Avastin trial breast cancer

VEGF is continuously expressed throughout the development of many tumor types and is the only angiogenic factor known to be present throughout the entire tumor life cycle [ 15 ]. It is expressed in a wide range of human tumors, including breast cancer [ 16 , 17 ]. High levels of VEGF in primary breast tumor tissue were associated with poor prognosis [ 18 — 20 ]. Moreover, VEGF levels were significantly predictive of both disease-free survival DFS and overall survival OS in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy [ 21 ].

Recently, a VEGF profile that consists of 13 genes has been shown to be highly expressed in metastatic breast tumors relative to primary breast tumors or regional metastasis [ 22 ]. Overall, VEGF plays an important role in the process of angiogenesis that is associated with the growth and metastasis of breast cancer, as well as with clinical outcome of breast cancer patients.

Therefore, targeting the VEGF pathway represents a promising approach in the treatment of breast cancer. Bevacizumab is intravenously administered and has a terminal half-life of 17—21 days. Sustained inhibition of VEGF with bevacizumab results in the regression of existing tumor micro-vasculature and normalization of surviving tumor vasculature as well as inhibition in the formation of new vasculature [ 24 , 25 ].

However, withdrawal of anti-VEGF therapy has led to the rapid regrowth of tumor vasculature in preclinical models [ 26 ]. This suggests that anti-VEGF treatment should be continued until disease progression or beyond.

Bevacizumab was approved by the US FDA as first-line treatment for metastatic colorectal cancer in February [ 27 ], and subsequently as second-line treatment in June [ 28 ]. In October , the FDA approved bevacizumab, administered in combination with carbo platin and paclitaxel, for first-line treatment of patients with unresectable locally advanced, recurrent or meta-static, non-squamous, non-small-cell lung cancer [ 29 ]. This was based on a statistically significant improvement in OS in patients who received bevacizumab in combination with carboplatin plus paclitaxel compared with those who received carboplatin and paclitaxel alone.

In February , the FDA granted accelerated approval for bevacizumab in combination with paclitaxel as first-line treatment in patients with metastatic HER2-negative breast cancer [ 30 ]. Progression-free survival PFS , but not OS, was significantly improved in patients who received bevacizumab plus paclitaxel compared with those who received paclitaxel alone. Recently, in May , bevacizumab was approved for use as a single agent for patients with recurrent glioblastoma with progressive disease following prior therapy, since durable objective response rates ORRs were demonstrated from two single-arm trials, AVFg and NCI CE [ 31 , 32 ].

More recently, in July , based on significantly improved PFS by bevacizumab plus interferon versus interferon alone, bevacizumab was approved as first-line therapy in metastatic renal cell carcinoma [ ]. The first randomized Phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab in patients with metastatic breast cancer previously treated with an anthracycline and a taxane [ 33 ]. The addition of bevacizumab to capecitabine produced a significant increase in response rates That this trial did not meet its primary end point was ascribed to redundant angiogenic pathways caused by multiple angiogenic factors in patients with previously treated, highly refractory disease and this underscores the need to target VEGF-associated angiogenesis early in the disease process [ 34 ].

Of note, the results are in contrast to bevacizumab plus chemotherapy as second-line treatment in metastatic colorectal cancer, in which the addition of bevacizumab to FOLFOX4 significantly improved survival duration [ 28 ]. This raises the question of whether angiogenesis status or genomic make-up of tumors that have originated from different organ sites might be a factor in response to second-line bevacizumab plus chemotherapy. In addition, previous chemotherapy for the management of metastatic disease may have altered VEGF-associated angiogenic phenotype in metastatic breast cancer since chemotherapy agents, such as docetaxel and paclitaxel, have anti-angiogenic properties [ 35 , 36 ].

As VEGF plays an important role in tumor growth and metastasis, and limited angiogenesis pathways are active early in the metastatic disease process [ 37 ], it is compelling to target the VEGF-associated angiogenesis for initial treatment. In an open-label Phase III trial E of paclitaxel plus bevacizumab versus paclitaxel alone as first-line therapy of metastatic breast cancer, patients were randomly assigned to receive paclitaxel alone or with bevacizumab [ 30 ].

