National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
December 13, 2011 • Volume 8 / Number 24

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Cancer Research Highlights

Combination Therapy Shows Promise for Treating Advanced Breast Cancer

Adding the drug everolimus (Afinitor) to exemestane helped postmenopausal women whose advanced breast cancer had stopped responding to hormonal therapy live about 4 months longer without the disease progressing than women who received exemestane alone. Findings from the trial, called BOLERO 2, were presented last week at the San Antonio Breast Cancer Symposium.

For women who received the combination therapy, the median progression-free survival was 7.4 months compared with 3.2 months for those who received exemestane alone, Dr. Gabriel Hortobagyi of the University of Texas M. D. Anderson Cancer Center reported at the symposium. These were the latest available data, updated from preliminary results presented at the European Multidisciplinary Cancer Congress in September and results published online December 7 in the New England Journal of Medicine (NEJM).

The researchers do not yet have data on whether the combination therapy improves overall survival, but they expect to have it in late 2012. In July, the randomized phase of BOLERO 2 was stopped early after an interim analysis showed an improvement in progression-free survival. The study, which was supported by Novartis, the manufacturer of Afinitor, included many participants who had previously received multiple therapies.

Everolimus inhibits a protein called mTOR, which plays a role in a signaling pathway that promotes cell growth and proliferation. Exemestane, an aromatase inhibitor, is used to treat metastatic breast cancer.

“For postmenopausal patients with hormone receptor-positive metastatic breast cancer, the addition of everolimus to exemestane markedly improves the duration of disease control,” Dr. Hortobagyi said in a statement. This benefit should be weighed against the side effects associated with everolimus, such as fatigue and oral mucositis, the study authors noted in the NEJM article.

Most Common Adult Muscular Dystrophy Linked to Increased Cancer Risk

Adults with myotonic muscular dystrophy (MMD), an inherited disorder marked by progressive muscle wasting and weakness, may be at increased risk of developing cancer, a new study suggests. A research team led by Dr. Mark H. Greene and Dr. Shahinaz M. Gadalla, both of the Clinical Genetics Branch in NCI’s Division of Cancer Epidemiology and Genetics, found that patients with MMD from two independent cohorts had a twofold higher overall risk of cancer compared with people in the general population, with the increased risk mainly accounted for by cancers of the colon, brain, endometrium, and ovary. The results were reported in the December 14 issue of JAMA.

MMD is the most common form of muscular dystrophy that begins in adulthood. There are two types of MMD, type 1 and type 2, which affect multiple body systems and are caused by mutations in different genes. The signs and symptoms of the two types overlap, although type 1 is more severe.

“The impetus for this work came from [coauthor] Dr. Richard Moxley’s clinical impression that the cancer occurrence among his MMD patients was greater than expected,” Dr. Greene noted. The question then was whether those cancers were part of the MMD syndrome or just a coincidental finding.

To address this question, the researchers linked the health records of 1,658 MMD patients from two nationwide patient registries, one in Sweden and one in Denmark, to the corresponding national cancer registry in each country. They found the same patterns of increased cancer risk in both the Swedish and Danish MMD cohorts, which “provides substantial reassurance that our observations are genuine,” the study authors wrote.

“This study is the first formal quantitative assessment of cancer risk in MMD, which previously has not been considered a cancer susceptibility disorder,” Dr. Greene said.

“We don’t yet know for sure why MMD patients are at increased risk of cancer,” added Dr. Gadalla. “It may be that some of the genetic changes that cause MMD symptoms are also responsible for the increase in cancer risk.” Further research to explore the possible mechanisms involved may provide new insights into mechanisms of carcinogenesis, she noted.

In addition to pursuing that avenue of research, Dr. Greene and his colleagues are investigating whether the cancer risk differs between patients with type 1 versus type 2 MMD, and whether the excess risk can be explained by known risk factors for cancer—questions that this study could not answer.

In the meantime, Dr. Greene said, “It’s important that clinicians be aware of this possible increased risk of cancer in MMD patients.”

Two Drugs that Hit One Target Show Efficacy against Metastatic Breast Cancer

Combining two drugs that target the HER2 protein, trastuzumab (Herceptin) and the investigational agent pertuzumab, with chemotherapy may be a new treatment option for women with HER2-positive metastatic breast cancer, according to results from a large clinical trial.

