any tumor tests to predict which chemos work better?

[gdpawel]

Joan M

After reading Moss' book, you'll get a good understanding of your statement, "testing patients upfront is not the best interest of pharmaceutical companies." Pharmaceutical companies do not want them testing patients who aren't going to be responsive to their drug product. They like testing for their product, not someone else's product.

With some of these prognostic tests, it can eliminate some patients from having to receive chemotherapy treatment. With some of the functional profiling tests, it reveals those drugs that work from those drugs that don't (and this is what's important), on the "individual" cancer cells, not from average population studies.

The problem with genetic tests (a.k.a. Tarceva) is that it never even tests the individual's cancer cells against the drug (compatibility is not tested clinically). Molecular testing methods detect the presence or absence of selected gene or protein mutations which "theoretically" correlate with single agent drug activity. Cells are never exposed to anti-cancer agents. And it cannot test sensitivity to "combinations" of targeted drugs.

Even patients who are found to have an activating EGFR mutation, Tarceva is considered acceptable but not a definite superior choice. Genetic variations alone do not determine response to targeted therapy. Those patients who test negative for EGFR are left to the same guesswork as conventional therapy.

There are lots of things which determine if the drug works, beyond the existence of a given target. Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug?

Tarceva can be given selectively to patients with EGFR negative NSCLC. It is a challenge to identify which patients targeted treatments like Tarceva will be effective. Patients across a broad range of clinical characteristics could benefit. Being EGFR negative is no reason not to be given this drug.

BTW. Tarceva is not just for lung cancer. Tarceva is a tyrosine kinase inhibitor. However, it also has an anti-angiogenic effect on cancer cells. There are a number of classes of drugs that target angiogenesis (VEGF). At the protein level is Avastin. At the tyrosine kinase level is Iressa, Nexavar, Sutent and Tarveca. At the intracellular metabolic pathway mTOR level is Afinitor and Torisel.

When chemotherapy drugs work, they often cause tumors to shrink a lot, sometimes even making them disappear. But anti-angiogenesis drugs don't seem to work in the same way. In some cases they shrink tumors, but in others they just seem to stop them from growing any larger.

Newer approaches to treatment that combine anti-angiogenesis drugs with chemotherapy, other targeted drugs, or radiation may work better than using them alone. For instance, early studies that tested the drug Avastin by itself did not find that it helped people with cancer to live longer. But later studies found that when it was combined with chemotherapy to treat certain cancers, it helped people (some subsets of patients) live longer than if they got the chemotherapy alone.

Doctors aren't sure why this is the case. One theory is based on the fact that chemotherapy drugs may have a hard time getting to cells in the middle of tumors. Tumor blood vessels grow in a short amount of time and in an abnormal environment, so they are not as well-made and stable as normal blood vessels.

Because of this, they tend to be leaky. This affects how well drugs can reach the inside of the tumor. The theory is that anti-angiogenesis drugs may somehow stabilize these tumor blood vessels for a short period of time, allowing the chemotherapy to reach more tumor cells and be more effective.

Greg

[gdpawel]

Sarah

I can only add to your statement by deleting the word "may." We have ways to tell what will work and what won't. We just have to overcome the resistance to it by an entrenched cancer establishment. And I agree, the future looks so promising, but that future is already happening. It just has to be revealed.

The selection of a chemotherapy regimen for individual tumors is normally based on histology, clinical characteristics of the patient and retrospective evidence from randomized clinical trials.

However, patients with the same tumor histotype, especially in solid malignancies, often respond differently to the same chemotherapy regimen due to heterogeneity of cancer.

Systems Biology is the field of biology that examines biological processes in the context of an entire system of processes within a cell or organism.

Systems biology utilizes a combination of biochemistry, proteomics, genomics, metabolomics and bioinformatics to better understand the contribution of each element of the system to the whole.

This is what pioneers of cell function analysis (functional profiling) are doing with cancer treatment.

Despite knowledge of such heterogeneity, chemotherapy is still largely empirically planned (trial-and-error), and the acquisition of information for tailored therapy has consequently become a priority in the management of cancer patients today.

The chance that you are the median patient in a randomized clinical trial is quite small. Would you want to gamble with your health based on "odds" that you are just like the median patient in some population of patients tested in a clinical trial?

There is a large and growing volume of clinical data that establishes the predictive validity of the functional profiling platform. Both solid and hematologic tumors have been evaluated with statistically significant results.

Greg

[sarah]

Thank you Greg. I'd like to bring this up at the cancer hospital where we have our support group. Any suggestions for a few tests? Caris came and spoke to us and an oncologist sat in and said how helpful it would be to have tools that worked so it would be nice to encourage it. Obviously it would save payers money and patients time wasting on the wrong drugs.
thanks
sarah

[gdpawel]

Sarah

The choice of a lab is a technical consideration. 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. Absent the assays, the oncologist will perform "trial-and-error" treatment until he/she finds the right chemotherapy regimen.

