor was unwilling.

One more smallish issue to raise for now: what are the terms that are used for this procedure? Here, you're using "functional profiling," elsewhere I've seen "tissue assay." Are they the same process? Are there other terms, too?

Just when I think I'm getting a reasonable handle on everything I need to know, then there's something else that comes up! ;)

Posts: 130
Joined: Feb 2011

I was fortunate enough to have found this board when I was diagnosed with UPSC, before my surgery was done. I received valuable advice from the ladies here. I insisted on this testing be done to my original tumor after surgery. The tumor was sent to Caris Life Sciences lab and they called it "molecular profiling". It told the genetic markers and gene mutations/expressions in MY tumor and which chemo drugs would be beneficial and those that would not have benefit. My insurance company has still not paid for the tests and are protesting but I am still glad that I had the tests run.


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