Serial Topoisomerase II Expression in Primary Breast Cancer and Response to Neoadjuvant Anthracycline-Based Chemotherapy

Abstract

Objective: We analyzed the value of topoisomerase IIα (Topo II) in predicting the clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and the potential changes in Topo II after chemotherapy. In parallel, HER2, which is commonly coexpressed with Topo II, and p53, a modulator of chemotherapy activity, were also analyzed. Methods: Forty-one patients with primary breast cancer and treated with neoadjuvant anthracycline-based chemotherapy (FAC or FEC) were included for the present study. Topo II, HER2 and p53 expression were measured by immunohistochemistry in pre and post chemotherapy (at the time of surgery), tumor specimens and the results were correlated with the clinical response. Results: Topo II was overexpressed in 16 of 41 (31%) tumors before treatment, and this overexpression was significantly associated with clinical response (p = 0.03). HER2 and p53 were unrelated to response. Notably, Topo II overexpression, but not HER2 or p53, was lost in specimens after chemotherapy (p = 0.01). Conclusion: The observed link between Topo II and the clinical response to neoadjuvant anthracycline-based chemotherapy, together with its loss after chemotherapy, implies that Topo II deserves further testing in a prospective setting as a predictive marker.

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

“…For instance, in a study by MacGrogan et al (25), the response to neoadjuvant chemotherapy was found to correlate with the immunohistochemical expression of TopoII, but not with that of HER-2. Similar results were reported by Martin-Richard et al (29). In another study (26), a favorable response to chemotherapy regimens containing anthracyclines and taxanes was more frequently observed in patients with tumors displaying either TopoII overexpression or gene amplification, and in those displaying HER-2 amplification.…”

“…In two of these studies (29,30), changes in TopoII expression were found to correlate with response to treatment, but a consistent picture correlating these changes to prognosis has not yet emerged. Here, we show for the first time, that changes in the expression of TopoII are of prognostic value in patients with operable breast cancer receiving anthracycline-based chemotherapy prior to surgery.…”

Serial Changes in Expression of Proteins in Response to Neoadjuvant Chemotherapy in Breast Cancer

“…A seminal study (140) analyzed the value of Topo2α in predicting clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and its potential changes after chemotherapy. The study also looked at p53 and Her2 the latter being commonly coexpressed with Topo2.…”

Growth factor signalling in clinical breast cancer and its impact on response to conventional therapies: a review of chemotherapy

“…In another older French study among 79 patients treated with either low-dose FEC (epirubicin 50 mg/m 2 ) or with FEC100 (epirubicin 100 mg/m 2 ), there was no difference in the response rate with either regimen in HER2-negative tumours, but a much higher response in HER2-positive patients treated with FEC100 compared with the lower-dose regimen, suggesting a dose--response relationship for epirubicin in HER2-positive disease (Petit et al 2001). However, recently Martin-Richard et al (2004) have shown no correlation between HER2 status by IHC and response to anthracycline-based chemotherapy (FAC/FEC) in 41 patients receiving neoadjuvant therapy. Furthermore, Bonnefoi et al (2003) have also shown no correlation between HER2 status and treatment outcome for 187 patients receiving epirubicin-based neoadjuvant chemotherapy for locally advanced breast cancers.…”

“…The results were contradictory, with several studies supporting its role as a prognostic marker (Barnes et al 1993, Silvestrini et al 1993, MacGrogan et al 1995, Silvestrini et al 1996, Thor et al 1998, Chappuis et al 1999) and many failing to show this relationship (Elledge et al 1995, Sjogren et al 1996, Clahsen et al 1998, Broet et al 1999, Penault-Llorca et al 2003, Martin-Richard et al 2004. However, as is well known, the differing methodologies and antibodies used in these studies, and the failure to detect unstable p53 mutants, suggests that assessment of p53 status should be based on gene-sequencing methods for a proper evaluation of its role.…”