More information than they know what to do with
 

Story from today's NYT:

http://www.nytimes.com/2011/07/08/he...r=1&ref=health

How Bright Promise in Cancer Testing Fell Apart

By Gina Kolata

When Juliet Jacobs found out she had lung cancer, she was terrified, but realized that her hope lay in getting the best treatment medicine could offer. So she got a second opinion, then a third. In February of 2010, she ended up at Duke University, where she entered a research study whose promise seemed stunning.

Doctors would assess her tumor cells, looking for gene patterns that would determine which drugs would best attack her particular cancer. She would not waste precious time with ineffective drugs or trial-and-error treatment. The Duke program — considered a breakthrough at the time — was the first fruit of the new genomics, a way of letting a cancer cell’s own genes reveal the cancer’s weaknesses.

But the research at Duke turned out to be wrong. Its gene-based tests proved worthless, and the research behind them was discredited. Ms. Jacobs died a few months after treatment, and her husband and other patients’ relatives are suing Duke.

The episode is a stark illustration of serious problems in a field in which the medical community has placed great hope: using patterns from large groups of genes or other molecules to improve the detection and treatment of cancer. Companies have been formed and products have been introduced that claim to use genetics in this way, but assertions have turned out to be unfounded. While researchers agree there is great promise in this science, it has yet to yield many reliable methods for diagnosing cancer or identifying the best treatment.

Instead, as patients and their doctors try to make critical decisions about serious illnesses, they may be getting worthless information that is based on bad science. The scientific world is concerned enough that two prominent groups, the National Cancer Institute and the Institute of Medicine, have begun examining the Duke case; they hope to find new ways to evaluate claims based on emerging and complex analyses of patterns of genes and other molecules.

So far, the Food and Drug Administration “has generally not enforced” its regulation of tests created by individual labs because, until recently, such tests were relatively simple and relied heavily on the expertise of a particular doctor, said Erica Jefferson, a spokeswoman for the agency. But now, with labs offering more complex tests on a large scale, the F.D.A. is taking a new look at enforcement.

Dr. Scott Ramsey, director of cancer outcomes research at the Fred Hutchison Cancer Center in Seattle, says there is already “a mini-gold rush” of companies trying to market tests based on the new techniques, at a time when good science has not caught up with the financial push. “That’s the scariest part of all,” Dr. Ramsey said.

Doctors say the heart of the problem is the intricacy of the analyses in this emerging field and the difficulty in finding errors. Even well-respected scientists often “oversee a machine they do not understand and cannot supervise directly” because each segment of the research requires different areas of expertise, said Dr. Lajos Pusztai, a breast cancer researcher at M. D. Anderson Cancer Center at the University of Texas. As a senior scientist, he added, “It’s true for me, too.”

The Duke case came right after two other claims that gave medical researchers pause. Like the Duke case, they used complex analyses to detect patterns of genes or cell proteins. But these were tests that were supposed to find ovarian cancer in patients’ blood. One, OvaSure, was developed by a Yale scientist, Dr. Gil G. Mor, licensed by the university and sold to patients before it was found to be useless.

The other, OvaCheck, was developed by a company, Correlogic, with contributions from scientists from the National Cancer Institute and the Food and Drug Administration. Major commercial labs licensed it and were about to start using it before two statisticians from M. D. Anderson discovered and publicized its faults.

The Duke saga began when a prestigious journal, Nature Medicine, published a paper on Nov. 6, 2006, by Dr. Anil Potti, a cancer researcher at Duke University Medical Center; Joseph R. Nevins, a senior scientist there; and their colleagues. They wrote about genomic tests they developed that looked at the molecular traits of a cancerous tumor and figured out which chemotherapy would work best.

Other groups of cancer researchers had been trying to do the same thing.

“Our group was despondent to get beaten out,” said Dr. John Minna, a lung cancer researcher at the University of Texas Southwestern Medical Center. But Dr. Minna rallied; at the very least, he thought, he would make use of this incredible discovery to select drugs for lung cancer patients.

First, though, he asked two statisticians at M. D. Anderson, Keith Baggerly and Kevin Coombes, to check the work. Several other doctors approached them with the same request.

Dr. Baggerly and Dr. Coombes found errors almost immediately. Some seemed careless — moving a row or a column over by one in a giant spreadsheet — while others seemed inexplicable. The Duke team shrugged them off as “clerical errors.”

And the Duke researchers continued to publish papers on their genomic signatures in prestigious journals. Meanwhile, they started three trials using the work to decide which drugs to give patients.

Dr. Baggerly and Dr. Coombes tried to sound an alarm. They got the attention of the National Cancer Institute, whose own investigators wanted to use the Duke system in a clinical trial but were dissuaded by the criticisms. Finally, they published their analysis in The Annals of Applied Statistics, a journal that medical scientists rarely read.

The situation finally grabbed the cancer world’s attention last July, not because of the efforts of Dr. Baggerly and Dr. Coombes, but because a trade publication, The Cancer Letter, reported that the lead researcher, Dr. Potti, had falsified parts of his résumé. He claimed, among other things, that he had been a Rhodes scholar.

“It took that to make people sit up and take notice,” said Dr. Steven Goodman, professor of oncology, pediatrics, epidemiology and biostatistics at Johns Hopkins University.

In the end, four gene signature papers were retracted. Duke shut down three trials using the results. Dr. Potti resigned from Duke. He declined to be interviewed for this article. His collaborator and mentor, Dr. Nevins, no longer directs one of Duke’s genomics centers.

The cancer world is reeling.

