National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 23, 2010 • Volume 7 / Number 4

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Cancer Research Highlights

Lower-dose Radiation Regimen for Breast Cancer Less Harmful to Quality of Life

In the United Kingdom, women who have early-stage breast cancer are often treated after surgery with hypofractionated radiation therapy, a lower-dose radiation regimen given in fewer but larger doses. According to a report published online February 5 in Lancet  Oncology, this regimen is slightly less harmful to quality of life, including a woman’s body image, than the standard dosing regimen after 5 years of follow up.

Dr. Penelope Hopwood of the Institute of Cancer Research in the United Kingdom and her colleagues reviewed data from 2,208 women enrolled in the Standardisation of Breast Radiotherapy (START) trials A and B. In the START A trial, women were randomly assigned to receive the international standard regimen—adjuvant radiation of 50 Gy given in 25 fractions over 5 weeks—or one of two hypofractionated regimens: either 39 Gy or 41.5 Gy given in 13 fractions over 5 weeks. In the START B trial, women were randomly assigned to receive the standard regimen or an even shorter hypofractionated regimen of 40 Gy in 15 fractions over 3 weeks.

The studies included women who had mastectomies and women who had breast-conserving surgery (BCS), with 78 percent in trial A and 88 percent in trial B receiving BCS. Most of the women had medium-sized breasts, had undergone dissection in the lymph nodes of the armpit, and had not received radiation to the armpit. At 6-month intervals, participants completed questionnaires to report pain, swelling, stiffness, or sensitivity in the breast, shoulder, or arm, as well as skin problems and body image. They were also photographed so that researchers could objectively assess changes in their breast and skin appearance.

Women who received lower doses of radiation (i.e., 39 Gy or 40 Gy) had better skin appearance after 5 years than those who received either of the two higher doses (41.5 Gy or 50 Gy). Patients who received hypofractionated radiation reported a quality of life after 5 years that was similar to those who had received the standard regimen. There were some differences in specific symptoms that seemed to favor the hypofractionated treatment, but these were not statistically significant.

“These ratings by patients…strengthen evidence in favour of hypofractionated regimens, with a potential for fewer adverse effects on the normal breast tissues,” the authors wrote. They noted, however, that regardless of whether the women received hypofractionated or standard adjuvant radiation, 40 percent of women still reported moderate to severe concerns about body image after 5 years and nearly one-third had significant arm and shoulder pain, underlining the need for more research into patient-reported outcomes of quality of life following surgical and radiation treatment.

Chemo-switch Plus Sorafenib Regimen Shows Promise in Advanced Kidney Cancer

Findings from a small phase II clinical trial suggest that a three-drug treatment that includes the targeted agent sorafenib (Nexavar) and two different ways of delivering chemotherapy, dubbed a “chemo-switch” regimen, has potential as a treatment for advanced renal cell cancer (RCC). Patients who received the treatment regimen had progression-free survival (survival without tumor growth) and response rates comparable to what has historically been seen with other first-line treatment options for metastatic RCC, including sunitinib (Sutent). The results were published online February 15 in Lancet Oncology.

The researchers treated patients with traditional chemotherapy—the drug gemcitabine (Gemzar) delivered at the maximum-tolerated dose—followed by metronomic chemotherapy—frequent, low doses of chemotherapy—using capecitabine (Xeloda) along with sorafenib. Both metronomic chemotherapy and sorafenib inhibit tumor blood vessel formation. Some patients continued to receive sorafenib after chemotherapy was completed.

The 40 patients in the trial, led by Dr. Joaquim Bellmunt of University Hospital del Mar-IMIM in Barcelona, had yet to receive treatment for their disease and were not candidates for treatment with either IL-2 or interferon-α, immune-stimulating treatments that are commonly used in patients with metastatic RCC.

Half of the patients experienced a partial response (tumor shrinkage of 30 percent or more) during the trial, and 17 had stable disease. The median progression-free survival in these 40 patients was 11.1 months; it was 12 months in the 34 patients for whom complete efficacy data were available. Adverse events “were mild to moderate in severity,” the researchers wrote, although seven patients halted treatment altogether because of side effects.

