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Researchers Identify Proteins that Help Hepatitis C Virus Enter Liver Cells

Posted May 05 2011 10:22pm

Tool Weighs Benefits, Risks of Raloxifene or Tamoxifen to Prevent Breast Cancer

Researchers have developed a benefit-risk index to help guide decisions on whether postmenopausal women at increased risk of developing breast cancer should take raloxifene or tamoxifen to reduce that risk. Although studies have shown that these drugs can reduce breast cancer risk , the drugs can also cause adverse side effects, so women and their physicians must decide whether the potential benefits of one or the other drug outweigh the risks in each patient’s particular situation.

The results of the benefit-risk analysis, reported online May 2 in the Journal of Clinical Oncology, showed that the risks and benefits of taking raloxifene or tamoxifen depend on a woman’s age, race/ethnicity, projected 5-year breast cancer risk, and whether she has had a hysterectomy . Overall, the analysis showed that raloxifene is better than tamoxifen for reducing breast cancer risk in women with a uterus. For women who have had a hysterectomy, the benefit-risk profiles for raloxifene and tamoxifen are similar.

Dr. Worta McCaskill-Stevens of NCI’s Division of Cancer Prevention , Dr. Andrew Freedman of NCI’s Division of Cancer Control and Population Sciences , and their colleagues used data from the Women’s Health Initiative, SEER , and two large clinical trials—the Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) trial—that evaluated the ability of tamoxifen and raloxifene to prevent invasive breast cancer (IBC) in women at high risk for the disease. They considered non-breast cancer health outcomes, including bone fractures, blood clots, stroke, and endometrial cancer , rates of which were potentially increased or decreased by raloxifene or tamoxifen.

The researchers then assigned a weight to each possible health outcome, and to IBC and in situ breast cancer, and calculated the probability that a woman with various risk factors would have each outcome in 5 years with and without raloxifene or tamoxifen. They used these calculations to create color-coded tables for each drug that show, for each age group and 5-year projected risk of IBC, whether there is strong or moderate evidence that the benefits outweigh the risks or that the risks outweigh the benefits. The researchers created separate tables for white non-Hispanic, black, and Hispanic postmenopausal women 50 years of age or older, with and without a uterus.

“By using NCI’s Breast Cancer Risk Assessment Tool (BRCAT) to estimate the projected 5-year risk of IBC, a health care provider can obtain a benefit-risk index from the corresponding table entries,” the study authors wrote. “By combining this information with information on clinical features and personal preferences, the health care provider and patient can make an informed decision.”

In an accompanying editorial, Drs. Eitan Amir and Pamela J. Goodwin, of the University of Toronto, described some limitations of the analysis but noted: “[This new tool is] the most comprehensive attempt to date to individualize chemoprevention by enabling clinicians to select tamoxifen or raloxifene for patients on the basis of a number of key patient attributes. This is a clear step forward for breast cancer prevention and may ultimately lead to improvement in uptake of chemoprevention strategies.”

Intensity-Modulated Radiation Therapy Use for Breast Cancer Influenced by Reimbursement

A new study finds that intensity-modulated radiation therapy (IMRT) use for breast cancer is five times higher in regions where Medicare covers the technique than in regions where Medicare does not cover the technique. The study , published online April 29 in the Journal of the National Cancer Institute, also found that IMRT use was 36 percent higher for women treated at private radiation clinics than in hospital-based outpatient clinics and that regional differences in reimbursement policies appear to strongly influence the use of IMRT. 

Because other 3-dimensional radiation planning methods that are less expensive than IMRT but likely as effective are available, the study authors suggest that Medicare reimbursement options for breast radiation therapy be expanded to allow the use of these less-expensive radiation planning methods.

Between 2001 and 2005, the number of Medicare claims for IMRT for breast cancer rose from 0.9 percent to 11.2 percent of overall radiation therapy claims. The increased use of IMRT contributed to a 26 percent increase in the cost of radiation therapy for breast cancer during the time period studied, reported researchers led by Dr. Benjamin D. Smith of the University of Texas M. D. Anderson Cancer Center.

Dr. Smith and his colleagues used the linked SEER-Medicare database to collect data on 26,163 women 66 years of age and older treated with surgery and adjuvant radiation therapy for nonmetastatic breast cancer.
The mean cost of radiation therapy given in the first year after diagnosis was $7,170 for women who did not receive IMRT and $15,230 for women who received IMRT. Costs related to radiation therapy accounted for 33 percent of total medical care costs for women who did not receive IMRT and 52 percent of costs for those who received IMRT.