The Duke researchers had even set up a company — now disbanded — and planned to sell their test to determine cancer treatments. Duke cancer patients and their families, including Mrs. Jacobs’s husband, Walter Jacobs, say they feel angry and betrayed. And medical researchers see the story as a call to action. With such huge data sets and complicated analyses, researchers can no longer trust their hunches that a result does — or does not — make sense.

“Our intuition is pretty darn poor,” Dr. Baggerly said.

Re: More information than they know what to do with
 

Joan,
In this day and age, I am saddened to see that this stuff happens. Just imagine if all the great Cancer Centers collaborated to prevent and cure cancer. Egos and profits aside.

Kris....

How Bright Promise in Cancer Testing Fell Apart
 

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. 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.

Until such time as cancer patients are selected for therapies predicated upon their own unique biology (and not population studies), we will confront one targeted drug after another. The 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.

Personalized Cancer Cytometrics More Accurate than Molecular Gene Testing
 

Clinical Trial Finds Personalized Cancer Cytometrics More Accurate than Molecular Gene Testing

In the first head-to-head clinical trial comparing gene expression patterns with Personalized Cancer Cytometric testing (also known as “functional tumor cell profiling” or “chemosensitivity testing”), Personalized Cancer Cytometrics was found to be substantially more accurate.

In a clinical trial involving ovarian cancer patients, patterns of gene expression identified through molecular gene testing were compared with results of Personalized Cancer Cytometric testing (in which whole, living cancer cells are exposed to candidate chemotherapy drugs). Four different genes were included in the molecular part of the study. The four genes were selected as those which researchers believe to have the greatest likelihood of accurately predicting individual patient response to specific anti-cancer drugs.

Study Results:

For two of the genes studied, there was no significant correlation between gene expression pattern and patient response. In other words, results for these genes were found to be meaningless. For the third gene studied, there was a 75% correlation between expression and patient response. This means that the gene was 75% accurate when it came to identifying an active drug for that patient. For the fourth gene studied, the accuracy in identifying an active drug was only 25%. In marked contrast, Personalized Cancer Cytometric testing was found by the researchers to be 90% accurate in identifying active drugs for ovarian cancer patients in this study.

Discussion:

Molecular testing – that is, testing for gene expression patterns – is widely studied and heavily promoted as a method to identify effective chemotherapy drugs for individual cancer patients. However, most studies of molecular testing carried-out to date show only modest correlation or no correlation between test results and actual patient response. In other words, much work remains to be done before molecular gene testing can be regarded as an accurate tool for chemotherapy selection. And yet in this, first ever, head-to-head study of test accuracy, Personalized Cancer Cytometrics was found to be highly accurate when it came to identifying effective drugs.

Comparing this study with previous studies:

Although this was the first head-to-head trial, the accuracy levels found in this trial for Personalized Cancer Cytometric testing are strikingly consistent with those documented in dozens of previous studies, published by respected cancer researchers around the world. In those studies, as in this one, extremely high levels of correlation (in other words, high levels of test accuracy) were found for Personalized Cancer Cytometrics.

Arienti et al. Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. Journal of Translational Medicine 2011, 9:94.

http://www.translational-medicine.com/content/9/1/94

The different genes that were studied in the molecular part of the above study were ERCC1, GSTP1, MGMT, XPD and BRCA1. These are putative drug resistance genes. ERCC and XPD are response elements for CDDP repair. BRCA1 is also a response element for DNA damage and part of FANC gene family (a genomic fidelity function).

GSTP1 is a detoxifying enzyme associated with thiol conjugation (alkylator resistance) while MGMT is the specific enzyme associated with the removal of temozolomide residues from DNA base pairs.

What the investigators did was to examine the "Target Now" types of targets and compare clinical responses against the results with functional analyses, establishing that when one measures the biology of the disease it provides a more robust prediction of response. The "driver" term is less operative as these genes are not causative of the disease but causative of drug resistance.

Re: More information than they know what to do with
 

Joan thank you for this interesting post: there has been an increase of publication retraction of 500% in the field of medecine inthe past 4 years compared to the previous 4 years (increase of publication of 44% only).. (reuters studies).. basically people are lying about their results to get ahead and/or to be published..who pays the price cancer patients.. something needs to be done, company are audited, results needs to be accessible.

Re: More information than they know what to do with
 

fullobeans,

Thanks for your reply. I agree, and that's why I advocate for the Department of Defense's Breast Cancer Research Program, by contacting my congressional representatives each year to continue to fund the program. One of the BCRP's hallmarks is its transparency. That is, unlike pharmaceutical companies and the like, researchers are accountable to the government and the taxpayer.

Here's more on the program:http://cdmrp.army.mil/bcrp/

See the link to congressional appropriations.

Everybody should call their representatives each year when the budget comes on the table to keep this program going.

Further, when I was at the Scripps Research Institute in California in July, several scientists said that the government's grants are the best because researchers are guaranteed funds each year for several years, whereas funds from big pharma can be easily cut off in the middle of research.

Actively support the DoD BCRP!

Joan

Re: More information than they know what to do with
 

This article discusses how using genetic testing in trials to find out which cancer drugs work early on for specific patients will cut down the length of time it takes for a drug to get to market and the cost of a drug -- in Britain, that is. The National Institute for Health and Clinical Excellence will not approve drugs that are too expensive for the return they offer (or as Fran Visco, President of the National Breast Cancer Coalition has said, breast cancer survivors have been conditioned to jump for joy if the FDA approves a drug that extends life by 4 months). The article mentions Herceptin. The ideas in the article are similar to the I-Spy trial.

Article;
http://www.guardian.co.uk/science/20...rch-golden-era

I-Spy trial
http://ncicb.nci.nih.gov/tools/trans..._research/ispy

Joan