Combination treatment may improve survival of breast cancer patients with brain metastases

November 1, 2012

Adding an angiogenesis inhibitor to treatment with a HER2-inhibiting drug could improve outcomes for patients with HER2-positive breast cancer who develop brain metastases. In their report published online in PNAS Plus, Massachusetts General Hospital (MGH) investigators report the first preclinical study combining antiangiogenic and anti-HER2 drugs in an animal model of brain metastatic breast cancer.

"We have shown dramatic improvement in survival by slowing the growth of brain metastatic, HER2-amplified breast cancer," says Rakesh Jain, PhD, director of the Steele Laboratory for at MGH, Cook Professor of (Tumor Biology) at Harvard Medical School and senior author of the study. "This is particularly important because patients with this type of breast cancer have an increased risk of , which have not responded to current therapies."

A quarter of breast cancers are driven by overexpression of the growth factor HER2, making them particularly aggressive. Treatment with drugs that block the pathway controlled by HER2 – trastuzumab () and lapatinib (Tykerb) – suppresses the growth of these tumors and extends patient survival. But these patients are at increased risk of developing brain , which have resisted anti-HER2 treatment. Angiogenesis is also known to have an important role in breast cancer, and although previous studies combining chemotherapy with the antiangiogenesis drug () delayed disease progression, they have not extended overall survival.

In addition to directly blocking the HER2-controlled growth pathway, anti-HER2 drugs also contribute to suppression of tumor-associated blood vessels. Previous studies in Jain's lab suggested that the proangiogenic factor VEGF may overcome the antiangiogenic effects of anti-HER2 drugs. This observation led the researchers to investigate whether blocking the VEGF pathway would improve the results of anti-HER2 treatment. Their study used a new mouse model in which the proliferation of HER2-amplified breast cancer cells implanted into brain tissue could be monitored over time. The researchers first confirmed that, as in human patients, treatment with a single anti-HER2 drug suppressed tumor growth in breast tissue but not within the brain.

While treatment with DC101, an antibody that blocks the VEGF pathway in mice, improved survival compared with either anti-HER2 drug, combining DC101 with one anti-HER2 drugs produced even greater survival improvement, including the death of tumor cells through significant reduction in tumor-associated angiogenesis. A triple combination of DC101 with both anti-HER2 drugs had the most dramatic effects. Animals receiving a single anti-HER2 drug along with DC101 lived more than three times as long as control animals, while those receiving all three drugs lived five times as long.

Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, co-corresponding author of the PNAS Plus report, notes that a clinical trial now underway combining chemotherapy with bevacizumab in addsanti-HER2 treatment for those participants whose tumors are HER2-amplified. The results of the current MGH study suggest that investigating a triple combination may be particularly beneficial. "With targeted therapies like anti-HER2 drugs suppressing the growth of tumors outside the central nervous system, brain metastasis is becoming a more common cause of treatment failure."

Co-corresponding author Dai Fukumura, MD, PhD, of the Steele Lab adds, "A clinical trial of this sort of triple combination will be an important next step. And in the meantime, we will continue to investigate the mechanisms of resistance to the effects of both double and triple combinations." Fukumura is an associate professor of Radiation Oncology and Engelman an associate professor of Medicine at Harvard Medical School.

Explore further: New therapy for HER2-positive breast cancer developed

Related Stories

New therapy for HER2-positive breast cancer developed

July 26, 2011
Patients with HER2-positive breast cancer may soon have an alternative therapy when they develop resistance to trastuzumab, also known as Herceptin, according to a laboratory finding published in Clinical Cancer Research.

Trastuzumab and chemotherapy improved survival in HER2-postive breast and brain cancer patients

July 18, 2011
The use of trastuzumab, chemotherapy and surgery among women with HER2-positive metastatic breast cancer significantly improved survival from the time central nervous system metastases were diagnosed.

Enhancing the effectiveness of a breast cancer treatment

February 13, 2012
Breast cancers expressing the protein HER2 have a particularly poor prognosis. Treatment with trastuzumab (Herceptin) benefits some patients with HER2-positive breast cancer, but it is not as effective as had been hoped. ...

Recommended for you

Vitamin C may encourage blood cancer stem cells to die

August 17, 2017
Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone ...

Outdoor light at night linked with increased breast cancer risk in women

August 17, 2017
Women who live in areas with higher levels of outdoor light at night may be at higher risk for breast cancer than those living in areas with lower levels, according to a large long-term study from Harvard T.H. Chan School ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

Cell cycle-blocking drugs can shrink tumors by enlisting immune system in attack on cancer

August 16, 2017
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs—designed to halt cancer ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.