National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 8, 2009 • Volume 6 / Number 17

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Cancer Research Highlights

Genetic Study Points to Potential Treatment for Melanoma

A survey of genetic changes in melanoma skin cancer has found that nearly one patient in five may have mutations in a gene called ERBB4. The investigators believe that these mutations contribute to cancer and may make tumors susceptible to therapies that target the mutations. One such drug, lapatinib (Tykerb), which is used to treat some breast cancers, slowed the growth of cells with ERBB4 mutations in the laboratory.

The study, in the September Nature Genetics, is part of ongoing efforts by researchers at the National Human Genome Research Institute (NHGRI) and NCI to investigate the biology of melanoma and to identify potential targets for new therapies. Dr. Steven Rosenberg, chief of surgery at NCI’s Center for Cancer Research, co-led the study and provided tissue from patients with metastatic disease.

When Dr. Yardena Samuels of NHGRI and her colleagues sequenced the family of tyrosine kinase genes in 79 samples, they found ERBB4 mutations in 19 percent of them. Tyrosine kinases are proteins that help regulate the growth of cells, and mutations in these proteins can lead to cancer. Mutant kinases interest researchers because they have been the basis of successful drugs such as imatinib (Gleevec).

Lapatinib, which targets a related gene, eradicated cells with ERBB4 mutations. “The drug specifically kills cells with these mutations, and not cells without the mutations,” noted Dr. Samuels. “This observation suggests that we have found what appears to be an Achilles' heel of a sizable share of melanomas.”

No single tyrosine-kinase inhibitor is likely to have dramatic effects for patients, cautioned Dr. Rosenberg, who will lead a planned trial to test the strategy in patients. Nonetheless, he added, “this study is an elegant example of the translation of basic science to patient care. By pursuing basic research questions, we developed the information that could lead to an important treatment for patients.”

Earlier this year, these investigators published a similar study of the family of matrix metalloproteinase (MMP) genes in melanoma. Knowledge gained from this study has informed efforts to develop therapies against tumors with MMP mutations, the researchers said.


Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic Cancer

In a clinical trial testing an experimental enzyme regimen against gemcitabine-based chemotherapy for advanced pancreatic cancer, patients receiving chemotherapy lived an average of 9.7 months longer. This trial was “among the first controlled, clinical studies to compare allopathic treatment to an alternative medicine program for a survival end point,” wrote the authors from Columbia University. The results were published August 17 in the Journal of Clinical Oncology.

The trial was opened in 1998 as a randomized controlled study, but was altered in 2001 to a controlled, observational design due to slow patient accrual. Between 1998 and 2005, the researchers enrolled 23 patients into the chemotherapy group and 32 patients into the experimental group.

Patients in the chemotherapy group received treatment on a schedule chosen by their treating physician. Patients in the experimental group followed the Gonzalez regimen, in which they received pancreatic enzyme pills and nutritional supplements, ate a strict organic diet, and underwent a detoxification program. Patients in the experimental group survived for an average of 4.3 months after beginning treatment, compared to 14 months in the chemotherapy group.

The report was “a good attempt to bring as much rigor to the analysis as was feasible, given the inability to do a randomized controlled trial,” said Dr. Jeffrey D. White, director of NCI’s Office of Cancer Complementary and Alternative Medicine. “The study used a concurrent control with identical eligibility criteria and a statistical approach to check if significant bias was allowed in by the lack of randomization. That is a good strategy for other studies having similar difficulties with randomization.”


Denosumab Keeps Bones Strong during Prostate Cancer Treatment

Treatment with the monoclonal antibody denosumab increased bone mineral density (BMD) and reduced the risk of fractures in men who received a common treatment for prostate cancer that had not spread to other parts of the body, according to the results of a large, placebo-controlled clinical trial. The findings appeared in the August 20 New England Journal of Medicine.

The Hormone Ablation Bone Loss (HALT) trial included nearly 1,500 men with nonmetastatic prostate cancer who were undergoing androgen deprivation therapy, a treatment that can increase the risk of bone fractures. The trial showed that two injections of denosumab, one every 6 months, increased BMD in the lumbar spine (the lower back) by 5.6 percent, whereas men who were randomized to receive a placebo experienced a 1 percent decrease in BMD in the same region. Denosumab also increased bone density in other areas, including the neck and hip.

“The beneficial effects in the denosumab group appeared robust, as they were found as early as 1 month after therapy was begun and were sustained for 3 years,” wrote lead investigator Dr. Matthew R. Smith of Massachusetts General Hospital and his colleagues. The rates of adverse events were similar between the two treatment groups.

Denosumab is the first drug developed that targets a molecule called RANKL, which spurs the activity of cells called osteoclasts that break down bone. It works in a different way than several other classes of drugs, including bisphosphonates, that are currently used to treat osteoporosis and bone loss.

