Bevacizumab in HER2-negative inflammatory breast cancer

Inflammatory breast cancer (IBC) is a rare (~5%) but aggressive form of breast cancer with high metastatic potential [1]. Despite the successful introduction of neoadjuvant anthracycline/taxane-based chemotherapy, combined with neoadjuvant/adjuvant trastuzumab in case of HER2-positivity and adjuvant hormone therapy in case of hormone receptor (HR)-positivity, the 5-year survival ranges from 50 to 60% as compared to more than 85% in non-IBC. Besides its aggressiveness and frequent resistance to treatment, IBC displays other characteristics that make progresses difficult. The disease is rare and the diagnosis challenging, based on clinical signs including rapid (no more than 6 months) onset of breast erythema and oedema, with or without underlying palpable mass. Such features exclude IBC from mass screening, lead to frequent misdiagnosis and delayed diagnosis, and complicate the setup of IBC-specific clinical trials. However, IBC is biologically different from non-IBC [2]. Notably, IBCs are more angiogenic tumours than non-IBC, displaying higher microvessel density, and showing presence of dermal lymphovascular tumour emboli. Combined with the negative prognostic value of VEGF expression, these observations made IBC attractive for testing anti-angiogenic drugs. Based on these observations, and with the intent to continue to study IBC as a separate entity as we did previously [3, 4], we launched in 2008 the BEVERLY-1 trial, a French, multicentric, single arm, prospective phase 2 trial assessing the benefit of neoadjuvant/ adjuvant bevacizumab in patients with HER2-negative (BEVERLY-1) non-metastatic IBC. Bevacizumab is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF, approved in 2008 by the US Food and Drug Administration under an accelerated plan in combination with chemotherapy in metastatic breast cancer. During the neo-adjuvant phase, the patients received four cycles of FEC100 plus bevacizumab every three weeks, followed by four cycles of docetaxel plus bevacizumab every three weeks. Then, the surgery included total mastectomy and axillary lymph node dissection, and was followed by adjuvant radiation therapy plus 10 cycles of bevacizumab (every 3 weeks), and hormone therapy if the tumour was HR-positive. Each patient theoretically received 8 cycles of neo-adjuvant chemotherapy and 18 cycles of neo-adjuvant/adjuvant bevacizumab. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes after neo-adjuvant treatment, centrally assessed using the Sataloff classification: the regimen was regarded as efficacious if 30% or more patients had a pCR. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and analysis of circulating tumour cells and endothelial cells. BEVERLY-1 was the …