However, some testing is still "trial-and-error" because the tumor analysis is based on the same clinical literature search (population study), which tries to match therapies to patient-specific biomarker information to generate a treatment approach. This is not really personalized medicine, but just a refinement of statistical data. In other words, information that may help when considering "potential" treatment options (theoretical analysis). It's never measured against your actual cancer cells. If you are okay with that, go for it!

Some testing takes the tumor with the surrounding tissue (intact and live) and then puts chemo on it to see which chemo (actually) kill the cancer cells. The ability to monitor cell "function" provides clinicians with a vital method to characterize and compare "activity" of actual live cells. Programmed cell death (apoptosis) is critical in cancer formation and is often used to determine if cells are functioning properly.

Functional profiling analysis measures biological signals rather than DNA indicators, provides clinically validated information and plays an important role in cancer drug selection. It "actually" measures the response of the tumor cells to drug exposure. Following this exposure, it measures both cell metabolism (metabolic) and cell morphology (structure), 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.

In short, Caris is testing for mutations, while Rational Therapeutics and Weisenthal Cancer Group are testing for drugs. Rating the efficacy of population research vs rating the efficacy of drugs actually tested against your individual cancer cells. The choice is theoretical vs actual analysis. The choice of a lab is a technical consideration.

Greg

[Rich66]

Hmmm. Having an oncology company rep meet with a support group seems..unusual. Feels a little too close to selective marketing considering you had to come here to learn about other options.
Eh..back to your friend..

Maybe this will be helpful:

There are no guarantees the chemosensitivity test results will prove true if used to choose treatment. Same for markers like ER or Her2. Those are routinely used to guide treatment choices but have no guarantees either.
The same is true for testing antibiotics against cells from patients with infections. You could take a look at characteristics of the bacteria and the type of infection and pick some antibiotics through averages or experience. That would be similar to observing markers on a slide and using that to guide choice. But often, when a route to gather an adequate sample is available, say a urine sample for UTI, it is typical to test various antibiotics against the sample to see which one kills the bug. Results from that test suggest starting points for best chance of controlling the infection before resistance sets in. No guarantees..just a better informed starting point.That would be more like the functional profiling/chemosensitivity test.

The need for a larger than normal biopsy is the main hinderance, to my mind, of functional profiling. It seems typical that Interventional Radiologists unfamiliar with FP and/or its benefits will balk at taking multiple biopsy passes on an organ like the liver. Some have gone to California and had procedures done there by folks who are more on board with the idea. Although benefits may outweigh the negatives, I personally have some concern about extensive surgery in cancer patients considering general anesthesia can suppress the immune system and surgery can disseminate cancer cells. But again, if it leads to identifying a powerful treatment that really gets the job done, probably outweighs the negatives. If there is enough sample, FP can allow for testing of drugs and off label combinations not normally considered.

Another issue is that FP doesn't test for sensitivity to endocrine therapy (Tamoxifen, Femara etc)..probably because endocrine therapies take time (sometimes months) to work whereas FP evaluates cancer cell death within a brief time window. Sometimes they will combine Tamoxifen with chemo, but the evaluation window is still brief. But if endocrine therapies have been exhausted or the cancer is considered ER negative, less of an issue.

[gdpawel]

Rich

I found that having an oncology company rep meet with a support group seemed unusual too. It's like those stories I hear of some of these lab reps being in the operating room waiting for the specimen. I guess they need to satisfy their venture capitalist owners?

These laboratory tests are a "tool" for medical oncologists actually treating the patient. The oncologist should take advantage of all the tools available to him/her to treat a patient. However, you cannot make him/her use those tools, effectively. The labs vary considerably with regard to technologies, approach to testing, what they try to achieve with testing, and cost. It is a complex and thorough analysis. Not many medical oncologists understand them.

[Joan M]

Greg,

Thanks for your response and explanation. Drug response is definitely a complex process.

Joan

[gdpawel]

Rich

There are no guarantees that physician's choice will prove true if used to choose treatment. The widespread and inappropriate use of chemotherapy is an obstacle to controlling cancer growth and metastasis in patients. Patients would certainly have a better chance of success had their cancer been "chemo-sensitive" rather than "chemo-resistant," where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most "effective" chemotherapy would be more likely to improve survival.

It would seem more prudent to invest the time in using diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize, and match the most "effective" therapeutics to your "individual" cancer cells.

Going after a surgical/biopsy specimen has a role in eliminating ineffective agents and avoid unnecessary toxicity and in directing "correct" therapy. Data has shown that 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.

There is no consistent associations between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy. Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective.