The primary end point of this trial was PFS assessed by the investigators, and OS was the secondary end point Table 1. The addition of bevacizumab significantly improved median PFS However, OS was similar in two treatment arms Nonetheless, this is a landmark study that first demonstrated benefit from the addition of bevacizumab to conventional chemotherapy in patients with metastatic breast cancer.

In this analysis, nonprotocol therapy was censored. HRs for PFS 0. Phase III trials comparing bevacizumab plus chemotherapy with chemotherapy alone in locally recurrent or metastatic breast cancer. The bevacizumab plus docetaxel trial Avastin plus Docetaxel [AVADO] has confirmed the benefit of adding bevacizumab to first-line taxane therapy for metastatic breast cancer [ 39 ].

The primary end point was PFS, and secondary end points were OS, time to treatment failure, best overall response, duration of response and safety. OS was not ready to be reported due to a short follow-up. Higher bevacizumab dose appeared to be better than the lower dose although the study was not powered to detect a difference between the two bevacizumab arms.

Patients were randomized in a ratio to receive bevacizumab plus chemotherapy or placebo plus chemotherapy Table 1. Bevacizumab was administered every 3 weeks until disease progression. The duration in median PFS gained varied from 0. These data suggest that the benefit from the addition of bevacizumab to chemotherapy is modest and consistent in unselected patients with metastatic breast cancer.

Table 2 lists some of the ongoing Phase III trials of bevacizumab in combination with chemotherapy, hormone therapy or anti-HER2 therapy. The rationale for combining bevacizumab with hormone therapy CALGB is that hormone therapy with tamoxifen or letrozole blocks the effect of estrogen on the growth of breast tumors, and bevacizumab may inhibit tumor growth through blocking blood supply to the tumor.

It is postulated that combining hormone therapy with bevacizumab may be more effective in women with hormone receptor-positive advanced breast cancer. Another promising regimen E is to combine bevacizumab plus chemotherapy with trastuzumab in the treatment of metastatic breast cancer.

Overexpression of HER2 has been shown to associate with the increased angiogenesis and expression of VEGF in tumor cells, thus promoting metastasis of tumor cells. Trastuzumab inhibits tumor cell growth and VEGF expression in preclinical studies [ 41 ]. E is testing whether first-line chemotherapy plus trastuzumab is more effective with or without bevacizumab in patients with metastatic breast cancer that overexpresses HER Anti-angiogenic therapy using bevacizumab in combination with chemotherapy versus chemotherapy alone or plus another biologic agent in early breast cancer is being evaluated in the adjuvant setting.

Table 3 lists some of the ongoing adjuvant bevacizumab-containing Phase III trials, the results of which will be available within 5 years. Of note, ABCDE is a randomized Phase III study of adjuvant bevacizumab, metronomic chemotherapy, diet and exercise in patients with pathologic residual disease in the breast or lymph nodes removed after neoadjuvant chemotherapy Table 3.

The trial is to determine if additional treatment after preoperative chemotherapy and surgery with bevacizumab and metronomic chemotherapy would reduce recurrence compared with the standard of care, by observation alone. Ongoing Phase III trials of adjuvant bevacizumab plus chemotherapy for early breast cancer.

Trials evaluating the clinical and biological activities of neoadjuvant bevacizumab in combination with chemotherapy in locally advanced and inflammatory breast cancer have shown promising results.

Together, these early neoadjuvant trials indicate that the addition of bevacizumab to chemotherapy is feasible. Ann Oncol. Lancet Oncol. Epub Aug 7. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Breast Cancer. Drug: Bevacizumab Drug: Standard adjuvant chemotherapy. Phase 3. Study Type :. Interventional Clinical Trial.

Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Experimental: Bevacizumab and Chemotherapy Participants randomized to receive bevacizumab in combination with chemotherapy as prescribed.

If you experience any of these serious side effects, your doctor will stop treatment with Avastin. Since Avastin is given with chemotherapy, you may also experience chemotherapy side effects. Create a profile for better recommendations. Breast implant illness BII is a term that some women and doctors use to refer to a wide range Sign up for emails about breast cancer news, virtual events, and more. Subscribe to our podcast for conversations on the issues that matter most.

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Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : January 6, Last Update Posted : August 2, Study Description. This single arm study will assess the efficacy and safety of preoperative treatment with Avastin combined with Herceptin-based chemotherapy in patients with primary inflammatory HER2-positive breast cancer.