Despite its limitations, such as small size and nonrandomized design, the study results suggest that the approach “is worthy of further pursuit” in future trials, said Dr. Ramaprasad Srinivasan of the Urologic Oncology Branch in NCI’s Center for Cancer Research. These are the strongest results seen with sorafenib as a first-line treatment in metastatic RCC, Dr. Srinivasan noted, and “are better than might have been expected with sorafenib alone.”

Scientists Map Gains, Losses of DNA in Thousands of Tumors

Researchers have conducted a large-scale analysis of thousands of tumors to identify a particular type of genetic alteration known as DNA copy number changes. These changes occur when regions of chromosomes are duplicated inappropriately or deleted during cancer development. The new study may provide the most comprehensive view to date of the types and extent of copy number changes across cancers.

A majority of the copy number changes found in one tumor type were found in several others as well, the researchers reported in the February 18 Nature. “We have known that many cancer-causing genetic events are the same across different types of cancer, and this study expands our understanding of this phenomenon,” said lead investigator Dr. Matthew Meyerson of the Dana-Farber Cancer Institute.

The analysis included 3,100 tumors representing 26 types of cancer. More than 150 chromosome regions were found to be duplicated or missing in several cancers, including many regions that had not previously been linked to copy number changes. More work is needed to identify which DNA segments within these chromosome regions may be driving the cancer and which ones are merely present but do not contribute to the disease.

The most common copy number changes involved either relatively small segments of chromosomes (about 1.8 million units of DNA, or .03 percent of the human genome, in size) or much larger ones, the length of a chromosome arm or a whole chromosome. Certain families of genes were more commonly involved in copy number variations than others, including those that regulate cell death, such as the genes MCL1 and BCL2L1.

“We’re starting to see that copy number changes are going to be critically important for certain diseases,” said NCI Deputy Director Dr. Anna Barker. The results of large-scale genomic studies like this one are going to give researchers direction as they try to identify the changes that are most important in cancer, she added. To facilitate these efforts, the study authors have made their data available through the Web site Tumorscape.

Researchers Learn How a microRNA May Promote the Spread of Breast Cancer

A microRNA, a short RNA molecule that regulates the activity of genes, called miR-9 appears to be important in breast tumors’ ability to spread to other parts of the body and gather nutrients to survive and grow, according to a study published online February 21 in Nature Cell Biology.

Researchers from the laboratory of Dr. Robert Weinberg at the Whitehead Institute for Biomedical Research showed that, in breast cancer cell lines, miR-9 inhibits the expression of the protein E-cadherin, which helps cells adhere to one another and form tissues. The result, wrote Dr. Li Ma and colleagues, was that tumor cells underwent a transformation known as the epithelial-mesenchymal transition, or EMT, meaning they gained the ability to both migrate from their original location and invade other tissues. The researchers also found that the microRNA was activated by the well-known cancer-inducing gene MYC.

They confirmed these activity patterns in mouse models of breast cancer, showing that increasing levels of miR-9 in mice with breast tumors that normally do not spread led to large numbers of small lung tumors. Conversely, blocking miR-9 in mice carrying a breast tumor known to be particularly metastatic led to fewer metastases.

In addition to the metastasis findings, experiments in breast cancer cell lines and mouse models of breast cancer showed that miR-9 induced a cascade of events within tumor cells—including activation of the protein β-catenin—that led to the production of VEGF, a key driver of tumor blood vessel development. Tumors in mice implanted with breast cancer cells that expressed miR-9 had an abundance of blood vessels both within the tumor and at the tumor edges.

However, the research team found that blocking E-cadherin and activating β-catenin “seem to be necessary but not sufficient” for increasing VEGF activity, indicating that there are other miR-9 targets that are needed for this effect.

One such target may be α-catenin, suggested Drs. Yeesim Khew-Goodall and Gregory J. Goodall from the Center for Cancer Biology in Adelaide, Australia, in an accompanying commentary. The α-catenin protein is located near β-catenin inside cells, and α-catenin can block the β-catenin activity that leads to VEGF production.

The Australian researchers also noted that other studies have shown that miR-9 RNA is active in tumor samples from metastatic but not localized breast and liver cancers, indicating that the molecule may promote metastasis in multiple tumor types.

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