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Tests Could Predict Benefit From Cancer Drugs

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  • gpawelski
    Personalized Cancer Care Off to Slow Start

    It was hoped some day that Genomic Analyses of cancer tumors would be able to identify in advance which patients will benefit from use of cancer drugs (clinical responders). A new draft report from the Agency for Healthcare Research and Quality (AHRQ) suggests that day is still a ways off.

    The study looked at whether the presence of specific mutations in people who had breast and colon cancer and chronic myeloid leukemia determined if patients would respond to expensive new drugs commonly used to fight the diseases. Only in colon cancer did the mutation matter and in that case, while it ruled out the effectiveness of drug therapy, the relevant mutation only appears in a small percentage of cases.

    In the finding most likely to cause controversy, the AHRQ report found there was "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. A number of companies sell a $300 test that can show if women have the allegedly telltale CYP2D6 polymorphism.

    As is often the case, the 13 studies identified by the systematic review didn't contain enough data to draw definitive conclusions. "Most studies were relatively small and thus underpowered to detect what would be a plausible effect size for the modification of response to tamoxifen by a single polymorphism," the report noted.

    Numerous studies in recent years have noted that colon cancer patients with the KRAS mutation do not respond to epidermal growth factor receptor inhibitors like cetuximab (Imclone Systems/Bristol Myers Squibb's Erbitux) and panitumumab (Amgen's Vectibix). The Food and Drug Administration, the European Medicines Agency and the American Society of Clinical Oncology have issued guidelines suggesting patients with the mutation shouldn't be given the drugs.

    The AHRQ-sponsored review confirmed that finding. "Patients with KRAS mutations were less likely to experience treatment benefit, compared to patients whose tumors were wild-type for KRAS mutations," the report said. About 20 percent of patients have KRAS mutations, which generally signal a more virulent form of the disease.

    Chronic myeloid leukemia is one of the great success stories for targeted chemotherapy drugs and imatinib (Novartis' Gleevec) has been a godsend for patients with CML since it came on the market a decade ago. But resistance is growing, and at least two similar drugs are now on the market, dasatinib (Bristol-Myers' Sprycel) and nilotinib (Novartis' Tasigna).

    Some mutations of the BCR-ABL1 gene make the cancer resistant to imatinib (Gleevec), which is designed to block the action of the hyperactive tyrosine kinase receptors in people with CML. But don't look to any tests currently on the market to determine what they are. The review of 31 studies found that "the presence of any BCR-ABL1 mutation does not appear to predict differential response to treatment in CML patients treated with imatinib-, dasatinib- (Sprycel), or nilotinib- (Nilotinib) based regimens."

    Indeed, the report said there is "no evidence that presence of any BCR-ABL1 mutation can differentiate response to tyrosine kinase inhibitor therapies."

    "It is possible that pharmacogenetic (how our inherited genes affect the way we respond to drugs) testing and the subsequent use of targeted therapies will add cost without producing clinically meaningful improvements in patient outcomes," the report said.

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    There are some challenges in the development and practical use of pharmacogenomics. Many doctors now do not widely practice pharmacogenomics when treating patients since the field is still new.

    Pharmacogenetic testing is also expensive, and insurance plans may not cover the costs of available tests. Researchers are working to develop more efficient and less expensive testing methods.

    Although federal legislation has been passed that makes it illegal for companies and insurers to discriminate against people based on their genetic information, some ethical, legal, and privacy issues remain unresolved, which may affect the continued development of pharmacogenomics.

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  • gpawelski
    Tests Could Predict Benefit From Cancer Drugs

    Genomics are far too limited in scope to encompass the vagaries and complexities of human cancer biology. The human genome project will give way to the human epigenome project which will give way to the human proteome and human kinome project. The next generation of tests will be biosystematic.

    If you find one or more implicated genes in a patientís tumor cells, how do you know if they are functional; is the encoded protein actually produced? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

    Without the advantage of knowing how cancer cells will respond to a chemotherapy drug before it is administered, physicians face an unmitigated risk that the wrong chemotherapy could further weaken a patientís immune system while allowing the cancer to continue its progression. Ultimately, use of ineffective drugs during initial therapy may lead to treatment failure.

    The most effective use of cytotoxic chemotherapy is in the first-line setting. While some patients present with inherently resistant disease, it is possible that the resistance identified against one "standard" regimen may not be obtained with all regimens.

    Functional profiling has the capacity to measure genetic and epigenetic events as a real-time adjunct to static genomic and proteomic testing, by examining small clusters of cancer cells in their native state, which contains all the complex elements of tumor bio-systems found in the human body and have a major impact on clinical response.

    It can help make the right choices for patients whether at first-line therapy or thereafter by providing a snapshot of the response of tumor cells to drugs, combinations and targeted therapies.

