Molecular profiling helps cancer patients survive

[News]

Cancer patients can survive longer under treatments based on their individual genetic profiles, according to a nationwide study released jointly today by Phoenix-area healthcare organizations.

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[gdpawel]

In chemotherapy selection, molecular profiling examines a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response.

Functional profiling tests not only for the presence of the molecular profile but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

The goal of molecular testing is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. However, just because a gene is present, it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even Protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs.

Gene and protein testing involve the use of dead, formaldehyde preserved cells that are never exposed to chemotherapy drugs. Gene and protein tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene and protein tests cannot discriminate among the activities of different drugs within the same class. Instead, gene and protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can gene and protein tests tell us anything about drug combinations.

Functional tumor cell profiling tests living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

Gene and protein tests are better suited for ruling out "inactive" drugs than for identifying "active" drugs. When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect.

Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

Although gene and protein testing currently are limited in their reliability as clinical tools, the tests can be important in research settings such as in helping to identify rational targets for development of new anti-cancer drugs.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.

Source: Cell Function Analysis

[Jackie07]

Here's a personal story related to genetic 'profiling':

Just got the result back fromt Myriad, the genetic testing lab referred by my health service provider.

Guess what? I have a genetic 'variant' of 'uncertain significance'

'Variants of this type may or may not affect the function of th protein encoded by the gene in which it is found. Therefore, the contribution of this variant to be relative risk of breast or ovarian cancer cannot be established solely from this analysis.'

Out of the thousands of samples the company had analyzed, there were only 36 observations of this variant in unrelated families:

Predominant ancestry of individuals with the variant:

2 African (4.3%)
2 Ashkenazi (4.3%)
21 Asian (45.7%)
2 Central/Eastern European (4.3%)
4 Latin American/Caribbean (8.7%)
1 Near Eastern (2.2%)
2 None Specified (4.3%)
5 Other (10.9%)
7 Western European (15.2%)

There's a notation on the report:

*In general, variants that are observed with deleterious mutations in the same gene, and/or do not consistently track with cancer in families, are more likely to be of limited clinical significance than they are to be deleterious.

The lab is offering 'free' analysis for 1)Either parents and/or 2)Any female relatives diagnosed with invasive breast cancer before 60, and/or 3) Any relative diagnosed with ovarian cancer or male breast cancer at any age.

I am not sure if they will be able to arrange the testing for my parents (age 94 and 86 respectively) who are living overseas. Both of my parents are quite healthy - no known chronic illnesses. My Mother had treatments for non-Hodgekins lymphoma 12 years ago and has been doing well since.

But this does strike me how close our bonds are in the HER2 family. Thank you, my sisters - I would never have thought about genetic testing had I not joined this group and gained the knowledge from you. And the discovery is indeed surprising.

*ps. The company asked me to 'call them to arrange for the testing of my relatives'. But my oncologist was telling me to wait for the new geneticist who's going to be on board in August/September.

I requested for the test because the irritating feeling in my abdominal area. I wanted to get rid of my ovaries and uterus. But the CT scan showed the 2+ cm and a new .4 cm 'hepatic hemangioma' in my liver. Guess I'll wait till the geneticist is on board to dicide on my action.

Q. My new job (start June 1) provides a 20/80 PPO type of insurance and I am afraid my future consult will be costly. I don't think I can keep my COBRA with the HMO [The health insurance company/Hospital where all my operation/treatment were done] once I am eligible for the insurance from the new job (does anyone know the answer?). And I am really worried that if I used my new insurance in that way, I'd lose my new job pretty soon. [Don't tell me that I am protected - I lost every one of my full-time, 'permanent' job a little more than a year after each one of my 'serious illnesses' had been treated.

[Note on 6/24: The 'job' has already been 'lost'. 10 days into work, I was called to the personnel office to sign a form related to my Texas Rehabilitation Commission Counselor - while several others were filling out forms related to the 'Welfare to Work' program. Another week later, I was let go. Glad I saw this old posting.]

[gdpawel]

Why hasn’t there been any progress at all in drug selection through the use of molecular diagnostics and biomarkers? Simply put, they do not work! Little progress has been made in identifying which therapeutic strategies are likely to be effective for individual patients by molecular prognostic and predictive markers.

It was hoped that any patient with cancer would have their tumor biopsied and profiled. The profile would then be displayed as a unique genetic signature, which would in turn predict which therapy would most likely work. However, gene-expression signatures are not ready for prime time.

Although molecular profiling of tumors has led to the identification of gene-expression (biological activity) patterns, a new review published in the March 16, 2010 JNCI has found little evidence that any of the signatures are ready for use in the clinical setting.

Then further analyses revealed evidence that the technologies for the prediction of response in individual patients could not be reproduced. The NCI concluded, it’s absolutely premature to use these prediction models to influence the therapeutic options open to cancer patients. The genomic methodology is not ready for clinical application.

What went wrong? The simple answer is that cancer isn’t simple. Cancer dynamics are not linear. Cancer biology does not conform to the dictates of molecular biologists. Once again, we are forced to confront the realization that genotype does not equal phenotype.

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. Out 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.

Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one targeted drug after another. Our solution to this problem has been to investigate the targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that the targeting will favorably influence each patient’s outcome. Functional profiling results to date in patients with a multitude type of cancers suggest this to be a highly productive direction.