Because the characteristics of patients’ tumors were not strongly associated with whether IMRT was used, whereas allowed reimbursement was associated with IMRT use, the study results “would appear to confirm the suspicion…that medical decision making is too heavily influenced by reimbursement rather than medical necessity,” wrote Drs. Lisa A. Kachnic and Simon N. Powell of the Boston University Medical Center in an accompanying editorial

Whether IMRT for breast cancer is more effective at targeting cancer cells or reducing side effects than less-expensive 3-dimensional radiation techniques is still unclear. Clinical trials are needed to understand which women with breast cancer benefit the most from IMRT, they added.

Whole-Genome Sequencing Improves Cancer Diagnoses

Although whole- genome sequencing is not yet ready for routine clinical use, two studies show how the approach could improve the diagnosis and, potentially, the treatment of cancer. The reports, in the April 20 Journal of the American Medical Association, describe how researchers at Washington University School of Medicine in St. Louis and their colleagues used whole-genome sequencing to investigate the cases of two patients.

The first study focused on a 42-year-old woman who died from leukemia that was probably related to previous treatment for breast and ovarian cancers. The woman did not have a known family history of cancer, and tests for mutations in the breast cancer-associated genes BRCA1 and BRCA2 were negative. But a comparison of the genomes of her cancer cells and normal cells revealed a novel mutation in the TP53 gene that altered the function of the encoded protein. TP53 gene mutations have been implicated in a number of cancers, including some early-onset breast and ovarian cancers, as well as Li-Fraumeni syndrome .

The TP53 mutation does not appear to have been inherited from one of the patient’s parents. But because the mutation was seen in both normal and cancer cells, it had to have occurred very early in the patient’s life, possibly at conception. Thus, the mutation could have been present in her germline DNA and been passed on to her children, the researchers noted.

As specified by the study protocol , the researchers contacted the woman’s primary care physician, who then discussed the issue with the patient’s family members and encouraged them to seek genetic counseling. “Even though the patient died, her contribution to this study yielded new knowledge that might one day save the lives of her children,” study co-author Dan Koboldt of the Genome Institute at Washington University wrote in a post about the studies on his blog, MassGenomics.

The second study involved a 39-year-old woman with a form of acute myeloid leukemia (AML). A comparison of DNA from her tumor and normal cells revealed a fusion of two genes in her blood cells that was not detected through routine cytogenetic testing. The presence of this gene fusion is associated with good outcomes after chemotherapy. Consequently, the patient’s doctors recommended chemotherapy rather than stem cell transplantation, the treatment that had been indicated by the standard diagnostic testing results.

At the time of publication, the woman had been in remission for 15 months. The sequencing, analysis, and validation of the fusion gene were completed in just 7 weeks, which was quick enough that doctors could use the information to choose the most effective treatment for the patient, the researchers noted.

“These cases of personalized genomic medicine are just some of the first examples of what will likely be commonplace in the near future,” wrote the authors of an accompanying editorial .

“Clearly, the technology will no longer be the major impediment to widespread clinical use of these tools, and the main challenges will soon move to the clinical implementation and interpretation of genomic data,” the authors added.

Researchers Identify Proteins that Help Hepatitis C Virus Enter Liver Cells

Scientists have identified two proteins found on the surface of liver cells that help the hepatitis C virus (HCV) enter the cells, the first step in a viral infection that causes liver disease and increases the risk of liver cancer . Both proteins are a type of molecule called receptor tyrosine kinases. Anticancer drugs called tyrosine kinase inhibitors (TKIs) blocked the action of the identified proteins and reduced HCV infection in laboratory models of the disease, reported researchers led by Drs. Joachim Lupberger and Mirjam B. Zeisel from the University of Strasbourg in France. The results were published online April 24 in Nature Medicine.

To identify liver cell proteins that the virus exploits to gain entry, the researchers first used small inhibitory RNAs to block several kinase proteins one by one. They found that silencing the expression of two such proteins— epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2)—stopped HCV particles from entering the cells.

Two approved TKIs, erlotinib and dasatinib , inhibit EGFR and EphA2, respectively. When the researchers treated liver cells with the drugs, HCV entry was impaired. Two other TKIs that inhibit EGFR, gefitinib and lapatinib , had similar effects. In experiments testing cell-to-cell transmission of HCV, erlotinib and dasatinib stopped the virus from spreading from infected cells for up to 2 weeks (the length of the experiment).

Further studies of the cell-signaling networks controlled by EGFR and EphA2 indicated that these proteins do not appear to be necessary for HCV to bind to cells. Instead, they seem to be involved in the virus’ ability to enter the cell. When tested in a mouse model of HCV infection, erlotinib substantially reduced the level of viral infection and was well tolerated.

Chronic hepatitis infection is one of the most common causes of liver cancer, and current treatments are inadequate. Although these findings are preliminary, the authors suggest that targeting receptor tyrosine kinases may provide a new way to prevent HCV infection after exposure and to treat existing HCV infections.



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