New analyses of data from 2 large trials have found no association between the CYP2D6 genotype and the effectiveness of tamoxifen in preventing breast cancer recurrence, in contrast to several previous positive studies. So CYP2D6 testing not be used routinely to decide whether or not to prescribe tamoxifen. Physicians should not routinely test for CYP2D6 status before deciding whether to prescribe tamoxifen or an aromatase inhibitor.

Although the functional profiling platform usually does not give strong cell-death signals for tamoxifen exposure in most tumors, sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

A functional profiling assay is conducted on human tumor samples utilizing native microspheroids (fresh, live cells) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment. This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Tamoxifen at concentrations of 2.5 micromolar (concentration of one millionth of a mole per litre) or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

Joan

Cancer is many things, but simple is not one of them.

Greg

[sarah]

Hello Rich and Greg,
reading your posts is illuminating.
As for Caris, they did not approach us. One of our members whose wife with bc at age 38 was seriously ill (she died soon after sadly) and the trade off was they would come and talk and would use her tumor as an example, unfortuantely it was too late but it was the first time we had heard of this type of thing being done and of course it is an encouraging area if it works.
The distress with patients with metatasis is that they often "lose" time on drugs that don't work or don't work well enough and so as we all realize if a way to narrow done the choices to those that are more likely to work, it would be great. As you say Greg, cancer is not simple, if it was it would have been solved and certainly lots of people are working on it and there is a lot of money to be made finding drugs that work.
Obviously oncologists depend mostly on the stats that point to what has worked most of the time and follow those protocols.
Greg, I found your post on chemo-sensitive versus chemo resistant etc post particularly interesting.
I have a question for Rich and Greg: (others welcome!) when a tumor is removed, what do you consider are the ideal markers that you think should be answered?
I know in '99 they checked about 6 markers on my bc, some of which I believe today are no longer relevant but they were supposedly to show the tendancy to progression unfortunately despite the indication of possible progression, (I was DCIS but...) I was lightly treated and progression did happen so it would seem to me to be better to have the clearest picture of what could happen. I seem to ok for the moment but I'm worried about new patients and those in our group who are actively metatastic. So think about what you feel are the most important markers and please pass them on to me so that I can talk to the oncologists at the hospital where we have our meetings to find out if these are all done and if not, can they be.
thanks in advance and boy do I love that you are so informative, I only wish I could understand all of the medical terms.
Thanks guys, love you.
If you come to the south of France, you'd better look me and my husband up!
Sarah
ps these were the markers they did for me in '99:
ER, PR, Ploidy/DNA index, S-phase Fraction, MIB-1, HER2, p53

[gdpawel]

Sarah

The reference to cancer being not simple was the genotyping analysis that goes on. Looking for that simple gene and seeing how it is expressed in the individual's cancer cells. The genomic profile is so complicated, with one thing affecting another, that it isn't sufficient and not currently useful in selecting drugs. The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway, or a few targets or pathways.

Some years back, three federal agencies (NCI, FDA and CMS) announced a program to try an identify biological indicators (biomarkers) which may indicate whether a cancer patient is likely to benefit from a given anti-cancer therapy, or even whether they will suffer from certain side effects. Biomarkers were already a part of drug development (Her2 = Herception, etc.), but health officials wanted to routinely incorporate those measurements into clinical trials.

They should be able to detect cancer pathways with biomarkers and choose patients for a trial based on who responds very quickly to a drug. The ordinary trial system did not suffice if they were to encourage new drugs for restricted numbers of patients. Hence the BATTLE clinical trials. Clinical trials designed applying Bayesian adaptive randomization for targeted therapy development in lung cancer. They thought this was a step toward personalized medicine.

http://cancerfocus.org/forum/showthread.php?t=3432

But giving instructions on the genetic differences that determine how a person responds to a drug will still have cancer medicine being prescribed on a trial-and-error basis, with adverse drug reactions remaining a major cause of injury and hospitalizations. There have been technologies, developed over the last twenty years, that hold the key to solving some of the problems confronting cancer medicine: matching individual patients with the treatments most likely to benefit them. Being chemo-sensitive rather than chemo-resistant.

Greg

[sarah]

Hello Greg,
Yes I read about Steve Jobs having a complete tumor analysis done (he could afford it but didn't have the "time") but my secondary question is now, what besides knowing the 3 big ones (ER,PR and HER2) what are the next important ones to know?
thanks
Sarah
ps maybe I should post this as a new thread?
Again thanks for the testing info.

[gdpawel]

Sarah

Steve Jobs had his entire genome sequenced. It was reported this week that the $100,000 price tag of his testing can be done for $900 now. I hope he didn't spend all that money just to find out he had pancreatic neuroendocrine cancer and not pancreatic cancer. These cancers behave very differently. But gene sequencing is not ready for "drug selection."

