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Also in the July 29 JNCI
Date:7/29/2008

The Same Dose of Anthracycline Is Not Safe for Everyone

Not all patients can tolerate the currently recommended cumulative dose of epirubicin. New models can help physicians calculate the epirubicin dose associated with a 5 percent risk of cardiotoxicity for individual patients.

Oncologists frequently use anthracyclines, including epirubicin and doxorubicin, to treat breast cancer patients. However, the drugs cause lasting heart problems in a substantial number of patients. To limit the problem, current treatment guidelines suggest that patients receive no more than 900 mg/m2 epirubicin over the course of their cancer care.

In the current study, Marianne Ryberg, M.D., of the University of Copenhagen and colleagues followed 1,097 patients with metastatic breast cancer who were treated in a single hospital near Copenhagen between 1983 and 2003. The researchers assessed patients' risk factors for cardiotoxicity and corrected for the risk of death from all other competing causes of death, including cancer. (The studies that have previously concluded that the upper safe limit of epirubicin is 900 mg/m2 have not generally corrected for other causes of death.) Using these data, they calculated the maximum cumulative dose of epirubicin that is associated with a 5 percent risk of developing heart disease.

Ryberg and colleagues found that patient age, predisposition to heart disease, previous chest irradiation, and prior hormonal cancer therapy were associated with an individual's risk of developing heart problems following epirubicin treatment. By contrast, the researchers found that treatment with less epirubicin, a higher tumor burden, prior chemotherapy, and older age of the patient were associated with an increased risk of death from other, non-cardiac, causes.

Based on these data, the researchers lowered the cumulative dose recommended for most patients, with maximum doses ranging from 300 mg/m2 to 900 mg/m2. "Treatment with a potentially cardiotoxic drug may often be inevitable to extend survival for a cancer patient. However, it is essential to be aware of the risk of cardiotoxicity, not only because cardiotoxicity can progress to a potentially fatal outcome if not treated but also because it lowers the quality of patient life," the authors write.

In an accompanying editorial, Dawn Hershman, M.D., and Alfred I. Neugut, M.D., Ph.D., of Columbia University Medical Center in New York write that it has been difficult to predict which patients are most likely to develop cardiotoxicity following anthracycline therapy. Neither randomized clinical trials nor studies that rely on large administrative databases are adequate for addressing the issue. Therefore, Ryberg's study is an important step to helping physicians personalize cancer care for their patients.

"If we can better predict who is at greatest risk for toxicity and who is not, we may be able to comfortably offer standard treatment to a larger percentage of the population," the editorialists write.

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Lapatinib Reduces Brain Metastases in Mouse Model of Metastatic Breast Cancer

Lapatinib reduces the number of large brain metastases in a mouse model of metastatic breast cancer, relative to untreated mice.

Symptomatic brain metastases affect between 10 and 20 percent of women with metastatic breast cancer, and the problem is particularly common for women whose tumors overexpress the HER2 protein. However, trastuzumab, an antibody that blocks the HER2 protein activity and is the standard of care for HER2-positive disease, does not cross the bloodbrain barrier. Therefore, other therapies are needed to reduce the brain metastases in patients with HER2-positive disease. Lapatinib, a small-molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR), is able to cross the bloodbrain barrier.

In the current study, Patricia Steeg, Ph.D., of the National Cancer Institute and colleagues injected mice with a breast cancer cell line that preferentially gives rise to metastases in the brain, called MDA-MB-231-BR. The researchers engineered some of the cells to overexpress the HER2 protein. Five days after the mice were injected with the cancer cells, the researchers started treating them with lapatinib or a placebo. After 24 days of therapy, the investigators measured and counted brain metastases.

Among mice injected with the HER2-overexpressing cells, those treated with lapatinib developed fewer than half of the large metastases as those that did not receive the drug. A similar reduction occurred among mice injected with the unmodified cells, although a higher dose of lapatinib was required. Lapatinib did not completely prevent the formation of brain metastases, suggesting that some of the tumor cells are resistant to the drug.

"We propose a scenario in which standard treatments such as neurosurgery and stereotactic radiosurgery are used to treat clinical metastases and currently unavailable molecular therapeutics are then used to hold the remaining micrometastases in check. One possible molecular therapeutic is lapatinib, a dual inhibitor of EGFR and HER2 kinases," the authors write

Contact: National Cancer Institute, office of media relations, ncipressofficers@mail.nih.gov, (301) 496-6641


Mitochondrial DNA Copy Number Associated with Risk of Kidney Cancer

Genetic factors were shown to influence the number of copies of mitochondrial DNA (mtDNA) in healthy cells. A lower mtDNA copy number was associated with an increased risk of renal cell cancer in a case-control study.

The degree to which mtDNA copy number is controlled genetically has been unknown. Previous studies have suggested that low mtDNA copy number may be associated with an increased risk of a variety of cancers, but researchers have not explored its possible association with kidney cancer.

In the first portion of the study, Xifeng Wu, M.D., Ph.D., of the University of Texas M. D. Anderson Cancer Center in Houston and colleagues analyzed mtDNA copy number from the peripheral blood cells of more than 300 identical and non-identical twins to estimate the influence of genetics on copy number. In the second portion of the study, the researchers analyzed mtDNA copy number from 260 renal cell cancer patients and 281 control subjects to examine the association between copy number and renal cancer risk.

The investigators estimate that genetics accounts for 65 percent of the variation in mtDNA copy number in the population. On average, renal cancer patients had a lower mtDNA copy number in peripheral blood cells than did control subjects. They also observed a statistically significant trend for increased risk of renal cell cancer with decreasing mtDNA copy number.

"To the best of our knowledge, this is the first molecular epidemiological study to evaluate mtDNA content in lymphocytes as a susceptibility biomarker for cancer," the authors write.

Contact: Robin Davidson, RDavidson@mdanderson.org, (713) 794-1731


Modified Salmonella Slows Tumor Growth

Attenuated Salmonella bacteria engineered to express the Fas ligand (FasL) accumulate in tumors and reduce their growth.

Salmonella typhimurium concentrates in tumors following intravenous injection in mice. Taking advantage of that observation, Markus Loeffler, M.D., and John Reed, M.D., Ph.D., of the Burnham Institute for Medical Research in La Jolla, Calif., engineered a genetically modified, less pathogenic strain of Salmonella to express FasL, a signaling protein that can attract neutrophils and can promote tumor cell killing by cytotoxic T cells. Although FasL is toxic when injected into the bloodstream, the authors hypothesized that Salmonella might be used to safely target this protein to tumors.

In the current study, Loeffler, Reed, and colleagues injected mice with tumors derived from mouse breast and colon cancers with attenuated FasL-expressing Salmonella.

Following the treatment, primary tumor growth was substantially inhibited in mice with either breast or colon tumors and lung metastases were reduced in the mice with breast cancer. The anti-cancer effect appeared dependent on the presence of inflammatory cells called neutrophils.

Although toxicology and other studies are needed before the approach can be tested in human clinical trials, "these results from murine cancer models suggest that FasL-expressing [Salmonella] could offer an acceptable strategy for employing FasL and possibly other toxic cytokines for cancer therapy," the authors conclude.

Contact: Andrea Moser, amoser@burnham.org, (858) 646-3146


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Contact: Liz Savage
elizabeth.savage@oxfordjournals.org
301-841-1287
Journal of the National Cancer Institute
Source:Eurekalert

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