Introduction
Locally advanced breast cancer (LABC) was historically defined as cancers that were inoperable, T4 and/or advanced regional nodal disease at presentation, and had poor survival outcomes with locoregional therapy alone. However, the definition has expanded to include potentially operable tumors greater than 5 cm [
1‐
3]. Inflammatory breast cancer (IBC) characterized by diffuse erythema or edema of the affected breast, with or without histologically confirmed involvement of the dermal lymphatics, is a highly aggressive form of LABC that has poor prognosis, with 10-year disease-free survival rates reported at 20–25 % [
4]. Few randomized studies have targeted LABC and/or IBC and most large adjuvant and neoadjuvant trials exclude these patients. Anthracycline- and taxane-based neoadjuvant chemotherapy represents the standard of care for LABC. Pathologic complete response (pCR), commonly defined as the absence of residual invasive cancer in both the breast and axillary lymph nodes, has emerged as a surrogate endpoint for disease-free and overall survival, as the achievement of a pCR is associated with a favorable long-term prognosis in all breast cancer subtypes, while extensive residual disease predicts for poor outcomes, especially in triple-negative [estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) negative] and HER2-positive breast cancers [
5‐
7].
Angiogenesis is believed to play a significant role in LABC/IBC [
8‐
12]. Bevacizumab is a recombinant, humanized, monoclonal antibody that binds and neutralizes the vascular endothelial growth factor A, thus acting as an antiangiogenic agent. Bevacizumab has activity in multiple advanced neoplasms, including breast cancer [
12‐
17]. However, after initial enthusiasm over the combination of bevacizumab with chemotherapy in the metastatic setting, subsequent analyses suggested that bevacizumab produces more toxicity than benefit, and initial accelerated approval for the drug in this setting was subsequently withdrawn by the Food and Drug Administration (FDA) [
18]. In addition, two prospective randomized trials failed to document benefit for the addition of bevacizumab to adjuvant chemotherapy in any subset of breast cancer patients [
19,
20].
However, in the initial metastatic trials, bevacizumab showed activity in some patients when administered with chemotherapy [
21]. Despite suggestions that patients with ER/PgR-positive and those with triple-negative cancers may benefit from the addition of bevacizumab [
25‐
28]; retrospective analyses have failed to identify predictive biomarkers that might permit more efficient use of this agent [
22]. Therefore, in the current trial (SWOG0800-ClinicalTrials.gov NCT00856492), we prospectively examined whether neoadjuvant bevacizumab might be more active within selected intrinsic subtypes when administered with neoadjuvant chemotherapy. Furthermore, the vascular pruning hypothesis proposed by Jain suggests that antiangiogenesis might improve flow and oxygenation and enhance the delivery and proapoptotic effect of certain chemotherapy agents, in particular the taxanes [
17,
23]. Thus, we considered whether the addition of bevacizumab to neoadjuvant weekly nab-paclitaxel followed by dose-dense doxorubicin and cyclophosphamide (“AC”) would increase the pCR rates in patients with HER2-negative LABC/IBC. Nab-paclitaxel was chosen as the taxane backbone based on several advantages compared to paclitaxel at the time of trial initiation, including increased intratumoral drug levels [
24], albumin-mediated receptor transport of the drug via secreted protein acidic and rich in cysteine (SPARC)/osteonectin [
25] overexpressed in around 55 % of primary breast tumors [
26], specific receptor-mediated transport mechanisms due to overexpression of caveolin-1 and -2 in IBC [
27], and antiangiogenic activity as well as synergistic activity with antiangiogenic agents [
28,
29]. More recently,
Nab-paclitaxel was shown to be more effective than conventional paclitaxel as part of a neoadjuvant regimen for patients with high-risk early breast cancer in a large German study, the GeparSepto [
30]. This study found that 38 % of patients who received
nab-paclitaxel during the randomized phase III trial achieved a pCR, compared with 29 % of participants who were given conventional paclitaxel,
p < 0.001.
