Hot Topic Report from San Antonio Breast Cancer Symposium December 2005
Will Bevacizumab (Avastin) Be An Effective Agent for the Treatment of Metastatic Breast Cancer?
Scientists are studying new agents that can be used to treat and control cancer. Bevacizumab, (Avastin), is one agent that has been found effective in extending the life of persons with metastatic colon cancer. Scientists are studying the drug for its effectiveness in fighting metastatic breast cancer as well.
Bevacizumab binds to a protein in the cell called vascular endothelial growth factor, or VEGF. VEGF is a growth factor that stimulates the development of blood vessels. When a tumor has access to blood vessels it grows. In turn, the tumor produces its own VEGF which contributes to the development of a disorganized mass of micro blood vessels in a process called angiogenesis. While angiogenesis provides the vasculature which nourishes the tumor, scientists believe that the disorganized nature of the vessels, together with the increasing interstitial pressure of the growing tumor, impedes the penetration of chemotherapy to the tumor.
Scientists have learned that bevacizumab can be used to interrupt the process of angiogenesis. When bevacizumab binds to VEGF, it inhibits new blood vessel formation. It also causes the existing microvasculature to the tumor to break down. The result is, the tumor shrinks. Scientists hypothesize that when bevacizumab disrupts this vasculature to the tumor, the tumor cannot continue growing and the interstitial pressure inside the tumor decreases. Thus, it allows for more effective penetration of the chemotherapy.
In an oral presentation, during the general session of the San Antonio Breast Cancer Symposium, lead investigator, Dr. Kathy Miller, reported on the preliminary results of A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as a first-line therapy for locally recurrent or metastatic breast cancer, (E2100). This trial was initiated a year after another phase III trial began ( capecitabine versus capecitabine plus bevacizumab for the treatment of breast cancer, November 2000 to March 2002), which failed to show an increase in progression-free survival time in the group treated with bevacizumab. However, Dr. Miller believed that, because bevacizumab had shown an initial significant response when it was used with capecitabine, that the drug was clearly active. In her estimation, the failure was tied to the fact that the patients had been heavily pretreated and their tumors had already progressed to the point where they had become resistant to therapy. She believed that if bevacizumab was administered earlier in breast cancer treatment that it would have increased impact.
This assumption led her and other researchers of the Eastern Cooperative Oncology Group to persist with trials of bevacizumab for breast cancer. Between December 2001 and May 2004, the E2100 trial enrolled patients diagnosed with recurrent (metastatic) breast cancer who had not yet been treated with chemotherapy since their re-diagnosis, and who were also HER2-negative. 722 women were randomized into one of two arms: Group A received paclitaxol (a chemotherapy agent) and Group B received paclitaxol with bevacizamab.
Side effects of bevacizumab in this study were neuropathy (nerve pain in hands and legs) (21% of patients), hypertension (13%), hyperglycemia (elevated blood sugar)
( 25%), and proteinuria (elevated protein in urine) (2%). Except in rare instances, the researchers felt that the majority of the side effects were manageable.
The E2100 trial was stopped early when preliminary results showed the primary end point had been met. Twice as many women who received bevacizumab plus paclitaxel responded to treatment than in the group of women who had received paclitaxel alone, (28.2% vs.14.2%). The length of time of progression-free survival in the group receiving bevacizumab increased from an average of 6 months to an average of 11 months. This correlated to a 50% reduction in risk of progression.
Dr. Miller’s group of researchers concluded that bevacizumab with paclitaxel improves outcomes in the treatment of breast cancer compared to treatment with paclitaxel alone, but that more time is needed with this study to assess overall survival.
Another oral presentation was given by Dr. Burstein: Metronomic chemotherapy with and without bevacizumab for advanced breast cancer: a randomized phase II study. In this study, researchers evaluated the effects of low-dose repetitive chemotherapy (given at rhythmic intervals, thus the term“metronomic”) combined with anti-angiogenesis therapy. At the time of reporting, 42 patients had enrolled in the study which had two arms. One arm was for metronomic treatment with cyclophosphamide and methotrexate and the second arm was for the same but with the addition of bevacizumab. At the planned interium analysis, enrollment to the metronomic chemotherapy alone arm was discontinued as per the designed stopping rule which called for one arm to be discontinued if the other arm was deemed more beneficial. At that point, only 9.5% of patients in the discontinued arm had responded to treatment. In the second arm which included treatment with bevaizumab, 41.2% of the women had a partial response, 41.2% had disease stabilization, and 26.5% had disease progression. While enrollment of patients to the second arm continues along with further study, Dr. Burstein’s conclusion is that “metronomic chemotherapy in combination with bevacizumab has clinical activity in advanced breast cancer.”
A much smaller study of bevacizumab was exhibited in a poster presented by Traina, Dickler, and Caravelli, titled, A phase II trial of letrozole in combination with bevacizumab, an anti-VEGF antibody, in patients with hormone receptor-positive metastatic breast cancer. This study showed that out of eleven patients, five had achieved stable disease greater than six months, four had stable disease, and two had progression. The researchers concluded that “combination letrozole and bevacizumab appears well tolerated.”
The attitude of physicians at the San Antonio Breast Cancer Symposium toward treatment with bevacizumab in metastatic breast cancer appeared to be very positive as observed during two other audience interactive seminars. The first was the presentation on the Oncotype DX Breast Cancer Assay.