The phase III CLEOPATRA trial showed that combining both of the HER2-targeting agents with the chemotherapy drug docetaxel as an initial treatment led to a 6-month improvement in progression-free survival compared to treatment with docetaxel and trastuzumab alone. The results were presented at the San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine last week.

Targeting HER2 with two different drugs has shown promise in multiple trials, said the trial’s lead investigator, Dr. José Baselga of Harvard Medical School and the Massachusetts General Hospital, during a press briefing. “I think dual HER2 blockade is coming soon, and it will be in our daily practices.”

Although both drugs target the HER2 protein on the surface of cancer cells, they do so in different ways. Laboratory studies have indicated that the drugs may have a synergistic effect on HER2-positive tumors, which Dr. Baselga explained, are “addicted” to HER2 signaling.

More than 800 women were enrolled in the randomized trial; half received all three drugs and half received trastuzumab and docetaxel, a standard first-line treatment for women with metastatic HER2-positive breast cancer, plus a placebo. Progression-free survival was 18.5 months in the three-drug arm and 12.4 months in the two-drug plus placebo arm. More women who received the three-drug combination experienced significant shrinkage of their tumors than women who received trastuzumab, docetaxel, and the placebo, Dr. Baselga reported.

Although there is a trend toward better overall survival in women treated with pertuzumab, the trial hasn’t been running long enough to clearly determine whether the three-drug combination helps women live longer, Dr. Baselga said.

Trastuzumab has been associated with significant cardiac side effects in some women, but no  increase in such side effects was seen in women in the trial who received both HER2-targeted drugs.

Genentech, which manufactures pertuzumab and trastuzumab and funded the trial, has submitted an application to the Food and Drug Administration for approval of pertuzumab for use as an initial treatment in women with HER2-positive metastatic breast cancer.

Prostate Cancer Trials Show No Link between Androgen-Deprivation Therapy and Cardiac Deaths

Several studies have suggested that men who receive androgen-deprivation therapy (ADT) to treat prostate cancer may face an increased risk of dying from cardiovascular causes. But a new analysis of clinical trial results has found no evidence that ADT increases cardiovascular deaths among men with high-risk, nonmetastatic prostate cancer.
The findings, from a meta-analysis of eight randomized clinical trials, appeared in the December 7 issue of JAMA. Androgen-deprivation therapy, which suppresses the production of male hormones, is a mainstay of prostate cancer care. A form of ADT known as gonadotropin-releasing hormone agonist therapy has been linked to heart disease in some, but not all, studies.

Citing these studies, the Food and Drug Administration last year issued a safety warning for this class of drugs. Several medical societies have also issued a science advisory stating that there may be a relationship between ADT and cardiovascular events and death.

To explore this question further, Dr. Paul Nguyen of Dana-Farber Cancer Institute and his colleagues analyzed data on more than 4,000 participants in ADT trials. Among 2,200 men treated with ADT, there were 255 cardiovascular deaths (an overall incidence rate of 11.0 percent); among 1,941 men in the control groups, there were 252 deaths (11.2 percent).

The study also showed a benefit: Men who received ADT had a lower risk of dying from prostate cancer and other causes of death than men who did not. “Our study should be reassuring to most men with high-risk prostate cancer considering ADT,” noted Dr. Nguyen.

The main caveat of the study is that the researchers could not assess the risk of cardiac death for specific subgroups of patients, including those at highest risk for cardiovascular disease. Therefore, Dr. Nguyen said, “our study could not rule out the possibility that men with a history of cardiac disease could still be harmed by ADT.”

For men with significant underlying cardiac disease, the study authors recommend a careful examination by a cardiologist and a discussion of the risks and benefits of ADT.

Although ADT is not new, doctors are still learning about its risks and benefits, noted the authors of an accompanying editorial. Some research, for example, has suggested that ADT may shorten the time before a cardiovascular event occurs. (The current study could not address this question.)

To answer such questions, future prospective trials involving ADT should classify patients according to cardiovascular risk factors at the beginning of a study, noted the study’s senior author, Dr. Toni Choueiri of Dana-Farber Cancer Institute.

“While it is important to raise awareness of the possible cardiac side effects of ADT, it may be the case that the pendulum had swung too far away from the use of ADT, even for men with high-risk disease in whom ADT has been shown to save lives,” Dr. Choueiri wrote in an e-mail.

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