Future role of bevacizumab in breast cancer

In the past years, anti-angiogenic therapies have rapidly developed for many solid tumors, including breast cancer.

The first phase III trial of bevacizumab in combination with capecitabine versus capecitabine alone was conducted in 462 patients with MBC previously treated with antracycline or taxane: although the addition of bevacizumab did not improve PFS, there was an absolute increase of approximately 11% in ORR (20 vs 9%; P = 0.001) [1]. In the E2100 trial the addition of bevacizumab to first-line weekly paclitaxel resulted in doubling of both the objective RR (36.9 vs 21.2%; P < 0.0001) and median PFS (11.8 vs 5.9 months; P < 0.0001), compared with paclitaxel alone in more than 700 HER2-negative MBC patients, although there was no impact on OS [2]. These findings were corroborated by more complete analyses for regulatory purpose and confirmed by IRF. The AVADO phase III trial compared bevacizumab with placebo in combination with docetaxel as first-line chemotherapy for patients with HER2-negative locally recurrent breast cancer or MBC, showing a significant improvement in PFS (8.8 months for bevacizumab 15 mg/kg vs 8 months for docetaxel; P < 0.0001) [3]. These results have led to the development of multiple phase III trials of bevacizumab in combination with chemotherapy agents in first-line MBC, along with trials investigating the addition of bevacizumab to other anticancer therapies such as trastuzumab and endocrine agents.

To date no predictive biomarkers for benefit from bevacizumab have been identified; several ongoing trials incorporate molecular studies with the aim of targeting the correct subset of patients (such as triple-negative patients) for bevacizumab therapy.

Clinical trials are underway to evaluate the use of bevacizumab in the adjuvant and neoadjuvant setting. The BEATRICE phase III trial will assess the benefit of adding bevacizumab to standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) in triple-negative early breast cancer. The addition of bevacizumab to adjuvant chemotherapy (docetaxel/carboplatin or docetaxel–FEC) and trastuzumab will be studied in a further phase III trial (BETH) in patients with HER2-positive breast cancer. Other phase III adjuvant trials are evaluating the addition of bevacizumab to standard chemotherapy in HER2-negative and in node-positive or high-risk breast cancer.

The NSABP B-40 ongoing phase III trial will evaluate the addition of bevacizumab to either neoadjuvant docetaxel, docetaxel plus capecita-bine or docetaxel plus gemcitabine followed by doxorubicin plus cyclophosphamide in patients with operable breast cancer. The phase III GeparQuinto trial will evaluate the integration of bevacizumab, everolimus and lapatinib into current neoadjuvant regimens [4].

Bevacizumab will probably have an established role in the treatment of some subgroups of MBC and as adjuvant therapy in early breast cancer; we need to identify which subgroups of patients may specifically benefit from bevacizumab therapy.