The Oncotype Dx is a laboratory test that analyzes genes within a tumor to assess the aggressiveness of the cancer. The assay results in a score that predicts the likelihood of recurrence within a ten year period. In aseries of case study discussions, the audience was asked to select from a list of treatment regimens which they would chose for each case presented. Using individual hand held devices the responses were input electronically, transposed, and presented graphically in percentages shown on the screen. The assay for recurrence score for each case was then presented. This allowed us to compare whether our choice of treatment remained the same or changed due to the assay score. In this seminar it was observed that many physicians in the audience recommended using bevacizumab in appropriate cases.
In the second seminar titled, Monoclonal Antibodies in the Management of Early and Advanced Breast Cancer: Where we’ve been; where we are; where we’re headed, a panel of physicians including doctors Burstein, Leyland-Jones, Miller, Pegram, and Perez, debated a series of statements regarding treatment for breast cancer including: For most patients being treated with first-line chemotherapy for metastatic disease, the addition of bevacizumab should now be standard of care, and: In addition to paclitaxel, other agents/regimens that should currently be considered in combination with bevacizumab are vinorelbine, capecitabine and low-dose, metronomic cyclophosphamide and methotrexate.
This audience in this seminar was also asked to make selections of treatment for the various cases presented and responses were electronically presented on screen. In spite of the fact that some clinical trials of bevacizumab in combination with hormonal and or chemotherapy regimens to treat breast cancer are still underway, it appears that, in light of results of trials presented this year at ASCO and at the SABCS, physicians are taking positive note of the benefits of bevacizumab and are inclined to prescribe it.
Though bevacizumab has not yet been FDA approved for the treatment of breast cancer, some doctors are already using it. A survey printed in the 2005 issue of Patterns of Care in Medical Oncology; Management of Breast Cancer in the Adjuvant and Metastatic Setting (Vol. 2 Issue 3, figure 55) showed that 73% of the breast cancer specialists interviewed said they have already prescribed this monoclonal antibody as have 4% of general oncologists. When asked if they had not yet used it but intended to in the near future, 18% of breast cancer specialists answered yes, as did 64% of general oncologists.
To the question of: Will bevacizumab (Avastin) be an effective agent in the treatment of metastatic breast cancer? From the results of the trials presented at this conference, I believe the answer is yes. The results of studies so far look promising, however, questions remain as to how effective bevacizumab will be. For example, the study of letrozole in combination with bevacizumab was very small so we will need to look toward a phase lll trial for more conclusive evidence. As clinical trials proceed, we will learn if women with advanced Her2-positive cancer can benefit from taking Avastin with Herceptin. We will see if women who have already received chemotherapy for recurrent disease may benefit from Avastin in combination with another therapy, and we will learn more about its long term safety.
Presentation # 1 Poster Board # 3
Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, Shenkier TN, Davidson NE, Indiana University Cancer Center, Indianapolis, IN; Dana Farber Cancer Institute; Puget Sound Oncology Consortium; Memorial Sloan-Kettering Cancer Center; Rush University Medical Center; Mayo Clinic Vancouver Cancer Center, Johns Hopkins Oncology Center
Presentation # 2 Poster Board # 2030
Traina TA, Dickler MN, Caravelli, JF, Yeh BM, Brogi E, Panageas K, Flores SA, Norton L, Park J, Hudis C, Rugo H, Memorial Sloan-Kettering Cancer Center, New York, NY; University of California, San Francisco, San Francisco, CA
Presentation #1 Poster Board Number 4
Burstein HJ, Spigel D, Kindsvogel K, Parker LM, Bunnell CA, Partridge AH, Come SE, Ryan PD, Gelman R, Winer EP, Dana-Farber/Harvard Cancer Center, Boston, MA; Sarah Cannon Cancer Center, Nashville, TN
Oncotype DX Tumor Board Case Study Luncheon
Shak S, Cobleigh M, Vogel V, Oratz, R
Monoclonal Antibodies in the Management of Early and Advanced Breast Cancer: Where we’ve been; where we are; where we’re headed. A CME Satellite Symposium Held in Conjunction with the 28th San Antonio Breast Cancer Symposium, Moderator Love, N, Co-Chairman, Tripathy, D, Faculty, Burstein HJ, Leyland-Jones B, Miller KD, Pegram MD, Perez EA
Genentech Advocacy Briefing Breakfast meeting
Other Articles Referenced
Medscape Conference Coverage of the 26th Annual San Antonio Breast Cancer Conference, Dec. 3-6, 2003. “The Current Status of Targeted Therapies for Breast Cancer: An Interview With Kathy Miller, MD.”
Hugo, Hope S, “Bevacizumab in the Treatment of Breast Cancer: Rationale and Current Data,” The Oncologist, Vol. 9, suppl 1, 43-49, June 1, 2004, AlphaMed Press
Miller, K.D. et al, “Avastin Combined with Taxol Slows Advanced Breast Cancer,” American Society of Clinical Oncology Annual Meeting, May 2005, Latebreaking session, www.breastcancer.org/r_0505d.html
Patterns of Care in Medical Oncology, Management of Breast Cancer in the Adjuvant and Metastatic Settings, Vol. 2, Issue 3, 2005, p. 41.
The above article was submitted to Alamo Breast Cancer Foundation Patient Advocacy Program
by Diane Lane Chambers
Hearing the Stream, A Survivor's Journey into the Sisterhood of Breast Cancer
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