Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer

Headquarters, German Breast Group, Neu-Isenburg, Germany.
New England Journal of Medicine (Impact Factor: 55.87). 01/2012; 366(4):299-309. DOI: 10.1056/NEJMoa1111065
Source: PubMed


Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer.
We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk.
Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications.
The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; number, NCT00567554.).

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Available from: Hans Tesch, Sep 14, 2015
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    • "Bevacizumab, a VEGF-A inhibitor, has shown great efficacy in combination with chemotherapy in patients with HER2- metastatic breast cancer, especially in TNBC patients [45]–[46]. In the neoadjuvant setting, the NSABP B-40 and GeparQuinto trials have demonstrated that bevacizumab could increase the pCR rate in NAT of HER2- patients [25]. However, subgroup analysis showed that the pCR improvement in the GeparQuinto trial was restricted to TNBC patients [25], while the greatest bevacizumab effect was only seen in the non-TNBC patients in the NSABP B-40 trial [24]. "
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    ABSTRACT: Triple negative breast cancer (TNBC) is associated with high pathological complete remission (pCR) rate in neoadjuvant treatment (NAT). TNBC patients who achieve pCR have superior outcome than those without pCR. A meta-analysis was done to evaluate whether integrating novel approaches into NAT can improve the pCR rate in TNBC. Medical subject heading terms (Breast Neoplasm) and key words (triple negative OR estrogen receptor (ER) negative OR HER2 negative) AND (primary systemic OR neoadjuvant OR preoperative) were used to select eligible studies. Experimental arm in each study was considered as the testing regimen, and control arm was defined as the standard regimen in this meta-analysis. A total of 11 studies with 14 paired regimens were included in the final analysis. Aggregate pCR rate was 37.3% and 44.6% in the standard and testing group, respectively. Novel approaches in the testing regimen significantly improved the pCR rate in NAT of TNBC patients compared with the standard regimen, with an odds ratio (OR) of 1.34 (95% confidence interval (CI) 1.11-1.62, P = 0.002). Considering specific regimens, we demonstrated the pCR rate to be much higher in the carboplatin-containing (OR = 1.80, 95% CI 1.39-2.32, P<0.001) or bevacizumab-containing regimens (OR = 1.36, 95% CI 1.11-1.66, P = 0.003) than in the control regimens. The addition of carboplatin in NAT had a pCR rate as high as 51.2% in TNBC patients, with an absolute pCR difference of 13.8% as compared with control regimens. No significant heterogeneity was identified among studies evaluating the addition of carboplatin or bevacizumab efficacy in NAT. This meta-analysis indicates that these novel NAT regimens have achieved a significant pCR improvement in TNBC patients, especially among patients treated with carboplatin-containing or bevacizumab-containing regimen. This can help us design appropriate trials in the adjuvant setting and guide clinical practice.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Recent randomised trials have proven increased efficacy of adding bevacizumab, a monoclonal antibody against VEGF, to standard neoadjuvant chemotherapy in HER-2-negative early breast cancer (Bear et al, 2012; von Minckwitz et al, 2012). A second class of antiangiogenic agents, small molecules with multityrosine kinase inhibitor activity that target several pro-angiogenic axes (TKIs), has been studied in breast cancer as well. "
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    ABSTRACT: Introduction: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. Methods: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). Results: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. Conclusions: The combination allows the delivery of full-dose intensity, while efficacy seems promising.
    Full-text · Article · Jul 2014 · British Journal of Cancer
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    • "We suggest that, in breast cancer, high-level expression of CD74 could be a marker of increased vascularity in stroma. Since bevacizumab, an anti-VEGF antibody, appears to be more efficient in TRN breast cancer (35), stromal CD74 expression could be examined as a predictive marker of response to bevacizumab-based therapy. "
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) and its receptor CD74 appear to be involved in tumorigenesis. We evaluated, by immunohistochemical staining, the tissue expression and distribution of MIF and CD74 in serial sections of human invasive breast cancer tumor specimens. The serum MIF level was also determined in breast cancer patients. We showed a significant increase in serum MIF average levels in breast cancer patients compared to healthy individuals. MIF tissue expression, quantified by a modified Allred score, was strongly increased in carcinoma compared to tumor-free specimens, in the cancer cells and in the peritumoral stroma, with fibroblasts the most intensely stained. We did not find any significant correlation with histoprognostic factors, except for a significant inverse correlation between tumor size and MIF stromal positivity. CD74 staining was heterogeneous and significantly decreased in cancer cells but increased in the surrounding stroma, namely in lymphocytes, macrophages and vessel endothelium. There was no significant variation according to classical histoprognostic factors, except that CD74 stromal expression was significantly correlated with triple-negative receptor (TRN) status and the absence of estrogen receptors. In conclusion, our data support the concept of a functional role of MIF in human breast cancer. In addition to auto- and paracrine effects on cancer cells, MIF could contribute to shape the tumor microenvironment leading to immunomodulation and angiogenesis. Interfering with MIF effects in breast tumors in a therapeutic perspective remains an attractive but complex challenge. Level of co-expression of MIF and CD74 could be a surrogate marker for efficacy of anti-angiogenic drugs, particularly in TRN breast cancer tumor.
    Full-text · Article · Jun 2014 · Oncology Reports
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