Predictive and prognostic value of Matrix metalloproteinase (MMP) - 9 in neoadjuvant chemotherapy for triple-negative breast cancer patients

Abstract

Background: This study aimed to investigate the clinical utility of serum and histological MMP-9 detection during neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC).

Methods: A total of 303 TNBC patients who underwent weekly paclitaxel plus carboplatin treatments followed by surgical resection were included in this study. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum level of Matrix metalloproteinase-9 (sMMP-9) at baseline and prior to surgery. Immunohistochemistry was used to detect histological MMP-9 (hMMP-9) expression in patients with residual tumors after NAC. The value of MMP-9 to predict the response to NAC and patient survival was studied.

Results: Of the 303 patients, 103 (34.0%) patients experienced pathological complete response (pCR) after completion of NAC. Univariate and multivariate analyses revealed that the relative change in sMMP-9, rather than sMMP-9 at baseline or surgery, had a remarkable predictive value for pCR. Each 1 ng/ml decrease in sMMP-9 after NAC was shown to result in a 0.3% increase in pCR rate. Additionally, in survival analyses, hMMP-9 expression in residual tumors was independently correlated with disease-free survival for non-pCR responders (P < 0.001).

Conclusions: Our findings indicate that monitoring serum MMP-9 and detection of histological MMP-9 could help identify TNBC patients who will respond to NAC and will display varying risks of disease relapse. MMP-9 may serve as a predictive and prognostic biomarker for tailoring and modifying the NAC strategy for TNBC.

Keywords: Breast cancer; MMP-9; Neoadjuvant chemotherapy; Pathological response; Prognostic marker.

Fig. 1

Immunohistochemical staining of MMP-9 in post-NAC samples of breast cancer. MMP-9 protein was detected with immunohistochemistry (IHC) using paraffin-embedded breast cancer samples collected after neoadjuvant chemotherapy. a Representative IHC images of strongly positive MMP-9 staining (200X). b Representative IHC images of moderate MMP-9 staining. c Representative IHC images of negative MMP-9 staining (200X). Scale bar: 50 μm

Fig. 2

Correlation between serum and histological MMP-9 in non-pCR patients. A higher serum MMP-9 (sMMP-9) level is more frequently observed in patients with higher positivity of histological MMP-9 level (hMMP-9), ***P < 0.001, **P < 0.01

Fig. 3

Correlation between serum MMP-9 value and Miller-Payne (MP) grades. MMP-9 change after NAC was significantly correlated to response to NAC. The mean absolute changes (ng/ml) in serum MMP-9 were − 88.30 ± 286.40, 47.70 ± 188.60 and 133.00 ± 190.40 in patients with a poor response (MP 2/1), a partial response (MP 3) and an ideal response (MP 5/4), respectively. ***P < 0.001, **P < 0.01, *P < 0.05

Fig. 4

Cumulative disease-free survival of non-pCR patients according to MMP-9 levels after NAC. High expression of hMMP-9 was significantly correlated with an unfavorable outcome (P < 0.001). a Disease-free survival according to histological expression of MMP-9 protein (hMMP-9); b Disease-free survival according to serum MMP-9 (sMMP-9) at baseline; c Disease-free survival according to sMMP-9 at surgery; d Disease-free survival according to sMMP-9 change