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1190 www.thelancet.com/oncology Vol 15 October 2014

Angiogenesis is the sprouting of new blood vessels from pre-existing ones, and is considered to be a prerequisite for the growth of both primary tumours and metastases. VEGF is a crucial factor involved in angiogenesis. Suppression of VEGF signalling in preclinical models results in suppression of tumour growth. These fi ndings led to the clinical development of VEGF-targeted therapies, such as the VEGF-neutralising antibody bevacizumab. However, despite showing effi cacy in other cancer types, VEGF-targeted therapies have done less well in advanced breast cancer.1,2

The combination of bevacizumab with cytotoxic chemotherapy for advanced breast cancer has been examined as fi rst-line therapy in three phase 3 trials (E2100, AVADO, RIBBON-1) and as second-line therapy in two phase 3 trials (AVF2119, RIBBON-2). Across these studies, the addition of bevacizumab invariably increased the proportion of patients achieving a response, and a statistically signifi cant improvement in progression-free survival was noted in four studies (E2100, AVADO, RIBBON-1, and RIBBON-2).3 However, no study published in this setting so far has shown an improvement in overall survival. This absence of substantial eff ect on overall survival has made the use of bevacizumab in advanced breast cancer controversial.

One potential explanation for the absence of eff ect on survival is that bevacizumab was not given for long enough to patients with breast cancer for a survival benefi t to manifest. Preclinical data show that tumour vessels can regrow on cessation of VEGF-targeted therapy4 or that disease can rebound during treatment cessation2 suggesting that prolonged administration of these cytostatic drugs might be necessary. In support of this, administration of bevacizumab with chemotherapy beyond progression has been shown to prolong overall survival in patients with advanced colorectal

cancer compared with chemotherapy alone beyond progression.5 But, could the same hold true for advanced breast cancer?

In this issue of The Lancet Oncology, Gunter von Minckwitz and colleagues6 report the results of the phase 3 TANIA study. This study enrolled patients with HER2-negative locally recurrent or metastatic breast cancer who had received fi rst-line bevacizumab and chemotherapy, and progressed after at least 12 weeks of disease control. Patients were randomly assigned to receive either bevacizumab and chemo therapy, or to receive chemotherapy alone. After a median follow-up of about 16 months, the second-line median progression-free survival was 4·2 months for chemotherapy alone versus 6·3 months in the bevacizumab containing group (HR 0·75, [95% CI 0·61–0·93]; p=0·0068). The authors can be congratulated for showing that continued treatment with bevacizumab, after previous progression on bevacizumab, is benefi cial in terms of delaying disease progression in patients with advanced breast cancer. In this selected population of patients, most have relatively chemosensitive disease, in that they achieve a long period of fi rst-line disease control: for more than two-thirds of patients, bevacizumab, with its long half-life, was eff ectively never interrupted. However, the diff erence in progression-free survival was not paralled by a signifi cant increase in the number of patients achieving a response, and the overall survival data are immature at the time of this analysis, although no new safety signals were reported. In a study of similar design, patients with advanced breast cancer progressing during or after a bevacizumab containing regimen were randomly assigned to one of two types of chemotherapy combined with either placebo or sorafenib, another inhibitor of multiple tyrosine kinases including the VEGF receptor. This study

Bevacizumab beyond progression in breast cancer

6 Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014; 120: 968–75.

7 Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802–07.

8 Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38.

9 Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943–47.

10 Raff erty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. Bioorg Med Chem Lett 2014; 24: 2444–47.

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Comment

www.thelancet.com/oncology Vol 15 October 2014 1191

showed longer progression-free survival for patients treated with sorafenib and chemotherapy than those treated with chemotherapy alone (2·7 months vs 3·4 months; HR 0·65 [95% CI 0·45–0·95]; p=0·02), but without an eff ect on overall survival.7 What might be the mechanism of improved disease control with continued VEGF inhibition? The absence of a clear benefi t in the proportions of patients achieving overall responses both in TANIA and in the colorectal cancer trial does not suggest classical synergy.5,6

However, and importantly, in the absence of mature overall survival data for the TANIA trial, interpretation of the clinical signifi cance of the fi ndings is diffi cult. Four mature phase 3 trials that assessed bevacizumab in advanced breast cancer also reported an extension in progression-free survival when bevacizumab was added to chemotherapy and yet no studies have shown an extension in overall survival.3 As in other studies, relations between the proportion of patients achieving a response, progression-free survival, and overall survival in patients with advanced breast cancer are unclear. Moreover, even in a large randomised trial assessing bevacizumab beyond progression in advanced colorectal cancer, the survival benefi t aff orded by bevacizumab beyond progression, albeit statistically signifi cant, was only 1·4 months.5

How do we explain why a benefi t in progression-free survival can be achieved with bevacizumab in advanced breast cancer without a gain in overall survival? One possibility is that, despite suppressing tumour growth initially, anti-VEGF therapy could lead to rapid changes in the biology of metastatic breast cancer that restrict the ability of the therapy to improve survival. For example, some have proposed that anti-VEGF therapies can result in a more invasive or more aggressive disease.2 Another possibility is the existence of alternative VEGF-independent mechanisms of tumour vascularisation in breast cancer, such as vessel co-option (whereby tumours grow along existing blood vessels instead of activating angiogenesis).1,8,9 Possibly, increased tumour

aggressiveness or VEGF-independent mechanisms of tumour vascularisation could rapidly take over when the VEGF pathway is blocked in metastatic breast cancer, thus providing an escape mechanism.

In conclusion, TANIA is a positive study confi rming that further investigation of VEGF inhibition in breast cancer is warranted. However, in the absence of mature survival data, whether the benefi t in progression-free survival reported will be of clinical signifi cance is diffi cult to know. To maximise the benefi t achievable with this method of treatment, further studies are needed to address how VEGF pathway suppression changes the biology of advanced breast cancer.

*Luc Y Dirix, Andrew R ReynoldsMedical Oncology, Sint-Augustinus-University of Antwerp, Antwerp 2610, Belgium (LYD); and The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK (ARR)luc.dirix@telenet.be

We declare no competing interests.

1 Vasudev NS, AR Reynolds. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 2014; 17: 471–94.

2 Ebos JM, RS Kerbel. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 2011; 8: 210–21.

3 Dirix LY, Van Dam PA, Prove AM, Vermeulen PB. Bevacizumab in the treatment of patients with advanced breast cancer: were have we landed. Ther Adv Med Oncol 2010; 2: 331–42.

4 Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006; 116: 2610–21.

5 Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after fi rst progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013; 14: 29–37.

6 Von Minckwitz G, Puglisi F, Cortes J, et al. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after fi rst-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label randomised phase 3 trial. Lancet Oncol 2014; published online Sept 28. http://dx.doi.org/10.1016/S1470-2045(14)70439-5

7 Schwartzberg LS, Tauer KW, Hermann RC, et al. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced brerast cancer that progressed diuring or after bevacizumab. Clin Can Res 2013; 19: 2745–54.

8 Stessels F, Van den Eynden G, Van der Auwera I, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Brit J Cancer 2004; 90: 1429–36.

9 Pezzella F, Di Bacco A, Andreola S, Nicholson AG, Pastorino U, Harris AL. Angiogenesis in primary lung cancer and lung secondaries. Eur J Cancer 1996; 32A: 2494–500.