    In a press release from Harvardís Dana-Farber Cancer Center, an oncologist announced that they are eager for this technology to be widely available to physicians and their lung cancer patients, as it can help identify those who are likely to dramatically respond and survive for extended periods of time with a relatively benign treatment.

    And what are the data which support the value of this new technology to patients? Two entirely retrospective studies, from two Harvard-affiliated hospitals, showing slightly improved response, but not improved survival, with a grand total of 26 assay/treatment correlations.

    And yet the Harvard press release reports that fully 50% of Dana Farber lung cancer patients now receive the test and Harvard has licensed it to Genzyme, a huge commercial laboratory which markets it for use in planning treatments for cancer patients, at $1,000 per test (to predict for the activity of a single drug).

    Meanwhile a different study, by a different institution and published in the New England Journal of Medicine failed to find any correlation at all between gene mutations and patient survival (N Engl J Med Volume 353:133-144, July 14, 2005, Number 2).

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  • gpawelski
    started a topic Tests Could Predict Benefit From Cancer Drugs

    Tests Could Predict Benefit From Cancer Drugs

    What if a blood test or biopsy could predict if a cancer therapy will help cure you, or only make you feel worse?

    Tests like these, based on genes, proteins or other "molecular markers" may someday do just that for people battling colon, lung and pancreatic tumors, scientists reported at a news conference Tuesday.

    "The ultimate goal is to bring personalized medicine to reality, to identify characteristics of tumors or patients where we can make a relatively dramatic impact using targeted agents," said Dr. Bruce Johnson of the Dana-Farber Cancer Institute and Harvard Medical School, in Boston.

    Johnson moderated the teleconference, sponsored by the American Society of Clinical Oncology (ASCO). The briefing focused on research being presented at the second annual meeting on Molecular Markers in Cancer, which will take place Oct. 30 through Nov. 1 in Hollywood, Fla. The meeting is co-sponsored by ASCO, the U.S. National Cancer Institute and the European Organization for Research and Treatment of Cancer.

    First up, colon cancer. Researchers pooled data from four clinical trials involving 715 patients. They confirmed that the cancer drug Vectibix (panitumumab) was only successful in treating advanced colorectal cancer in patients with the normal ("wild type") form of the KRAS gene -- not a mutated version.

    Vectibix blocks the epidermal growth factor receptor (EGFR) on cancer cells.

    The patient response rate to Vectibix was 14 percent if they carried the normal KRAS gene, but that rate sank to zero if the patient had a mutated form of the gene, said study lead author Daniel Freeman, a principal scientist in oncology research at Amgen Inc., which makes the drug.

    Progression-free survival (3.3 months versus 1.7 months) and overall survival (8.3 months versus 5.7 months) were also better in patients with the normal KRAS gene.

    This isn't the first time the KRAS gene has dictated just how well a cancer therapy might work. Just last week, researchers reported in the New England Journal of Medicine that colon cancer patients with a KRAS mutation would not respond to the drug Erbitux (cetuximab).

    "The data is quite consistent that KRAS is an important negative predictor of patients unlikely to get a benefit from EGFR antibodies," Johnson said.

    A second study discussed Tuesday focused on the predictive value of a marker for lung cancer, the No. 1 cancer killer in the United States.

    Spanish researchers found that when both blood and tumor samples from patients with metastatic non-small cell lung cancer had a mutated form of the EGFR gene, the patients had a more aggressive cancer, with less time to live -- even after taking Tarceva (erlotinib), another targeted therapy that blocks EGFR.

    It could be that more aggressive tumors lead to more mutant DNA in the blood, according to the researchers, from the Catalan Institute of Oncology in Barcelona.

    The finding has practical implications for lung cancer patients, they noted. That's because blood samples could yield the same critical information as hard-to-obtain tissue samples, circumventing the need for biopsy. In fact, about a third of patients with this type of lung cancer don't yield enough tumor tissue to analyze for the mutation, the study authors said.

    Finally, a third study looked at a particularly deadly malignancy, pancreatic cancer. Researchers found that patients whose pancreatic cancer tumors do not contain the S100A2 protein have double the life expectancy of patients whose tumors show high levels of the protein.

    Testing for the presence of the protein beforehand could help select which patients would benefit from surgery. Such surgeries are difficult to perform and available to only a minority of patients with this type of cancer.

    The protein may also provide a target for new treatments for this cancer killer, the team said.

    The goal of all three studies are tests that could pinpoint which patients will reap the biggest benefit from a particular cancer therapy, Johnson said.

    "Most of the pharmaceutical industry has been focused on making 100 percent of patients 20 percent better," he reasoned. "Today, we're talking about markers that can help 20 percent of patients get 100 percent better."