Bad Pet. I need you.

[michka]

Hi Sarah. Thank you so much for asking around you. I saw my onc today. It was strange. He kept looking at the Pet/Scan and said he wanted a scan next week and that then we would see. He seems to question some of the spots but did not say that that clearly.(Especially for the lungs(. He then said that if we can have a biopsy of a node he would ask a Dr in Gustave Roussy to do a chemo test on it plus on the slides from my last liver resection. I didn't even know they did that in France but it seems to be a sort of study in IGR in cooperation with a US hospital. I don't know more. Another week to wait. I am trying to keep my mind busy.

My original nationality? Well I am born in NY, in Sloan Hospital, from an American mother and a French father. My grandparents on my mother's side were American. My grandfather on my father's side became American before the war and my father became American just after the war towards 1946. So he was also american 10 years before I was born. My parents moved to France in 1960 when I was 3. So I learned English by speaking with my mother and I worked for american cies for years.. That's why my English should be better! But after 52 years in Paris and a poor brain....

[sarah]

You're english is perfect that's why I wondered and you have an unusual and lovely name - I thought maybe Russian background.
I lived in NY for many years and loved it, what an amazing city!!!
Sounds like you are in wonderful hands regarding your cancer and that's so important.
hope the next scans are clear.
hugs and love
Sarah
ps if you get down this way, let's get together.

[gdpawel]

Michka

The fact that your doctor would like a biopsy of a node is a positive step in the right direction, instead of more trial-and-error treatment. Tumor hormone-receptor and Her2 status can change in breast cancer patients during the course of their disease, and these changes can significantly influence survival and can completely change the patient's clinical management. Results of a 2011 European Multidisciplinary Cancer Congress study showed that there is substantial tumor instability during tumor progression.

How and what type of chemo test your doc has in mind, may have some bearing in the matter. The slides from your last liver resection may not have any affect in testing on what may be your disease now. There is the issue about cell-lines (slides) vs fresh cells. Cell-lines have always played an important role in drug screening and drug development. The problem is that cell-lines do not predict for disease or patient specific drug effects.

As a general rule, studies from established cell-lines (tumor cells that are cultured and maniplated so that they continue to divide) have not be very successful as models to predict the activity of drugs in cancer. An established cell-line is not reflective of the behavior of fresh "live" tumor samples (like from the node) in primary culture, much less in the patient. You will get different results when you test passaged cells (from cell-lines) compared to primary, fresh tumor.

My thoughts would be, do you want to utilize your tissue specimen for drug selection against your "individual" cancer cells or for mutation identification to see if you are "potentially" susceptible to a certain mechanism of attack?

Best of luck!

Greg

[StephN]

Dear Michka -
We are not happy to hear that you have those new issues to deal with. But I do like the fact that your onc wants another scan (what kind?) next week to coroborate this last one that is throwing you for a loop.

Was also thinking about a biopsy since you may have some tissue that can be gotten at for analysis. I imagine he would want the slide from your liver to compare with a new tumor biology.

There are many ways to go at these tumors, just as soon as your doctor is sure about what the scans say.

If you try for T-DM1 before you have had some other drugs, it may disqualify you from their use in future. Try to check the drug ladder for the new drugs and trials.

Certainly you feel bad for causing pain to those closest to you, but they are there for you and know that you have been fighting the NERDy cancer with all you have.

Hugs and bises.

[Mtngrl]

Dear Michka,

I would also hug you too if I could. I like the suggestion to think of it as "information." It doesn't mean the cancer is "winning." I'm glad you got the information and can take it from here.

There are people on this site who have beat the cancer back many times. You can too.

So disappointing. I'm sorry you are having to go through this.

[Elizabethtx]

Hugs and prayers for you from Texas. The first step has been taken. You know the facts, now find the treatment! Cry a few tears, then put a step forward to betting the beast!

