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Other highlights in the May 19 JNCI

Journal of the National Cancer Institute

Two Studies Examine Safe Three Agent Combination Therapy for HER2-Positive Advanced Breast Cancer

Combinations of docetaxel, cisplatin or carboplatin, and the monoclonal antibody trastuzumab are feasible for the treatment of patients with HER2-positive advanced breast cancer in which tumor response rates are high, according to two new studies.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in the tumors of 20-30% of breast cancer patients and is associated with an increased risk of relapse and death in patients with early-stage breast cancer. In earlier clinical trials, adding trastuzumab, which blocks the effects of HER2, to standard chemotherapy increased both the response rate of patients and survival, but an unacceptable number of patients experienced cardiac dysfunction, including congestive heart disease.

In the first of two studies designed to find safer chemotherapy combinations that include trastuzumab, Mark D. Pegram, M.D., of the University of California, Los Angeles, and colleagues characterized the interactions between trastuzumab and nine chemotherapy drugs commonly used in treating breast cancer in four cell lines that overexpress HER2. They found synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine, which indicated that these were reasonable combinations to test in human clinical trials.

In the second study, a second group of researchers also led by Pegram, conducted two phase II clinical trials to evaluate the combination of docetaxel and trastuzumab with either of two platinum salts, cisplatin or carboplatin. In each trial, the combinations were tested on 62 women with advanced breast cancer that overexpressed HER2. Both combinations had a similar toxicity to docetaxel plus platinum salts alone, and there was a low incidence of cardiac dysfunction. In addition, overall response rates were higher. The combinations are now being tested in two randomized phase III clinical trials.

In an editorial, George W. Sledge, Jr., M.D., of the Indiana University School of Medicine in Indianapolis, reviews the two articles and comments on this style of translational research. "Designing a sequential series of experiments, both laboratory and clinical, that lead intentionally to proof-of-concept adjuvant trials is all too rare. But, as Pegram et al. remind us, it is not impossible," he writes.

Contact: Kim Irwin, Media Relations, Women's Cancer Program Area, UCLA's Jonsson Cancer Center, 310-206-2805,

Multiple Sclerosis and Hodgkin Lymphoma Appear to Cluster Together in Families, Study Shows

New evidence that multiple sclerosis and young-adult-onset Hodgkin lymphoma cluster together in families supports a decades-old theory that the diseases share similar causes.

Multiple sclerosis and Hodgkin lymphoma share some characteristics: they often have an onset in young adulthood, they both have been associated with socioeconomic affluence, and both show evidence of clustering within families. These similarities have led some researchers to speculate that the two conditions may share environmental or physical causes.

To test whether individuals with multiple sclerosis and their families are at higher risk of Hodgkin lymphoma and vice versa, Henrik Hjalgrim, M.D., of the Statens Serum Institut in Copenhagen, Denmark, and colleagues examined Danish population registers to find people with the conditions and their first-degree family members. They found that family members of people with multiple sclerosis had an increased risk of developing young-adult-onset Hodgkin lymphoma and family members of people with Hodgkin lymphoma had an increased risk of developing multiple sclerosis.

The clustering of these two conditions within families is consistent with the hypothesis that they may have a common origin.

Contact: Henrik Hjalgrim, Statens Serum Institut, +45 3268 3961,

Study Identifies Melanoma Risks

A melanoma-predisposing gene, the number and type of moles on a person's skin, and sensitivity to ultraviolet (UV) light are risk factors for melanoma in families with and without a history of melanoma, according to a new study.

The few family studies that have explored the joint effects of genetic, environmental, and host factors--such as moles, hair color, eye color, skin color, and skin reaction to sun exposure--have focused on families in which melanoma is common. To look for joint effects of risk factors in people outside these families, Florence Demenais, M.D., of INSERM-Université d'Evry in Evry, France, and colleagues collected data on pigment traits, moles, and exposure and reactions to sunlight in individuals from 53 melanoma-prone families and 295 families unselected by family history. They also looked for genes that might confer a higher risk of melanoma.

A dominant gene was associated with an increased risk of melanoma in both sets of families. In melanoma-prone families, this gene was identified as CDKN2A, a gene for which mutations were already known to be associated with melanoma. The effect of the gene was enhanced by three risk factors: number of moles, sun exposure, and sunburn.

Studies such as this one may help to improve the prediction of melanoma risk in the general population and lead to the creation of better prevention and surveillance strategies, the authors suggest.

Contact: Séverine Ciancia, INSERM-Université d'Evry, 33 1 44 23 60 86,

Researchers Find Clues to Vitamin E's Anticancer Abilities

Some studies have shown that vitamin E, a mixture of tocopherols, has anticancer effects that are believed to stem from its ability to scavenge free radicals or to control tumor growth. Although these effects have not been seen in most trials of vitamin E supplements in humans, a new study provides clues to the chemical's anticancer abilities by showing that a diet that includes supplements of alpha-tocopherol, but not gamma-tocopherol, reduces two forms of genetic instability in a mouse tumor model.

H. Chaim Birnboim, M.D., of the Ottawa Regional Cancer Center in Ontario, Canada, and colleagues fed alpha-tocopherol supplement to mice injected with tumor cells, and examined the effects on the gene mutation frequency and transgene loss in tumors that developed. The tumors in mice fed the supplements had a statistically significantly decreased mutation frequency compared with tumors from mice fed no supplements. Also, transgene loss in the tumors decreased with increasing amounts of dietary alpha-tocopherol. Mutation frequency and gene loss are two types of genetic damage believed to contribute to tumor progression.

Contact: Bob Ledrew, University of Ottawa, 613-562-5800 x3154,

Also in the May 19 JNCI:
Direct Mailing of Blood Tests Increases Colorectal Cancer Screening:
Different Methods of Adjuvant Chemotherapy for Colorectal Cancer Have Similar Outcomes:


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