Discussion
We demonstrate that the addition of bevacizumab to neoadjuvant chemotherapy significantly increased the pCR rate in patients with LABC/IBC without significant additional toxicity, and that this increase was more pronounced in patients with TNBC. These data suggest that the addition of bevacizumab to anthracycline- and taxane-based chemotherapy enhances its cytotoxicity.
The addition of bevacizumab to chemotherapy in patients with metastatic breast cancer was initially approved by the FDA on the basis of improvements in response rate and PFS, but this approval was withdrawn when these studies failed to demonstrate improvement in OS [
40], while the European Medicines Agency (EMA) has approved its use with paclitaxel and capecitabine. Meanwhile, four large randomized trials, in addition to S0800, have investigated the addition of bevacizumab to neoadjuvant chemotherapy for breast cancer [
40‐
43]. All have reported a significant benefit with the addition of bevacizumab to anthracycline/taxane-based chemotherapy (Table
4). As in our trial, GeparQuinto, CALGB 40603, and ARTemis demonstrated a significant increase in the pCR rate in patients with TNBC, while NSABP B-40 demonstrated a higher pCR rate with bevacizumab in ER/PgR+ breast cancer but no statistically significant difference in TNBC.
Table 4
Neoadjuvant bevacizumab trials in HER2-negative breast cancer
S0800 (ypT0, ypTis, ypN0) | | | | 3 years | 3 years |
Bevacizumab | 36 | 24 | 59 | HR = 0.89
P = 0.71 | 86 % |
No bevacizumab | 21 | 18 | 29 | | 87 % |
GeparQuinto [ 41] (ypT0, ypN0) | | | | 3 years | 3 years |
Bevacizumab | 18.4 | 7.7 | 39.9 | 80.8 % | 90.7 % |
No bevacizumab | 14.9 | 7.8 | 81.5 | 81.5 % | 88.7 % |
Artemis [ 40] (ypT0, ypTis, ypN0) | | | | Not reported | Not reported |
Bevacizumab | 22.0 | 6.0 | 45.0 | | |
No bevacizumab | 17.0 | 7.0 | 31.0 | | |
NSABP-B40 [ 44] (ypT0, any pN) | | | | 5 years | 5 years |
Bevacizumab | 34.5 | 23.2 | 51.1 | HR = 0.8
P = 0.06 | HR = 0.65
P = 0.004 |
No bevacizumab | 28.2 | 15.1 | 47.1 | | |
CALGB 40603 [ 43] (ypT0, any pN) | | | | Not reported | Not reported |
Bevacizumab | NA | NA | 59 | | |
No Bevacizumab | NA | NA | 48 | | |
Our EFS and OS results failed to demonstrate significant differences favoring the addition of bevacizumab for the overall study population, but in the relatively small (
n = 67) TNBC subset, the EFS and OS hazard ratios trend in favor of the bevacizumab arm (HR 0.46,
p = 0.06 and HR 0.49,
p = 0.14), respectively, while the hazard ratios for these endpoints trend negatively in the larger ER/PGR+ population (HR 2.20,
p = 0.10 and HR 1.85,
p = 0.33, respectively). None of the neoadjuvant studies was powered to definitely demonstrate an EFS or OS benefit for the addition of bevacizumab, overall or in the TNBC population. The only study to show a survival benefit with bevacizumab was NSABP B-40, which was also the only one in which patients received bevacizumab in the adjuvant as well as the neoadjuvant settings; as with their pCR data, the survival benefit was seen only in the ER/PgR+ subset, and OS improvement was reported despite the absence of significant improvement in DFS [
44]. The addition of bevacizumab also failed to improve DFS or OS in two sizable trials in the adjuvant setting [
19,
20]; however, these trials were comprised largely of lower risk patients, and in E5103 the improvement in DFS with bevacizumab for TNBC approached significance (HR 0.77, 95 % CI 0.58–1.03).