[michka]

Thank you all for adding hugs and support. It makes me feel better.
Greg, thank you for your post. I learned a lot! Knowledge is important. In fact what the onc would like to do is a chemo sensitivity test. So I understand that they need fresh cells. I had a BRCA test in 2007 which was negative. The liver tumor was tested after resection last march and it was still HER2+ and ER+. So what the onc would like to do is not loose time and weaken me with chemos that have no chance to work. Greg, do we know how much chemo testing on fresh cells is reliable? And what chemo do they test? For example could they test if taxanes is an option although it did not work the first time?
Questions, questions...my head is empty. My heart is heavy.
Michka

[sarah]

Hello,
just curious, where are you being treated? sounds like you're in great hands. Greg, as usual has great info
take care
love sarah

[gdpawel]

Michka

It's going to depend on the understanding your onc has of a chemo sensitivity test. There are DNA/RNA-type tests based on "population" research (not individuals), virtually the same as it is with tradiational trial-and-error treatment protocol. 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!

Then there is cell-based functional profiling, which provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies (conventional and targeted drugs). By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Functional profiling approximates the cancer of the "individual" not populations.

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 larger the specimen, the more drug types there are in the selective arsenal (minimum 1gm).

For these functional profiling assays to be extremely effective, they need fresh "live" tumor specimens. There are very good reasons for using fresh "live' tumor specimens and not needle biopsies for cell-based functional profiling assays. The surgical specimen is the "personalized" part of personalized cancer medicine. In the body, cells interact with and are supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in small clusters, or microspheroids (microclusters).

Analysis of these microspheroids 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. It will be indicative of what will happen in the human body.

There is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

Real-life cancers grow as a complex organism that includes both malignant and non-malignant components. It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc.

In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

Human tumors represent micro-ecosystems composed of transformed cells, stroma, fibroblasts, vascular elements, extra-cellular protein matrices and inflammatory elements.

The behavior of human cancers and their reponse to therapy reflect the complex interplay between humoral, vascular, adhesion and cytokine-mediated events acting in concert.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironoment.

Cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

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

Each of these microspheres contains all the complex elements of tumor biosytems that are found in the human body and which can impact clinical reponse.

In short, it is a complex and thorough analysis. Not many medical oncologists understand it. Don't know if your onc does. Perhaps though, he/she does! The fact the he/she would like to do a chemo sensitivity test and not loose more valuable time and weaken you with ineffective chemotherapy, is a good sign.

Don't know whether he/she intends to ship a specimen stateside or use one of the European labs. All of the labs are experienced and capable of providing very useful information.

Greg

[Rich66]

If the onc is using pursuing a test of chemos on live cells (chemosensitivity as opposed to characteristics), my understanding is that the ordering oncologist picks from a list of available agents..this may be guided by the lab supervisor also. Unfortunately, the size of the tumor sample typically limits the number of chemos that can be tried. Since it's a test at a given point in the disease, I think it's important to focus on agents that you could actually gain access to...not investigational drugs with unknown timeline for availablity. Another issue in terms of not wasting time i.e. thinking ahead is that for actual chemosensitivity/functional profiling tests, they usually want a few weeks off therapy to prevent confounding test results.
For best feedback here, it would be good to find out exactly what test/lab your onc is considering.

[michka]

Thank you Greg. More information to understand. First as Rich pointed out a simple biopsy may not be enough. They would have to take out some piece of tumor somewhere. I will have to wait next week to see what is reachable. Then if it is a long process I may not want to wait but I do not know. The place where it could be done is Institut Gustave Roussy which is a very big cancer and research center. For now I am trying to find a place in France or in Europe where they have a TDM1 trial but I have not found one yet. On the US site for Clinical Trials the TDM1 ones indicate no foreign locations but I just started looking and my brain is not working very fast. Michka

[gdpawel]

Good point Rich. Patients' patterns of sensitivity and resistance do not change in the absence of intervening chemotherapy. And even after a patient fails a previous chemotherapy treatment, the test still can be done once a patient waits at least four weeks. If proper protocol is followed, evaluability rates are very high. Greater than 95% of all specimens submitted produce clinically useful results.