Ironically, functional profiling had found out that a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight breast, colorectal, lung and pancreatic cancers. Will one be able to find that out by testing just for the genes (the big three, or even the next ones on the list)?

It has become routine to test breast cancer patients for the mutation conferring sensitivity to Herceptin, test lung cancer patients for the mutation conferring sensitivity to Tarceva, and the KRAS mutation to predict for Erbitux. What these "theoretical" candidates may be missing out on is some other drug or combination that would be more sensitive to their individual cancer cells, not from some population study.

Good luck in finding the next ones.

Greg

[Rich66]

Rich

There are no guarantees that physician's choice will prove true if used to choose treatment.

You know that I know that to be the case. Just trying to avoid impressions that FP is guaranteed either. Cancer is even more complex than FP, which has no way to deal with endocrine, immune and other factors including putative stimulation of cancer stem cells by chemos that kill/shrink the majority of cancer cells. But I'm convinced it's a helluva lot better than lab tests that can't tell an activated path vs inactive and should be used when feasible..and I can't help but wonder what the impact would be if used in initial surgery, when ample sample is the easiest and cells are at their most vulnerable.

[sarah]

Hello Rich,
oh do I agree with you. We've got to help pinpoint the correct treatments quickly for all cancers and as you say, the time is when the original tumor is taken out.
I suppose until this becomes common practice, it's up to patients to demand and pay for a test which may at this time be costly, but most newbies have limited knowledge and are too worried about the diagnosis. Also until and unless you know the cancer is "invasive", how useful is it to do considering costs?
The thing is as a group, we could promote and encourage these be done???? I will ask the hospital in Mougins.
thanks
sarah

[Joan M]

Here's something in the news about the potential of biomarkers to indicate which chemos work best in which patients. It's from the European Commission.

http://cordis.europa.eu/fetch?CALLER...1802&RCN=34317

At SABCS, there was a lot of chatter about how over the last few years the Europeans are really getting it together. As I understood it from a few oncs I talked with, many more patients participate in breast cancer clinical trials than in the U.S., and scientists work more collaboratively across institutions and are more willing to link their databases.

Joan

[gdpawel]

I'd just wish they would use "fresh" live cells instead of formalin-fixed paraffin-embedded tissue. These proliferating populations of cells are biologically distinct in their behavior from "fresh" live cells that comprise human tumors.

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 NCI spent years trying to find patterns which correlated using NCI's various established cell-lines. They thought they had something, but when they started to apply them to fresh tumor specimens, none of the results in the cell-lines was applicable to the fresh tumors.

[Rich66]

The main focus of the project will be on ascertaining whether certain types of treatment should be administered before or after surgery.

Hmm. That seems like a whole other issue beyond genomics and markers. I mean..seems like that would concern itself with how the cells react to surgery.

[gdpawel]

When breast cancer presents as locally advanced disease, it is customarily treated with neoadjuvant (preoperative) chemotherapy, followed by definitive surgery. At the time of surgery, the specimen is assessed to determine if all visible tumor has been destroyed by chemotherapy. When this happens, it is said to be a “pathological complete response” (pCR). The pharmacogenomic predictors developed from "cell-line" studies (not fresh cells) were evaluated for their ability to predict patient pCR, using the supervised principle component regression method.

Using the CellSearch technique that quantifies circulating tumor cells, German investigators had shown that neoadjuvant chemotherapy with paclitaxel (taxol) caused a massive release of cells into the circulation, while at the same time reduced the size of the tumor. The finding helped explain the fact that complete pathologic responses do not correlate well with improvements in survival.

[Mandamoo]

I am not sure of the specifics of the testing that I have had done (I have donated tissue for research purposes) and I am awaiting the full reports but I have preliminary reports on the initial breast tumour and axillary node tissue - the key findings so far are that the cancer was/is resistant to anthracyclines and taxotere - of course two very commonly used first line and adjuvant treatments - no surprise that I metastasised. The other key finding is that I have (if that is the correct terminology) the p53 oncogene?

I asked my oncologist if the information is helpful and she said definitely and she wishes she had it earlier and we wouldn't have wasted time on treatment that was useless. The frustration will be regulations too. I am awaiting Tykerb approval (In Australia the government funds it but you need to qualify and to qualify I have to have had 3 taxotere treatments) - it has been approved after much lobbying from my oncologist who simply refused to give me a third dose just to tick a box and now with evidence that the cancer was indeed resistant to it.

I didn't get any lung tissue from the biopsy - well - lung tissue but not neoplastic tissue - i.e. they missed. I may try again after my next scans.
This is a very interesting area.
Amanda

[Rich66]

Greg,
Any idea what Amanda's (above) actual tests were? From earlier:

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?

Also "massive release of cells into the circulation" thought to happen during surgery..kindofa drawback of going after samples sometimes. Just sayin'.