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Combination Therapy May Help Some Patients with Advanced Breast Cancer

The 2011 European Multidisciplinary Cancer Congress meets to showcase the latest European basic, translational, and clinical studies.

A combination of two available cancer drugs could offer a new treatment option for postmenopausal women whose advanced breast cancer has stopped responding to hormonal therapy, researchers said last week at a scientific meeting in Stockholm, Sweden.

The experimental treatment is a combination of everolimus (Afinitor) and exemestane. In a phase III clinical trial, women who received the combination lived for a median of 11 months without the disease progressing, compared with about 4 months for women who received exemestane alone.

“The benefit is quite remarkable,” said lead investigator Dr. José Baselga of the Massachusetts General Hospital, who presented the findings at the European Multidisciplinary Cancer Congress. Many patients in the trial had already received multiple therapies, he noted.

In the United States, everolimus is approved for treating advanced kidney cancer and a form of pancreatic cancer. The drug inhibits a protein called mTOR, which participates in a signaling pathway that is highly active in many cancer cells and promotes cell growth and proliferation. Exemestane, an aromatase inhibitor, is used to treat metastatic breast cancer and may be effective when other aromatase inhibitors no longer work.

The combination of these drugs, Dr. Baselga noted at the European meeting, represents a new potential therapeutic option for these women. The study is “probably the most positive trial ever in metastatic estrogen receptor (ER)-positive disease,” he said in a video interview. 

In July, the trial, called BOLERO 2, was stopped after an early interim analysis of the results showed an improvement in progression-free survival for the combination therapy.

“These are impressive results,” commented Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis, who was not involved in the research.

Although there are no data on overall survival yet, Dr. Zujewski agreed that the combination therapy is a new potential option for some patients. The side effects were generally manageable, she added.

Dr. José Baselga presents trial results at the 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.

The trial included 724 patients from 24 countries. All of the participants had received the aromatase inhibitors letrozole or anastrozole, nearly half had received tamoxifen, and two-thirds had received chemotherapy.

Novartis, the trial’s sponsor, plans to seek regulatory approval this year for everolimus in treating ER-positive advanced breast cancer.

“I would be very surprised if this drug were not approved [for the new indication],” said Dr. Ruth O’Regan, director of the Translational Breast Cancer Research Program at Emory University’s Winship Cancer Institute, who also had no role in the trial.

She views the combination therapy as a potential alternative to chemotherapy for treating ER-positive advanced breast cancer when hormonal therapies have stopped working.

When resistance to hormonal therapies occurs, Dr. O’Regan explained, additional signaling pathways become activated. Unlike chemotherapy, which targets rapidly dividing cells, mTOR inhibitors are an example of the kind of treatment that may block growth-promoting signaling pathways.

Many lab studies have suggested the promise of this approach. “What’s nice about the current study is that we now have confirmation that this strategy works from a study in patients,” said Dr. O’Regan, who has led clinical trials of everolimus.

The results add to recent findings on everolimus and breast cancer. Last December at the San Antonio Breast Cancer Symposium, for instance, researchers presented positive results from a trial of everolimus plus tamoxifen for ER-positive, HER2-negative, metastatic disease.

And in 2009, Dr. Baselga and his colleagues reported that the addition of everolimus to letrozole benefited patients with newly diagnosed ER-positive breast cancer as compared with letrozole alone.

The next step is to “digest the data,” Dr. Baselga said in Stockholm. “But it would seem to me that mTOR inhibition will play a major role in all disease stages of ER-positive breast cancer.”

—Edward R. Winstead

Changing Face of Cancer in HIV-Positive Patients Requires New Approaches to Clinical Trials

The HIV virus (green) buds from a human immune cell (Image by C. Goldsmith, CDC)

In the mid-1990s, the widespread introduction of modern antiretroviral therapies changed a diagnosis of human immunodeficiency virus (HIV) infection from a rapid death sentence to a chronic condition that could be managed over decades. But as the first generation of patients receiving these therapies enters late middle age, new challenges are appearing, including a dramatic increase in the incidence of cancers that were not traditionally viewed as acquired immunodeficiency syndrome (AIDS)-associated malignancies.

Several types of cancer were seen frequently in the early years of the AIDS epidemic; three types—Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer—are called the “AIDS-defining cancers.” A diagnosis of one of these three cancers can mark the point where HIV infection has progressed to full-blown AIDS.

Researchers tracking the relationship between HIV and cancer over the decades have noticed a substantial shift in cancer epidemiology in HIV/AIDS patients. In April of this year, investigators from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) reported in the Journal of the National Cancer Institute that from 1991 to 2005, even with a quadrupling of the HIV-positive population in the United States, the number of AIDS-defining cancers diagnosed in that population had fallen by more than two-thirds.

In contrast, the number of non-AIDS-defining cancers had tripled, with the highest number of these new cases coming from anal, liver, prostate, and lung cancers and Hodgkin lymphoma. “A big part of it is that patients with HIV are getting older, and many types of cancer just become more common as people age,” said Dr. Eric Engels, senior author of the DCEG study.

“The HIV-positive population also has a lot of other risk factors for cancer, and that’s also contributing,” he added. These risk factors include co-infection with other cancer-causing viruses such as the human papillomavirus (HPV, which causes cervical, anal, oropharyngeal, and other cancers) and the hepatitis C virus (HCV, which causes liver cancer), a high rate of smoking, and possibly the long-term effects of HIV itself on the immune system.

