Elsevier

The Lancet Oncology

Volume 16, Issue 9, September 2015, Pages 1037-1048
The Lancet Oncology

Articles
Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial

https://doi.org/10.1016/S1470-2045(15)00041-8Get rights and content

Summary

Background

NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively.

Methods

In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c–3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2) with addition of capecitabine (825 mg/m2 oral twice daily days 1–14, 75 mg/m2 docetaxel) or with addition of gemcitabine (1000 mg/m2 days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2 and 600 mg/m2 intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408.

Findings

Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0–5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49–0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63–1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3–4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]).

Interpretation

The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent.

Funding

National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

Introduction

The National Surgical Adjuvant Breast and Bowel Project (NSABP; now part of NRG Oncology), undertook the B-40 trial with primary objectives of determining whether the addition of the gemcitabine or capecitabine, and the addition of bevacizumab to standard neoadjuvant chemotherapy would increase the proportion of women with operable breast cancer achieving a pathological complete response1 (the trial's primary endpoint). We reported previously that addition of neoadjuvant bevacizumab increased the proportion of women achieving pathological complete responses, particularly for hormone-receptor-positive tumours.1 Neoadjuvant chemotherapy is now used not only for locally advanced disease but also for earlier-stage cancers.2, 3, 4, 5 Increases in the proportion of women achieving pathological complete responses with new drugs in the neoadjuvant chemotherapy setting could be predictive of benefit in the adjuvant setting.4, 6, 7, 8, 9, 10, 11, 12, 13 Indeed, the US Food and Drug Administration recently established a pathway of accelerated approval of drugs for breast cancer treatment in the neoadjuvant setting based on improvements in pathological complete responses.14, 15

Research in context

Evidence before this study

This protocol was undertaken starting in 2007, before which, all relevant data from trials of adding gemcitabine, capecitabine, and bevavicizumab to chemotherapy in the metastatic, adjuvant, and neoadjuvant settings for breast cancer were reviewed using the PubMed database, personal files, and meeting presentations. However, no specific records of literature reviews were kept during the time this trial was developed during 2005–06. As noted in detail in our previous publication on the proportion of patients achieving a response, the decision to test capecitabine and gemcitabine was based on previous reports that these compounds added to taxane-based chemotherapy increased progression-free survival in patients with metastatic breast cancer. Likewise, previous trials had shown that bevacizumab added to chemotherapy increased response rates and progression-free survival in patients with advanced breast cancer. The potential benefit of addition of bevacizumab to treatment of breast cancer has also been reviewed not only by us but also by others. The previous results suggested that adding each of these compounds to chemotherapy in either adjuvant or neoadjuvant settings would increase the benefits in terms of response and patient outcomes. Those data are summarised in this paper and in the paper showing the proportion of patients achieving a response, published in 2012.

Added value of this study

The results reported here agree with the final results of neoadjuvant and adjuvant trials, which have shown that neither gemcitabine nor capecitabine improves on the efficacy of chemotherapy for early stage breast cancer. The results reported here on the effect of adding neoadjuvant and adjuvant bevacizumab, on the other hand, contradict other reports in which addition of either adjuvant or neoadjuvant bevacizumab to chemotherapy for breast cancer did not significantly improve the proportion of patients achieving a response or patient outcomes. We noted a significant increase in pathological complete response as well as disease-free survival and overall survival with bevacizumab given with neoadjuvant chemotherapy and continued postoperatively. We also noted a preferential effect in hormone-receptor-positive breast cancer, whereas others have suggested a greater benefit for triple-negative breast cancer. However, this is the only study in which bevacizumab was added to neoadjuvant chemotherapy and added to postoperative adjuvant therapy.

Implications of all the available evidence

Although it would be premature to apply the results of B-40 reported here to routine practice, there are biologically plausible explanations for the results reported here, despite the contradictory results from other trials. Based on these results in the context of other studies, we cannot recommend routine use of bevacizumab for neoadjuvant or adjuvant treatment of operable breast cancer. However, with the correlative science studies that will be done with the tumour tissue and blood collected in advance from the patients in this trial, a more refined selection of patients who might benefit most from adding bevacizumab might be possible. Moreover, additional trials could be appropriate to clarify and refine these results to obtain more actionable information about the use of bevacizumab in this setting, with possible emphasis on patients who do not achieve a pathological complete response with neoadjuvant chemotherapy plus bevacizumab.

The requirement for neovascularisation for cancer micrometastases to become clinically detectable was described more than 40 years ago,16 and is considered a hallmark of cancer.17 Prognosis in early breast cancer is inversely related to angiogenesis in the primary tumour.16, 18 Paradoxically, primary tumours can also secrete anti-angiogenic factors,19, 20, 21, 22, 23, 24 which could account for the rapid growth of metastases after removal of primary tumours in animal models.21, 22, 23, 25

In 1993, an anti-VEGF antibody was shown to reduce the density of blood vessels in tumours and to inhibit growth of tumours in mice.26 Bevacizumab is a humanised monoclonal antibody that binds VEGF isoform A and inhibits angiogenesis.27 Addition of bevacizumab to chemotherapy for breast cancer has resulted in increases in the proportion of women who achieve complete responses in the neoadjuvant setting and improved progression-free survival for women with metastatic breast cancer, but no trials have shown significant improvement in overall survival.28, 29, 30, 31, 32, 33 Unlike other studies in early breast cancer in which bevacizumab was used exclusively for either neoadjuvant or adjuvant treatment,31, 32, 33, 34, 35, 36 women in the B-40 trial randomly assigned to receive neoadjuvant bevacizumab were also to receive ten doses of adjuvant bevacizumab after surgery. Detailed rationale, methods, response rates, and toxicities have been reported previously.1 Here, we present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints, but for which data were collected prospectively.

Section snippets

Study design and participants

In this randomised controlled trial, we enrolled women aged 18 years and older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c–3, cN0, cN1, or cN2a, without metastatic disease (M0), and diagnosed by core needle biopsy. ECOG performance status of 0 or 1 and adequate cardiac, hepatic, and renal function were required. In addition to adequate baseline left ventricular function assessment and electrocardiogram,

Results

Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data collected between Oct 31, 2007, and March 27, 2014, were available for overall survival in 1186, disease-free survival in 1184, and distant recurrence-free interval in 1181 (198 in T→AC group, 195 in T plus bevacizumab →AC plus bevacizumab group, 202 in TX→AC group, 195 in TX plus bevacizumab→AC plus bevacizumab group, 190 in TG→AC group, and 201 in TG plus bevacizumab→AC plus bevacizumab group;

Discussion

Neither gemcitabine nor capecitabine added to neoadjuvant docetaxel followed by doxorubicin and cyclophosphomide had significant effect on disease-free survival or overall survival. Neoadjuvant and post-operative bevacizumab marginally increased disease-free survival overall, particularly in the hormone-receptor-positive subset. Addition of bevacizumab significantly improved overall survival for the entire cohort of women with operable HER2-negative breast cancer, particularly for those with

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