Changes of Topoisomerase IIα Expression in Breast Tumors after Neoadjuvant Chemotherapy Predicts Relapse-Free Survival

Abstract

and on behalf of the Consorzio Interuniversitario Nazionale per la Bioncologia Abstract Purpose:To assess the value of changes in the expression of topoisomerase IIa (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. Patients and Methods: Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapsefree survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. Results: Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressingTopoII (P < 0.0001). No significant change was observed for HER-2.TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. Conclusion:Changes inTopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.

Relationship between oestrogen receptor status and proliferation in predicting response and long-term outcome to neoadjuvant chemotherapy for breast cancer

“…However, in a multivariate model, HER2 status was the only significant independent predictor of pCR. These findings corroborate those of previous studies, where grade [2,14] and HER2 [15,16] were shown to be significant independent predictors of pCR in multivariate models including Ki67, HER2 and ER status. Furthermore, in analysing ER positive and negative subgroups separately, Ki67 did not have a significant influence on pCR (data not shown).…”

“…On multivariate analysis pre-therapy Ki67 was not an independent predictor of RFS or OS. In agreement, most other studies have demonstrated that preneoadjuvant chemotherapy Ki67 is not an independent predictor of relapse-free, disease-free and progression-free survival [2,15,16,18,[23][24][25][26][27], or OS [16,19,[23][24][25][26][27]. A recent meta analysis, of patients treated with and without adjuvant systemic chemotherapy, has found that high Ki67 is associated with worse survival [28].…”

Resistance to Chemotherapy in Cancer: A Complex and Integrated Cellular Response

“…In NSCLC the expression of topoisomerase II was not correlated with response to chemotherapy and mutations are rarely observed [277] , although a small study in SCLC found point mutations in 1 of 13 subjects following prior exposure to topoisomerase II inhibitors [278] . Breast tumour cells exhibiting increased topoisomerase II expression following chemotherapy may be associated with relapse and resistance [279] . However, despite this finding and the extensive in vitro evidence of a correlation, topoisomerase II ␣ expression alone is unlikely to predict response to chemotherapy in advanced breast cancer [280] .…”

The Trop-2 signalling network in cancer growth

“…Slides were treated with 0.3% bovine serum albumin in Tris-buffered saline at room temperature for 30 min to quench non-specific binding. The slides were then stained with the specific antibodies (Trop-2: 162-46.2 monoclonal; 44,53 ERa: MU368-UC monoclonal, Biogenex, Fremont, CA, USA; progesterone receptor: 1A6, Ventana, Tucson, AZ, USA; HER-2/neu: Hercep-Test (Dako, Glostrup, Denmark) 54 (Supplementary Table 1a). The bound antibodies were detected with goat antirabbit or antimouse horseradish peroxidase-labelled polymerised secondary antibodies (DAKO EnVision TM System).…”