Clinical Trials Conundrum

The increase in HIV-positive patients requiring treatment for non-AIDS-defining malignancies presents a new conundrum: how to provide the best and safest treatments when data from clinical trials are lacking for these patients. “Traditionally, HIV-positive patients were de facto excluded from NCI-sponsored clinical trials, except those targeted to AIDS-defining malignancies like Kaposi sarcoma,” said Dr. Robert Yarchoan, director of NCI’s Office of HIV and AIDS Malignancy (OHAM).

This exclusion was not based on discrimination, but rather reflected AIDS patients’ high susceptibility to drug toxicity, resulting from their profound immunodeficiency. Also, because they were at risk of death from AIDS, they would confound survival results, Dr. Yarchoan explained.

These concerns are now being reevaluated. The development of highly active antiretroviral therapy (HAART, also known as combination antiretroviral therapy) has converted HIV infection to a chronic, manageable disease in most cases, and such patients can now better tolerate chemotherapy. However, a lingering concern is the potential for unknown pharmacokinetic interactions between the antiviral treatments used to keep HIV under control and cancer chemotherapy drugs or newer biological therapies.

Five years ago, to address the changing pattern of cancers in HIV-infected patients, the NCI-sponsored AIDS Malignancy Consortium (AMC, which spun off from the National Institute of Allergy and Infectious Diseases’ AIDS Clinical Trials Group in 1995) created a new working group on non-AIDS-defining cancers. “We felt [cancer] was becoming a bigger part of the AIDS epidemic, and we needed to have a way of testing new drugs in these cancers,” said Dr. Ronald Mitsuyasu, director of the AMC and the Center for Clinical AIDS Research and Education at the University of California, Los Angeles.

The consortium has finished its first safety trial, looking at sunitinib in HIV-positive patients whose cancers have not responded to standard treatments. It has other such trials in development, testing a variety of newer treatments including vorinostat, erlotinib, and other targeted drugs. “Once we’ve defined that we can safely give a drug and how to give it, any NCI-sponsored trials of these drugs that excludes patients with HIV will be amended to allow individuals with HIV to enroll, assuming there’s no other medical reason they shouldn’t participate,” explained Dr. Richard Little, who leads HIV research in NCI’s Cancer Therapy Evaluation Program (CTEP).

“We’re trying to make physicians more comfortable with enrolling HIV patients in general oncology trials, so that [HIV status] won’t be an automatic exclusion in the future,” said Dr. Mitsuyasu. “Patients with HIV need access to these trials just as much as anyone else does.”

In a related effort, CTEP has funded the Blood and Marrow Transplant Clinical Trials Network to perform two clinical trials in HIV-positive patients, one of autologous bone marrow transplantation, and one of allogeneic transplantation. “Assuming that these studies indicate that it is feasible and safe to transplant HIV-positive patients for their underlying cancer, trials that currently exclude them based on concerns that this is not safe would be amended,” explained Dr. Little.

“I think the culture is actually changing as people are thinking more appropriately about why patients with HIV should be included or excluded,” he continued. “We’re trying to create a culture where the first idea is, yes, they should be included on a trial unless there’s a specific reason that would make that unsafe. People in the research community are being very responsive to that way of approaching patients.”

Increasing Visibility

In the early days of the AIDS epidemic, patients with HIV changed the clinical trials process in the United States, demanding rapid access to investigational drugs and encouraging community participation. Today, “people don’t volunteer like they used to,” said Dr. James Weihe, a psychiatrist who worked on the first AIDS unit at San Francisco General Hospital back in the early 1980s and now works as an advocate and community representative for the AMC.

“You saw all your friends dying around you, so people were motivated” to participate in clinical trials, he remembered. “In 1988, you walked down the street in San Francisco and you saw people with Kaposi sarcoma, you saw young people using canes and walkers and wheelchairs. You don’t see that anymore—people look healthy, and the disease has become more invisible.”

In addition, even though non-AIDS-defining cancers are becoming more common in people with HIV, “cancer is still relatively rare—people don’t know about [the risk], and they don’t necessarily talk to each other about cancer, like they would for antiviral trials,” he continued.

Since most people are referred to cancer clinical trials by their doctors, Dr. Weihe believes it is important to raise awareness among doctors about cancer trials for HIV-positive patients. “A lot of people don’t even know the AMC exists,” and outside big cities and academic centers, “a lot of doctors aren’t going to have a large HIV caseload. It’s especially important for us to work with community physicians, because that’s where most patients are going.”

Drs. Weihe and Mitsuyasu are excited about a new cancer prevention trial the AMC hopes to launch, which will look at whether anoscopy (an examination of the anal canal) and removal of abnormal tissue can prevent progression to anal cancer, similar to how the Pap smear and treatment of early cervical lesions can prevent the development of cervical cancer. (Both of those cancers are caused by HPV.) “I think the community might get more involved in this sort of trial—trying to prevent cancer,” said Dr. Weihe.

The shift from people with HIV getting cancers at an early age to them getting other cancers at a later age is evidence of the public health benefit of better treatments for HIV, concluded Dr. Yarchoan. “Instead of people dying of lymphoma (or AIDS) at the age of 30, they might possibly get lung cancer at the age of 55 or 60. They have many more years without cancer, if they develop it at all. That’s a real development that sometimes gets lost in the story,” he said.

—Sharon Reynolds