Elsevier

The Lancet Oncology

Volume 13, Issue 4, April 2012, Pages 375-384
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(12)70049-9Get rights and content

Summary

Background

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.

Methods

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 ClinicalTrials.gov, number NCT00717405.

Findings

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.

Interpretation

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.

Funding

Roche (France).

Introduction

Inflammatory breast cancer is a very aggressive form of locally advanced breast cancer, and accounts for up to 5% of all cases.1 Such cancer is characterised by the clinical appearance of inflammation with oedema (termed peau d'orange) and redness of the skin.2 Typically, inflammatory breast cancer is diagnosed in young women, who are more likely to have metastasis than are those with other types of breast cancer.3 Multimodal treatment regimens—including endocrine treatment, chemotherapy, surgery, and radiotherapy—and neoadjuvant approaches have greatly improved the prognosis for inflammatory breast cancer,4 resulting in a 5-year survival of about 40%.5 However, women with this cancer have worse prognosis than do those with non-inflammatory locally advanced breast cancer.1

Overexpression of HER2 occurs in 15–25% of patients with breast cancer.6 HER2 positivity is generally associated with aggressive disease; however, introduction of the humanised monoclonal antibody trastuzumab, which targets HER2, has improved outcomes in metastatic breast cancer and early disease.7, 8 Combination of trastuzumab with various chemotherapy regimens for the neoadjuvant treatment of locally advanced breast cancer, including inflammatory breast cancer, has also been assessed in several clinical studies.9, 10, 11, 12, 13 A substudy of the NOAH trial9 assessed response to standard chemotherapy in 76 women with inflammatory breast cancer, 62 of whom had HER2-positive disease. Trastuzumab was coadministered with chemotherapy in 31 patients with HER2-positive disease, 54·8% of whom achieved a pathological complete response (pCR), compared with 19·3% of those with HER2-positive disease who received chemotherapy alone.10

Inflammatory breast cancer is characterised pathologically by high vascularity and increased microvessel density because of high expression of angiogenic factors (eg, VEGF).3 VEGF is a key mediator of angiogenesis and is involved in endothelial and tumour cell growth and motility and blood vessel permeability.14 Inflammatory breast cancer's vascular nature probably makes it especially amenable to anti-angiogenic treatment. Use of bevacizumab, a VEGF-targeting monoclonal antibody, resulted in substantially improved progression-free survival and response in patients with advanced breast cancer in four randomised phase 3 trials15, 16, 17, 18 and showed neoadjuvant activity in a pilot study in patients with previously untreated locally advanced breast cancer or inflammatory breast cancer.19

Combination of bevacizumab and trastuzumab for treatment of advanced or HER2-positive metastatic breast cancer has been assessed in two trials.20, 21 First, an open-label, phase 1 dose-escalation trial20 of three doses of bevacizumab in combination with trastuzumab noted preliminary clinical responses in five (56%) of nine patients and two other patients developed stable disease. The combination of bevacizumab and trastuzumab was well tolerated with no reported grade 3–4 adverse events. After this encouraging outcome, a phase-2 study21 was done in 37 women with advanced HER2-positive breast cancer. Patients received trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) and bevacizumab at the recommended phase 2 dose (10 mg/kg every 2 weeks). The overall response rate was 54·1% (20 of 37 patients), with one patient achieving a complete response and 19 achieving partial responses; 11 patients (29·7%) had a best response of stable disease. Grade 3–4 drug-related adverse events included dyspnoea, left ventricular dysfunction, hypertension, and proteinuria.

We undertook this phase 2 study on the basis of previous results with trastuzumab plus chemotherapy, the reported activity of bevacizumab in inflammatory breast cancer, and the efficacy of bevacizumab plus trastuzumab in advanced and metastatic disease. We aimed to assess the efficacy and safety of preoperative treatment with bevacizumab, trastuzumab, and chemotherapy in patients with primary inflammatory HER2-positive breast cancer. We also assessed the potential of circulating tumour cells and circulating endothelial cells as efficacy biomarkers, since circulating tumour cell positivity has been shown to be an independent prognostic factor in patients with non-metastatic breast cancer receiving either adjuvant22 or neoadjuvant chemotherapy,23 and both circulating tumour and circulating endothelial cells have been reported as efficacy biomarkers in patients with metastatic breast cancer receiving antiangiogenic therapy plus chemotherapy.24, 25

Section snippets

Study design and patients

In our phase 2, multicentre, open-label, non-randomised, Simon (two-stage), single-arm, non-comparative trial, we enrolled women (aged ≥18 years) who had histologically confirmed breast cancer and confirmed inflammatory breast cancer. Inflammatory breast cancer was defined as T4d (any N), stage II (inflammation, erythema, and/or oedema localised to <50% of the breast surface), or stage III (generalised inflammation and oedema on >50% of the breast surface) by Institut Gustave-Roussy

Results

Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients with HER2-positive inflammatory breast cancer at 21 private or public oncology centres in France. Table 1 summarises baseline characteristics. 11 (21%) of 52 patients had a cutaneous biopsy, four of whom had lymphatic emboli in the superficial derma. Although the eligibility criteria for this trial allowed for the inclusion of patients solely on the basis of presence of tumour emboli within the vasculature of the superficial derma,

Discussion

In the BEVERLY-2 study, we showed that bevacizumab plus fluorouracil, epirubicin, and cyclophosphamide, followed by docetaxel and trastuzumab, is an active treatment regimen in HER2-positive inflammatory breast cancer (panel). Conventionally, patients with inflammatory breast cancer are less likely to respond to treatment and have a poorer prognosis than are those with other breast cancers. However, advances have been made in the treatment of patients with inflammatory cancer in the past 15

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