Topoisomerase IIα als prädiktiver Marker (FISH-Analyse) und der klinische Verlauf beim Mammakarzinom. Eine retrospektive Analyse an 128 Frauen mit Mammakarzinom aus den Jahren 2003 und 2004

INTRODUCTION: Adjuvant systemic therapy of HER2-positive breast cancer may cause two distinct different cardiotoxic side effects due to anthracycline based chemotherapy and anti-HER therapy with trastuzumab as well. In order to reduce these side effects and to ensure the optimal outcome benefit in survival a predictive marker for anthracycline based therapy is needed. TopoisomeraseIIα as target of anthracyclines seems to be eligible as such a predictive marker. The rationale of the study was to evaluate the prevalence of HER2 and TOP2A amplification as well as to analyze the prognostic and predictive value for anthracycline based therapy in a routine treatment collective outside of the setting of a clinical trial and before introduction of Trastuzumab. MATERIAL AND METHODS: The study group included 128 patients, who were treated due to breast cancer at the Städtische Kliniken Offenbach/ Main in the years 2003 and 2004. Primary endpoints were diseasefree survival (DFS) and overall survival (OS). Gene alterations asserted by Fish-analysis were correlated with the clinical course, received chemotherapy, and assumed risk of recurrence. RESULTS: Among 128 tissue samples 7 (5,47%) revealed TOP2A amplification and 20 (15,63%) samples were found to be positive for HER2 amplification. All TOP2A amplified tumors were found to be HER2-positive by amplification. Coamplification came along with a higher risk of recurrence due to HER2 positivity and lymphnode involvement. On the other hand all coamplified tumors were found to be hormone positive (100%). All high risk patients irrespective of genalteration showed benefit from anthracycline based therapy (Overall survival/ OS: 62 w/ chemotherapy vs. 47 months w/o). Among patients with medium risk of recurrence benefit of anthracycline based therapy was restricted to HER2 positive disease (OS: 60 w/ vs. 52 months w/o). Survival of patients with coamplified tumors exceeded those with HER2 amplified tumors even when lacking chemotherapy (OS: 59 w/ vs. 50 months w/o). TOP2A-amplification could not be confirmed as a predictive marker for anthracycline based therapy. DISCUSSION: The low prevalence of TOP2A amplification complicates the evaluation as a prognostic resp. predictive marker and demands for prospective randomized studies with large scale collectives. On the one hand HER2 and lymphnode positivity imply a high risk of recurrence, on the other hand endocrine responsiveness and prolonged relapse time hypothesize a lower risk of recurrence. A more favorable tumorbiology in coamplified breast cancer has not been adequately considered so far. CONCLUSION: The significance of TOP2A amplification as a predictive marker for anthracycline based therapy remains insecure. Current data could not confirm any evidence. To evaluate the predictive value of TOP2A amplification there is a need for equivalent anthracycline free regime of chemotherapy. In addition while selecting a study group heterogenity of breast cancer disease for example as defined by intrinsic subtypes has to be respected. In compliance of these requirements TOP2A may prove as the crucial criterium for anthracycline based chemotherapy.