National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 6, 2009 • Volume 6 / Number 19

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Cancer Research Highlights

Hormone Therapy for Prostate Cancer May Pose Heart Risks

The largest study of its kind indicates that hormone treatments used to block the effects of testosterone on prostate tumors can increase the risk of cardiac events and cardiac death. The retrospective study reviewed the health records of more than 30,000 Swedish men and found that the risk was highest in those men taking gonadotropin-releasing hormone (GnRH) agonists, the most commonly used hormone treatment in the United States. The results were reported at the ECCO 15-ESMO 34 conference in Germany.

The researchers looked at all men with prostate cancer in Sweden who were treated with hormone therapy between 1997 and 2006 and assessed their incidence of cardiac problems for 3 years after receiving the hormone treatment. The majority of patients received either GnRH agonists (which reduce testosterone production) or GnRH agonists plus anti-androgen drugs (which block testosterone from attaching to prostate cells). The remaining patients received anti-androgen therapy or orchiectomy (removal of the testicles).

According to study author Ms. Mieke Van Hemelrijck, treatment with any hormone therapy was associated with a 24 percent increase in the risk of a nonfatal heart attack and a 28 percent increase in risk of a fatal heart attack. The risks of heart failure, arrhythmia (irregular heart beat), and ischemic heart disease also increased, as did the risk of death from these cardiac problems. The lowest risk was associated with anti-androgen therapy, whereas GnRH agonists were associated with the highest risk.

The findings, stated Ms. Van Hemelrijck in a news release, “may have implications for treatment choice.”

Other studies have pointed to a potential increased risk for cardiac events associated with hormone therapy, explained Dr. Eric Horwitz, a radiation oncologist at Fox Chase Cancer Center. But that finding has not been consistent, he cautioned. “It’s hard to separate out this risk from patients’ other underlying health issues,” he said. For patients with aggressive disease, hormone therapy is very effective in conjunction with other therapies including radiation therapy and surgery. “But it’s a real risk,” he said. “It’s a discussion we’re now having every day with our patients.”

Breast Cancer Trial Suspends Recruitment

An NCI-sponsored phase III clinical trial for women with high-risk breast cancer has temporarily suspended accrual while researchers study the incidence of congestive heart failure among participants. The E5103 trial is comparing bevacizumab (Avastin) combined with standard adjuvant chemotherapy versus adjuvant chemotherapy alone for women with lymph node-positive or high-risk lymph node-negative breast cancer who have undergone lumpectomy or mastectomy. As a preplanned safety measure, the investigators suspended accrual after 6 of the first 200 women enrolled in the trial developed clinical congestive heart failure. In the cases where follow-up data were available, the symptoms of congestive heart failure resolved with treatment. More than 3,300 women are currently participating in the study.

NCI and the Eastern Cooperative Oncology Group suspended recruitment of new patients on September 24. Women currently participating in the trial will be notified of these adverse events and may choose to continue receiving their assigned treatment or withdraw from the study.

High-dose Daunorubicin Benefits Younger Adults with Leukemia

In two studies published in the September 24 New England Journal of Medicine, a high dose of daunorubicin given as part of initial treatment for acute myeloid leukemia (AML) increased the rate of complete remission and, in one study, improved overall survival compared with the standard dose given in the clinic. These beneficial effects of high-dose daunorubicin appeared to be confined to patients aged 65 or younger.

One clinical trial, designed by the Eastern Cooperative Oncology Group, randomly assigned 657 patients aged 17 to 60 to either high-dose or standard-dose daunorubicin; all patients also received the drug cytarabine. If a complete remission was not observed after the first course of the drugs, patients received a second course of cytarabine and standard-dose daunorubicin.

Significantly more patients in the high-dose daunorubicin group had a complete remission compared with those in the standard-dose group (70.6 percent versus 57.3 percent). The median overall survival was 15.7 months for patients in the standard-dose group and 23.7 months for patients in the high-dose group.

The second trial, performed by several European cooperative research groups, enrolled 813 patients between ages 60 and 83. Patients were randomly assigned to receive a first course of either standard-dose or high-dose daunorubicin, along with cytarabine. All patients received a second cycle of treatment with cytarabine alone.

Significantly more patients in the high-dose daunorubicin group had a complete remission (64 percent versus 54 percent in the standard-dose group). However, unlike in the American study, the two groups did not have significant differences in survival. An analysis showed that patients aged 60 to 65 had an increase in survival with high-dose daunorubicin; however, explained the authors, “these differences could be due to chance findings,” since the trial was not designed to analyze the results by age group.

Neither trial saw an increase in serious side effects from the higher dose of daunorubicin. “The lack of an increase in toxic effects and the benefit in overall survival strongly argue for incorporating high-dose daunorubicin into the initial treatment of younger patients with AML,” concluded the authors of an accompanying editorial.

