Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): An open-label, single-arm phase 2 study

Institut Curie, Paris, France.
The Lancet Oncology (Impact Factor: 24.69). 02/2012; 13(4):375-84. DOI: 10.1016/S1470-2045(12)70049-9
Source: PubMed


Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer; however, few data exist for this regimen in inflammatory breast cancer. In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer.
In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥ 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with, number NCT00717405.
Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure.
Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed.
Roche (France).

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Available from: Joseph Gligorov, Dec 16, 2014
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    • "The IJB dataset included CellSearch® images from women with non-metastatic (M0) and metastatic (M1) breast cancer treated according to the standard of care in Belgium [17]. The IC dataset consisted of CellSearch® images from women with inflammatory M0 breast cancer participating in the BEVERLY-I and -II phase-2 trials [25,26]. The UH dataset included CellSearch® images from women receiving neoadjuvant chemotherapy in the GeparQuattro and GeparQuinto studies (M0 cohort) [16,27] and women from the Detect Study (M1 cohort) [18]. "
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    ABSTRACT: Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch(R) system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. CellSearch(R) images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (kappa) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median kappa of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and >=3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median kappa of 0.74 (range 0.25 to 0.90). The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required.
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    • "Other clinical trials have been conducted to evaluate the effect of addition of bevacizumab to standard therapies in different subsets of patients such as HER2-positive breast cancers in the AVEREL trial (21) or the BEVERLY-2 study (22). Most of these studies have reported limited clinical benefit even though the combination regimen has shown to be well tolerated. "
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    Japanese Journal of Clinical Oncology 01/2014; 44(3). DOI:10.1093/jjco/hyt201 · 2.02 Impact Factor
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    • "Only one Grade ≥3 AE was regarded as related to bevacizumab (hypertension). Based on these results, the use of combination therapy with bevacizumab appears effective and well tolerated among patients with previously untreated inflammatory BC (Pierga et al. 2012). "
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    ABSTRACT: Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, is an effective and well-tolerated treatment option for patients with breast cancer. Bevacizumab has demonstrated a gain in progression-free survival and a trend towards an overall survival benefit in various subgroups of breast cancer. Given the lack of a predictive biomarker, we performed a literature search with regard to efficacy and tolerability of bevacizumab in different subgroups of breast cancer patients and in different settings. In the metastatic setting, the efficacy of bevacizumab has been most extensively studied and demonstrated in patients with triple-negative breast cancer, the most difficult-to-treat population among patients with advanced disease and also the group with the biggest need for new treatment options. Overall, bevacizumab is well tolerated with very few serious adverse events. Bevacizumab is also an active and feasible treatment option for patients above 70 years of age.
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