National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 1, 2010 • Volume 7 / Number 11

Cancer Research Highlights

Some Older Women Can Forgo Radiation after Breast Cancer Surgery

Women 70 years of age or older with early-stage breast cancer did not benefit from the addition of radiation therapy to breast-conserving surgery and tamoxifen, according to the findings of a phase III randomized trial released last week. The study results, presented May 20 in advance of the American Society of Clinical Oncology (ASCO) annual meeting, indicate that “death from breast cancer is a very rare event among [older] women with these small cancers,” said lead author Dr. Kevin Hughes of Massachusetts General Hospital in Boston. The trial was conducted by three NCI clinical trials cooperative groups: the Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, and Radiation Therapy Oncology Group.

Between 1994 and 1999, the researchers enrolled 636 women in the trial; 319 received tamoxifen alone after surgery, and 317 received tamoxifen plus radiation therapy. All women had early-stage, estrogen receptor (ER)-positive disease that had not spread to the lymph nodes. The researchers followed the women for a median of 10.5 years after treatment.

Although adding radiation therapy to tamoxifen reduced the chance of cancer recurrence in the same breast by 6 percent, it did not affect overall survival, breast-cancer-specific survival, cancer spread, or the need for later mastectomy due to disease recurrence. The 10-year breast-cancer-specific survival was 98 percent for women receiving tamoxifen alone and 96 percent for women receiving tamoxifen plus radiation therapy.

“Older women often have small tumors that are ER-positive, without evidence of spread to the lymph nodes. This [study] is certainly practice-affirming and may be potentially practice changing,” said Dr. Douglas Blayney, president of ASCO. “Many [older] women…elect to defer radiation therapy. This gives us some comfort as physicians in supporting that decision…and maybe it will change the recommendations we make to our patients,” he concluded.

Sorafenib Kills Malignant Glioma Cells by Blocking Vital Cell Survival Pathway

Researchers have identified a cell-signaling pathway in malignant glioma (a type of brain cancer) controlled by a protein called ATF5 that promotes cancer-cell survival. Using cell-culture experiments and mouse models, the researchers, led by Dr. Zhi Sheng from the University of Massachusetts Medical School, determined that this pathway can be blocked by the drug sorafenib (Nexavar), leading to cancer cell death, and that the addition of temozolomide—a chemotherapy drug used to treat malignant glioma—sensitizes cancer cells to sorafenib treatment.

In a study published online May 23 in Nature Medicine, the researchers used RNA-interference techniques to identify genes required for the expression of ATF5 in mouse malignant glioma cells. Treatment of these cells with sorafenib, which blocks proteins controlled by one of the identified genes, reduced the expression of ATF5 and induced cell death. These results were confirmed in a mouse model of malignant glioma, in which mice injected with cancer cells developed tumors, but mice injected with sorafenib along with the cancer cells did not develop detectable tumors.

The researchers also showed that blocking ATF5 caused cell death in various human cancer cell lines, including lines established from melanoma and prostate, lung, and ovarian cancers, in addition to malignant glioma. This cell-killing effect was also seen in human glioma stem cells, the cells that have been proposed to give rise to malignant glioma and that are extremely resistant to chemotherapy and radiation therapy.

When the researchers examined ATF5 expression in tumor samples taken from 23 patients with malignant glioma, they found that patients whose tumors expressed ATF5 had significantly shorter survival times.

In a final set of experiments, the combination of sorafenib and temozolomide synergistically killed human glioblastoma cells that expressed high levels of ATF5 and another protein in the cell-survival pathway that controls the expression of ATF5. “When combined with temozolomide, the sorafenib concentration obtainable in patients may be well above that required for an effective response,” concluded the authors.

Genome Study Profiles Aggressive Form of Breast Cancer

Preliminary results from a genome study of triple-negative breast cancers suggest that uncommon genetic variants may distinguish these aggressive tumors from more treatable forms of the disease, researchers said last month during the Biology of Genomes meeting at Cold Spring Harbor Laboratory. If confirmed, the findings could be used to create genetic signatures associated with triple-negative cancers, which disproportionately affect younger women and African Americans.

Breast cancers that test negative for the estrogen, progesterone, and HER2 receptors are called triple negative. In an effort to learn more about the genetic basis of these tumors, Dr. Christopher D. Brown and his colleagues at the University of Chicago sequenced the protein-coding genes in 15 triple-negative tumors and 11 estrogen receptor (ER)-positive tumors. In all, the study found more than 35,000 genetic variants, including many that commonly occur in the human population.

The researchers went on to identify several thousand uncommon, or rare, variants that distinguished the triple-negative tumors from ER-positive tumors. Common variants, however, did not distinguish the tumor types.

By comparing tumor tissue with each patient’s corresponding normal tissue, the researchers found that many of the uncommon variants appear to have been inherited rather than having occurred during the development of cancer. This finding suggests that it may be possible to profile a woman to assess her risk of developing this form of the disease, though such tests could be years away, noted Dr. Brown. 

“We think these initial results show promise for uncovering the genetic basis of tumor heterogeneity among these cancers, and we are validating the signature now,” he added. The work is part of a larger project to apply the tools of DNA sequencing to understudied cancers and to address clinically important questions.

Shark Cartilage Extract Ineffective Against Lung Cancer

A clinical trial to rigorously evaluate a shark cartilage extract as a cancer treatment found no benefit for patients with non-small cell lung cancer. Patients who took the extract, AE-941 or Neovastat, along with chemotherapy and radiation therapy lived no longer than patients who did not, according to a report published online May 26 in the Journal of the National Cancer Institute. Negative results from the study were first reported at the American Society of Clinical Oncology (ASCO) annual meeting in 2007.

The phase III randomized placebo-controlled clinical trial was cosponsored by NCI and the National Center for Complementary and Alternative Medicine. The study closed early because of slow patient accrual. Only 379 eligible patients were included in the final analysis. “It is, nevertheless, the largest phase III study ever conducted, to our knowledge, of a shark cartilage–derived agent, and the study outcome is unambiguous,” the researchers noted. The manufacturer of AE-941, Canadian pharmaceutical company Æterna Laboratories, worked closely with the investigators to ensure the purity of the extract used in the trial.

In a separate editorial about the study results, Dr. Jeffrey White, director of the NCI Office of Cancer Complementary and Alternative Medicine, noted, “This study was well designed and conducted and has gener­ated important and useful findings with regard to one specific product, AE-941.” Dr. White cautioned against concluding that the study “completely disproved the efficacy of shark cartilage” or other natural materials for treating cancer. “The potential value of complex mixtures of nat­ural materials in the anticancer armamentarium remains an open question for many and one that can only be answered one step at a time with high-quality research,” he wrote.