Publication of the trial results coincided with a meeting of an FDA advisory committee to consider whether denosumab should be approved by the agency for several indications. The committee voted in favor of an approval for denosumab for the treatment of bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer but against its use for bone loss prevention, due to the potential for the small, increased risk of certain infections, including skin and urinary tract infections, seen in some clinical trials involving denosumab.

“Some patients undergoing androgen deprivation therapy may not develop enough loss of BMD to cause an increased risk of bone fracture,” explained Dr. James L. Gulley, of the Laboratory of Tumor Immunology and Biology in NCI’s Center for Cancer Research, who was a voting member on the FDA advisory committee. “And the general feeling of the committee was, until we get more safety data, let’s not recommend an indication for prevention of BMD loss,” he said.


Weight Lifting Reduces Lymphedema Symptoms after Breast Cancer

Many breast cancer survivors develop lymphedema, an uncomfortable and sometimes painful swelling in the upper arm or hand that can be debilitating and disfiguring and for which there is no cure. Contradicting past recommendations to avoid heavy lifting and repetitive movement after breast surgery, the largest randomized controlled study conducted to date has shown that slowly progressive weight lifting does not increase arm swelling and appears to be safe. The women who lifted weights improved their strength, said the authors, and had far fewer lymphedema symptoms.

The study, which appeared August 13 in the New England Journal of Medicine, was led by Dr. Kathryn H. Schmitz, an exercise physiologist and assistant professor at the Abramson Cancer Center of the University of Pennsylvania. The researchers designed the intervention to be delivered by community fitness centers such as the YMCA with the hope that the program could be widely adopted.

Half of the 141 women were randomly assigned to the weight-lifting group. These women joined a local fitness center, where trainers taught them useful exercises, supervised their progress, and monitored them for lymphedema flare ups over the course of 1 year. The women assigned to the control group maintained their current level of exercise. Control patients received significantly more treatments for lymphedema flare ups than patients who lifted weights (195 times versus 77 times).

Dr. Wendy Demark-Wahnefried from the University of Texas M.D. Anderson Cancer Center in Houston called the study “a substantial contribution to the available evidence to support weight lifting intervention…[which] provides strong reassurance regarding the safety” of supervised weight training.  She added that inclusion of “nonwhite women and women with a broad range of occupational and educational levels suggests that the study findings are highly generalizable…and may be particularly worthwhile in disadvantaged populations” that are affected the most by lymphedema.

“This study advances our understanding of lymphedema and adds a potentially important management strategy for this troubling cancer treatment effect,” said Dr. Noreen Aziz, senior program director of NCI’s Office of Cancer Survivorship. “The lymphedema measurement methodologies used by these investigators could be disseminated to practitioners involved in the care of women at risk for lymphedema so that this condition can be detected early and carefully monitored.”   


In West African Women, Majority of Breast Cancers Have a Poor Prognosis


In a study published September 1 in Cancer Epidemiology, Biomarkers and Prevention, African Americans were significantly more likely than whites to die of pancreatic cancer, even after adjusting for all known risk factors for pancreatic cancer including smoking and obesity. These data suggest that unidentified genetic risk factors, environmental exposures, or gene-environment interactions may play a role in this health disparity. “Our data do not explain what is causing these disparities, but we hope it encourages researchers to continue looking for reasons why blacks develop and die from pancreatic cancer at higher rates than whites,” stated lead author Dr. Lauren Arnold of Washington University in St. Louis in an accompanying press release.

An analysis of the distribution of breast cancer subtypes in West African women has found that the majority of tumors were triple-negative cancers, either basal-like (with gene signatures similar to normal basal cells in the breast) or unclassified subtypes. The study led by Dr. Olufunmilayo Olopade of the University of Chicago was published August 24 in the Journal of Clinical Oncology.

Different breast cancer subtypes are associated with different prognoses. Triple-negative breast cancer, which lacks both hormone receptors and HER2 proteins, has a poor prognosis and has been shown to disproportionately affect African American women.

Since West Africa “is the founder population of most African Americans,” explained the researchers, they examined tissue samples taken from 507 women with breast cancer between 1996 and 2007 in six geographic districts in West Africa.

The proportion of breast cancers that were estrogen-receptor positive (which have a good prognosis) was only 25 percent among the West African women. A group of African American women with the same age distribution as the West African cohort would be expected to have 55 percent estrogen receptor-positive tumors.

The difference in subtype distribution observed “between whites, African Americans, and indigenous Africans suggests that both environmental exposures and genetic background determine breast cancer subtypes,” concluded the authors.

In addition, the study found that not all triple-negative tumors can be classified as basal-like; there is a less aggressive unclassified subset of triple-negative tumors that lack molecular markers found in the basal-like subset. These unclassified tumors could be split into two subgroups based on whether they expressed a protein called VEGF, and these two subgroups also showed distinct patterns of tumor aggressiveness, which may have implications for treatment, the authors noted.

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