Many Survivors of Childhood Cancers Have Healthy Babies

Most people who are treated for cancer as children or adolescents and go on to have children of their own are just as likely as other parents to have healthy babies, according to two studies in the October Archives of Pediatrics & Adolescent Medicine. After examining birth records of nearly 2,400 childhood cancer survivors and 18,000 comparison subjects, female survivors overall were not more likely to have major complications during pregnancy, to have babies with birth defects, or to experience infant death compared with other women, one study found. The other study found no major differences in birth outcomes between the offspring of male childhood cancer survivors and a matched comparison group.

The results are “very reassuring,” said Dr. Eric Chow of Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, an author of both studies. “People who have childhood cancers who then go on to have children of their own should be reassured that most likely their children will be fine.”

Concerns have been raised about the potential for birth defects and complicated pregnancies as a result of treatments such as radiation and chemotherapy. And some studies suggest that the offspring of childhood cancer survivors may have more health problems than other children. The new studies did find that among female survivors of childhood cancers, there was an increased risk of infants born prematurely or with a low birth weight. While premature birth and low birth weight are not insignificant, they do not necessarily predict health problems later in life, the researchers noted.

Women who survive cancer and intend to become pregnant should alert their health care providers so they can be monitored more closely to minimize the chances and consequences of having a low birth weight or premature baby, Dr. Chow said. He also cautioned that some of the survivors in the study were treated several decades ago and that more research is needed to follow more recent survivors who may have received different treatments.

“The most important take-home message is that for childhood and adolescent cancer survivors who go on to have families, the prospect for having healthy offspring is excellent,” said Dr. Julia Rowland, director of NCI’s Office of Cancer Survivorship.

Investigational Drug Effective Against Metastatic Melanoma in Early Phase Trial

An investigational agent called PLX4032 that targets a specific genetic mutation effectively shrunk tumors in an ongoing phase I clinical trial involving patients with metastatic melanoma, U.S. researchers reported on September 23 at the ECCO 15-ESMO 34 conference in Germany. Metastatic melanoma has proven particularly resistant to most treatments, and 5-year survival rates are below 20 percent. Based on the trial results, the company that developed the drug has begun enrolling patients in a phase II trial, and a phase III clinical trial is expected to begin enrolling patients by the end of the year.

Presenting the results, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center reported that nearly two-thirds of the 22 patients for whom data were available had at least a partial response to the drug—that is, tumor shrinkage of at least 30 percent. Some patients’ tumors have regrown after initially responding to the drug, and several patients have developed nonmelanoma skin cancers, he said.

Most of the patients in the trial had previously had their disease progress after receiving other treatments, including chemotherapy and interleukin 2. All trial participants have a specific mutation in a gene called BRAF, which is mutated in approximately half of advanced melanoma cases. The data presented at the conference came from a 30-patient extension of the original phase I trial, which involved 55 patients and was intended to find the best dose to use in future trials. The patients being treated in the extension trial are all receiving the same dose of PLX4032. Overall, 20 of 22 patients have had some level of tumor shrinkage following treatment.

“Right now we are seeing dramatic responses,” Dr. Chapman said in a news release, although he stressed that it’s too early to draw conclusions about patients’ long-term outcomes. The phase II trial of PLX4032 will enroll 100 patients with metastatic melanoma whose tumors have BRAF mutations that did not respond to previous treatment, whereas the phase III trial will test the drug as a front-line therapy in previously untreated patients with the mutation.

Invasiveness of Breast Cancer Cells Linked to Two Proteins

How breast cancer cells acquire the ability to break off from a tumor and travel to other parts of the body is poorly understood, but researchers have now identified a critical player in the process. In some breast cancer cells, increased levels of a protein called 14-3-3ζ (zeta) appears to trigger a molecular cascade that leads to the loss of molecular “glue” (E-cadherin) that binds cells together, allowing the cells to break free of the main tumor and spread to other tissues.

“We have discovered a key molecular mechanism for the deadly transition of non-invasive breast cancer into invasive disease,” lead investigator Dr. Dihua Yu of the University of Texas M.D. Anderson Cancer Center said in a press release. This transition was observed in cells that produced increased levels of both 14-3-3ζ and another cancer-related protein, ErbB2/HER2, the researchers reported in the September 8 issue of Cancer Cell

Women with advanced breast cancer commonly have their levels of ErbB2/HER2 tested to determine whether they should be treated with trastuzumab (Herceptin), but little has been known about the role of this protein in early stage disease. It now appears that ErbB2/HER2 and 14-3-3ζ may cooperate in transitioning some abnormal breast cells known as ductal carcinoma in situ (DCIS) into invasive breast cancer and metastasis.

Although it may be impractical to block the activity of 14-3-3ζ because it has many roles in normal cells, it is possible that the protein could be used to identify those women with DCIS who are at high risk of progressing to invasive cancer. It may also be possible to target the pathways and partners of 14-3-3ζ, including the growth factor TGF-β, the researchers said.

“This is a seminal paper,” commented Dr. Suresh Mohla of NCI’s Division of Cancer Biology. He noted that 14-3-3ζ is overexpressed in many human epithelial cancers, and the findings therefore could potentially be relevant to lung, liver, pancreatic, ovarian, and prostate cancers.