Dramatic increase in survival (7x longer) when combine antiangiogenic 2 two antiher2

[Lani]

drugs for brain metastatic her2+ breast cancer (in mice so far, but human trials beginning)

Another time they shouldn't throw out the baby with the bath water--if it turns out avastin should be the antiangiogenic drug in this combo (don't know that for sure yet) it will be another example of how they should not throw a drug away (or reverse its FDA approval) until they have looked for which subgroup it might tremendously benefit

Public release date: 1-Nov-2012

Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital


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

Adding angiogenesis inhibitor to anti-HER2 treatment significantly extends survival in mouse model

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 Tumor Biology at MGH, Cook Professor of Radiation Oncology (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 brain metastases, 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 (Herceptin) and lapatinib (Tykerb) – suppresses the growth of these tumors and extends patient survival. But these patients are at increased risk of developing brain metastases, 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 bevacizumab (Avastin) 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 breast cancer 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.

###
Co-lead authors of the PNAS Plus article are David Kodack, PhD, Euiheon Chung and Hiroshi Yamashita of the Steele Lab. Additional co-author are Joao Incio, MD, Annique Duyverman, Yuhui Huang, PhD, Eleanor Ager, PhD, Walid Kamoun, Shom Goel, MBBS, Matija Snuderl, MD, Alisha Lussiez, Lotte Hiddingh and Sidra Mahmood, Steele Lab; Youngchul Song and April Eichler, MD, MGH Cancer Center; Christian Farrar, PhD, MGH Martinos Center for Biomedical Imaging, and Bakhos Tannous, PhD, MGH Neurology. Support for the study includes grants from the National Cancer Institute and a Breast Cancer Research Innovator Award from the Department of Defense

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."



Copyright ©2012 by AAAS, the science society.

[DeenaH]

This is very interesting. I don't have brain mets, but a month ago I was on the brink of death due to lymphangetic spread and micro tumor emboli along with dehydration. My doctor didn't think I had a week, so he began me on avastin with herceptin, tykerb and abraxane. I was on oxygen 24/7 for 2 months, and I am now off of it. My breathing is improving everyday. The other doctors on my team are dumbfounded by my improvement. In my research about this type of spread, it often goes hand in hand with VEGF and angiogenisis, which is why we added avastin. I sure hope they can get this combo into trials and reinstate avastin for BC soon! I know Hope Rugo was interviewed about this and mentioned not throwing the baby out with the bath water re avastin. I think they may be looking at testing people for VEGF and then seeing if those who test pos respond to avastin.

[Pray]

Deenha, Now thats what I call kicking some cancer fanny! You are one strong woman! Gods blessings to you! I am amazed! Please know that you are in my prayers. You signify HOPE. Thank you so much for posting. I'm so in awe of your strength and courage. You make me feel like anyone of us can take on anything that gets in our way. Your a wonderful woman. I feel so blessed to have you here.

Your friend,

Nancy

[Mandamoo]

Wow DeenaH good on you and your team! Yes, let's see some personalised medicine here.

['lizbeth]

Deena,

I am so excited for you! You are a total miracle! Love it.

[Jean]

Deenha,
So thrilled to read your post. That was a winning combination for you.

Continued Blessing ...
Jean

[Lani]

more:

Combination treatment may improve survival of breast cancer patients with brain metastases
[Eureka News Service]

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 Tumor Biology at MGH, Cook Professor of Radiation Oncology (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 brain metastases, 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 (Herceptin) and lapatinib (Tykerb) - suppresses the growth of these tumors and extends patient survival. But these patients are at increased risk of developing brain metastases, 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 bevacizumab (Avastin) 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 breast cancer 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.

Co-lead authors of the PNAS Plus article are David Kodack, PhD, Euiheon Chung and Hiroshi Yamashita of the Steele Lab. Additional co-author are Joao Incio, MD, Annique Duyverman, Yuhui Huang, PhD, Eleanor Ager, PhD, Walid Kamoun, Shom Goel, MBBS, Matija Snuderl, MD, Alisha Lussiez, Lotte Hiddingh and Sidra Mahmood, Steele Lab; Youngchul Song and April Eichler, MD, MGH Cancer Center; Christian Farrar, PhD, MGH Martinos Center for Biomedical Imaging, and Bakhos Tannous, PhD, MGH Neurology. Support for the study includes grants from the National Cancer Institute and a Breast Cancer Research Innovator Award from the Department of Defense.

OPEN ACCESS: Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases
[Proceedings of the National Academy of Sciences]

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.

[DeenaH]

Just g saw my doctor and had treatment today. He said I am getting better and better. He said by thanksgiving I should be feeling like a normal person! I didn't know that was possible after how sick I was. He also said he has never seen anyone as sick as I was 6 weeks ago get better like I have. I credit avastin.