TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

Abstract

HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

“…Although there are no approaches in clinical use to address this aspect, this is an area that has received much attention. The association between TOP2A or TIMP-1 amplification with response to anthracyclines is one such avenue that has been pursued (45,46). In addition, the stimulation of ErbB3-mediated survival signaling in response to doxorubicin has been observed in some ovarian cancer cell lines (47).…”

The Predictive and Prognostic Role of Topoisomerase IIα and Tissue Inhibitor of Metalloproteinases 1 Expression in Locally Advanced Breast Carcinoma of Egyptian Patients Treated With Anthracycline-based Neoadjuvant Chemotherapy

“…Some studies reported that the 2T profile is a more accurate predictor of incremental benefit from anthracycline-containing chemotherapy than HER2/neu, TIMP-1, or TOP2a individually. 13,63 On contrary, others could not confirm any additive predictive value by combining TIMP-1 immunoreactivity with TOP2a analysis. 52 …”

TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group

“…The majority of breast cancer studies on TIMP-1 and association with prognosis and response to chemotherapy have focused on patients receiving adjuvant chemotherapy [2,8,18,20,34], whereas only two studies have included patients with advanced breast cancer [35,36]. These two studies both measured TIMP-1 levels in the primary tumors using an enzyme-linked immunosorbent assay-based approach and included patients receiving cyclophosphamide/methotrexate/5-fluorouracil or anthracycline-based chemotherapy.…”

“…K5007, Dako A/S). TIMP-1 was assessed semi quantitatively using the positive (any cytoplasmatic staining of tumor cells, > 0%) versus negative (no staining of tumor cells) staining signal as a measure of the TIMP-1 immunoreactivity in the epithelial breast cancer cells [2,8,20]. The whole-tissue sections were scanned and examined by light microscopy and reviewed blinded, without knowledge of patient characteristics and outcome, by three independent investigators (pathologist EB and two trained observers, technician AB and biologist CLTJ).…”

“…A prognostic value of TIMP- 1 in primary breast cancer has been suggested in several studies, with high plasma or tumor tissue content of TIMP-1 being associated with poor patient outcome [15-19]. Moreover, breast cancer patients with TIMP-1 positive cancer cells [2,8,20,21] seem to benefit less from adjuvant anthracycline-containing chemotherapy. Docetaxel (D), a taxane disrupting the dynamic function of microtubules [22], and gemcitabine (G), a pyrimidine analog arresting DNA replication and synthesis [23-25], are widely used in breast cancer therapy [26,27].…”