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MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study.

ABSTRACT: Addition of bevacizumab to trastuzumab-based neoadjuvant chemotherapy in HER2-positive inflammatory breast cancer (IBC) was associated with favorable outcome in the BEVERLY-2 phase II trial. Circulating levels of matrix metalloproteinases (MMP) 2 and 9 were correlated to high response rate and prolonged survival in high-grade glioma treated with bevacizumab. We examined the prognostic impact of MMP2 and MMP9 serum levels in BEVERLY-2 patients.MMP2 and MMP9 serum levels were assessed using ELISA at baseline and before surgery in 45/52 available samples. Correlations were tested with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS).Baseline (b) MMP2 and MMP9 serum levels were independent from patient characteristics and circulating tumor or endothelial cells, and were not correlated to pCR. High bMMP2 was correlated to better DFS (p=0.001) and OS (p=0.032), while low bMMP9 was correlated to better OS (p=0.022) and tended to be associated with longer DFS (p=0.071). In multivariate analyses, bMMP2 (p=0.003, Hazard Ratio [HR]: 0.115) and bMMP9 (p=0.041, HR: 3.511) remained correlated to DFS. As continuous variables, bMMP2 was associated with relapse (p=0.002) and death (p=0.049), while bMMP9 was associated with death (p=0.035). During treatment, significant increase in MMP2 and decrease in MMP9 levels (p<0.001 for both) were observed in 100% and 87% of patients respectively.High bMMP2 and low bMMP9 serum levels were associated with better survival in HER2-positive IBC patients treated with bevacizumab- and trastuzumab-based neoadjuvant chemotherapy. Their predictive value of bevacizumab benefit should be evaluated in a randomized trial.

SUBMITTER: Tabouret E

PROVIDER: S-EPMC4951307 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study.

Tabouret Emeline E Bertucci François F Pierga Jean-Yves JY Petit Thierry T Levy Christelle C Ferrero Jean-Marc JM Campone Mario M Gligorov Joseph J Lerebours Florence F Roché Henri H Bachelot Thomas T van Laere Steven S Ueno Naoto T NT Toiron Yves Y Finetti Pascal P Birnbaum Daniel D Borg Jean-Paul JP Viens Patrice P Chinot Olivier O Gonçalves Anthony A

Oncotarget 20160401 14

<h4>Purpose</h4>Addition of bevacizumab to trastuzumab-based neoadjuvant chemotherapy in HER2-positive inflammatory breast cancer (IBC) was associated with favorable outcome in the BEVERLY-2 phase II trial. Circulating levels of matrix metalloproteinases (MMP) 2 and 9 were correlated to high response rate and prolonged survival in high-grade glioma treated with bevacizumab. We examined the prognostic impact of MMP2 and MMP9 serum levels in BEVERLY-2 patients.<h4>Experimental design</h4>MMP2 and ...[more]

PMID: 26921265

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Project description:The incidence of oesophageal adenocarcinoma (OeC) has been increasing rapidly in most Western countries during the last few decades. Although multimodal treatment combining pre-operative chemotherapy with radical surgical resection has become the standard of care in the UK for all patients with locally advanced resectable disease, the 5-year survival rate in this patient group is less than 25%. Only 30% of all patients will benefit from pre-operative chemotherapy. Hence, there is an urgent clinical need to identify genomic markers that allow stratification of patients for a more individualised therapy approach. The goal of this study is to use whole genome high-resolution array CGH to examine the DNA copy number profile of a subset of OeC patients recruited into the OE02 trial and establish it’s relationship with clinicopathological variables including pathological tumor regression and patient survival. High-resolution array CGH analysis was conducted on 84 formalin fixed paraffin embedded resection samples obtained from subjects enrolled in the Oe02 trial. We compared the DNA copy number profiles between patients treated with chemotherapy and surgery and those treated with surgery alone. DNA copy number entropy was assessed to identify differences in overall copy number aberrations between the two treatment groups. Furthermore, the association between DNA copy number aberrations and tumor regression grade was investigated. The genetic make-up of OeCs investigated in the current study proved to be highly complex reducing our ability to determine the background normal copy number level in a tumor sample. Using DNA copy number entropy as a measure to compare sample profiles, we identified significant treatment arm specific DNA copy number aberration patterns predominantly in chromosome 1 and 5. High DNA copy number entropy was associated with longer overall survival. Differential DNA copy number entropy was observed between the two treatment groups, and the positions of the driving DNA regions were identified. To our surprise, the differences between the treatment groups went unnoticed when a standard test was applied. We also found that the DNA copy number entropy was strongly correlated with patients’ overall survival and clinicopathological characteristics. To the best of our knowledge, this is the first study in OeC quantitatively showed that the tumor heterogeneity was reduced by chemotherapy. And, the observed tumor heterogeneity was shown to has prognostic value. However, further research is needed to narrow down these regions to a few driving genes/probes that may aid in predicting whether a new patient will benefit from chemotherapy.

Project description:BackgroundBevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.MethodsWe randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.ResultsThe addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis.ConclusionsThe addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

Dataset Information

MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study.

Publications

MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study.

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