Rather than mixing and matching approved drugs, assayists have used combinations designed to work in tandem to block cancer. Twenty years of work on the human genome has helped illuminate the intertwined mechanisms of cancer. Scientists are beginning to understand the cellular and genetic links among different disease pathways. As a result, the FDA is ready to allow innovative testing of drug cocktails.

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

The application of synergy analyses may represent one of the most important applications of the functional profiling platform, enabling clinicians to explore both anticipated and unanticipated favorable interactions. Equally important may be the platform's capacity to study drug antagonism wherein two effective drugs counteract each others' benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs because they can.

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. As I stated before, 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.

[gdpawel]

Michka

Yes! The Institut Gustave Roussy signed a license agreement with ExonHit a few years ago for a novel breast cancer "diagnostic" assay. The "diagnostic" value of this new signature allows for the discrimination between malignant tumors and benign lesions from cells sampled through find-needle aspiration.

And they are using cell-death assays for "drug discovery." It may be helpful to use a form of chemosensitivity testing, which is based upon the measurement of actual cancer cell death. The results of cell death endpoints (point of termination) agree with each other pretty well with hematologic and lymphatic neoplasms (non-solid cancers).

As for using cell-death assays for "drug selection," here is a contact email for Dr. Andrew Bosanquet, Bath. Dr. Bosanquet has a list of labs in Europe.

agb.scientist@gmail.com

Here is a contact email for Dr. Ian Cree, Queen Alexandra Hospital. He does the ATP cell-death assay.

ian.cree@porthosp.nhs.uk

You can also ship tumor specimens via FedEx or World Courier to any of the labs in the United States.

Best of luck on your endeavors!

Greg

[schoonder]

Michka following links show sites where t-dm1 are looking for participants.
Marianne phaseIII trial - 1st line MBC
http://www.clinicaltrials.gov/ct2/sh...ow_locs=Y#locn

Emilia phaseIII trial - 2nd line MBC
http://www.clinicaltrials.gov/ct2/sh...ow_locs=Y#locn

T-DM1 vs physician's choice - 3rd line MBC
http://www.clinicaltrials.gov/ct2/sh...ow_locs=Y#locn

A phaseI about to get underway
http://www.clinicaltrials.gov/ct2/sh...tansine&rank=1

Looking with search key "t-dm1" or "emtansine" in http:/www.clinicaltrials.gov repository will show number of still active trials.

Hope this helps.

[Rich66]

Greg,
I think you meant fine needle aspiration.
Are they somehow able to get enough cells for chemosensitivity testing that way?

[gdpawel]

Rich

Thanks! Fine-needle aspiration, as in trying to fine-needle my way through reading glasses that need cleaning, badly. I put the word "diagnostic" in quotes in regards to fine-needle aspiration. A fine-needle aspiration does not preserve the histological architecture of the tissue cells, needed for "drug selection." An incisional biopsy or core biopsy (tru-cut) preserves the histological architecture of the tissue cells.

Greg

[krisvell]

Hi Michka;
So sorry to read that you did not receive a good report. The Stage IV ladies including you give me great hope and inspiration. It sounds like you have many options which is WONDERFUL. I pray that you stand up and brush yourself off and start fighting, So far, you have done well. You can do it again.
Love & Hugs,
Kris,,,,

[Rich66]

Ok..so Greg..you are essentially saying the test Michka is being offered where she is at is not a true chemosensitivity test? Sometimes less detail is more at the patient end

[gdpawel]

Rich

They are using a cell-death assay for diagnostics and drug discovery, not necessarily for drug selection. If they are using fine-needle aspiration for drug selection, then the histological architecture of the tissue cells will not be preserved, making for less accuracy in the testing.

[Rich66]

What do you mean by "drug discovery"?