These studies suggest that bevacizumab may be most helpful in patients with high-risk cancers, defined by both clinical stage and subtype. We have failed to identify any subset of breast cancer patients most likely to benefit from bevacizumab [
22,
45]. In CALGB 40603, a randomized phase II limited to stage II-III TNBC, investigators studied how intrinsic subtype assigned by PAM50 and other gene signatures affected the impact of bevacizumab on pCR rates [
46]. In basal-like cancers, the addition of bevacizumab significantly increased pCR in the breast (64 vs 45 %) and the breast/axilla (57 vs 43 %) rates, while paradoxically lowering pCR rates in relatively small (12.7 %) number of non-basal-like cancers, resulting in a significant interaction between subtype and bevacizumab-specific pCR benefit (
p = 0.02). mRNA signatures for high proliferative rate, low estrogen signaling, and high TP53 mutation were also associated with greater pCR benefit with the addition of bevacizumab, suggesting that even within TNBC there are biologically defined patient subsets that may benefit differentially from this agent. Similar analyses are underway for S0800, and will be reported separately. If confirmed, these findings could suggest that identifying and excluding a biologically defined subset of ‘bevacizumab-resistant’ patients lead to positive DFS and OS results from studies of bevacizumab in the adjuvant or neoadjuvant settings.
We also hypothesize that bevacizumab may have had activity in our study because of the unique eligibility requirement for LABC/IBC. Several studies have shown that such extensive tumors with high levels of neoangiogenesis are more likely to benefit from the addition of bevacizumab to chemotherapy than early-stage cancers with lower levels of tumor vasculature [
1,
8‐
11,
47]. Therefore, we propose that perhaps these patients are particularly susceptible to an antiangiogenic agent such as bevacizumab.
Our study has several limitations. The power of a trial to detect survival improvement from (neo) adjuvant chemotherapy is influenced by the subtype composition of the accrued patients [
48,
49]. Slightly more than two-thirds of our patients had ER/PgR+ cancers. Not only are these patients much less likely to achieve a pCR, they also have a better prognosis than TNBC and other more aggressive breast cancer subtypes. Nearly 80 % of our ER/PgR+ patients, across all treatment arms, were alive and free of disease recurrence at 4 years; EFS was only 50 % in TNBC patients assigned to the control arm, almost sufficient for demonstrating a significant benefit in a small cohort. Effective postneoadjuvant therapy, especially adjuvant endocrine therapy in ER/PgR+ cancers, improves outcomes in patients with residual disease and thus diminishes the impact of a more effective neoadjuvant regimen.
In summary, we find the trend favoring improvement in EFS in our high-risk TNBC subset encouraging and believing that the addition of bevacizumab to chemotherapy in the neoadjuvant setting for these patients warrants further investigation. While the role of bevacizumab remains uncertain due to the lack of OS improvement in several studies that included a high proportion of low- to moderate-risk patients, the consistent association between the addition of bevacizumab with higher response and pCR rates in metastatic and neoadjuvant trials is intriguing and underscores the importance of finding predictive biomarkers for this drug. Our results also suggest that it may worth re-evaluating the role of bevacizumab in locally advanced TNBC.
Funding
The work was supported in part by the National Institutes of Health (NIH)/National Cancer Institute (NCI)/National Clinical Trials Network (NCTN) grants CA180888, CA180819, CA180821, CA180835, CA180830, CA180846, CA180801, CA180834; NIH/NCI Community Oncology Research Program (NCORP) grants CA189954, CA189856, CA189971, CA189822, CA189952, CA189804, CA189817, CA189953, CA189858, CA189957, CA189872, CA189853; legacy NIH/NCI grants CA35119, CA52654, CA04919, CA37981, CA58416, CA16385; and in part by Genentech (Roche), Abraxis BioScience (Celgene), and Helomics™.
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