Molecular Markers Predictive Response to Dose Dense Chemotherapy With Epirubicin and Docetaxel in Sequences for Locally Advanced Breast Cancer.

Aim The scientific aim of this study is to explore mechanisms of resistance to chemotherapy in breast cancer. To do so, we explore molecular parameters predicting response to chemotherapy administered prior to local therapy in large, primary breast cancers.

Background Neoadjuvant (primary medical) therapy has got wide acceptance as primary therapy in breast cancer. In addition, this treatment provides an optimal setting studying the mechanisms of drug resistance in human cancers.

Considering chemotherapy for primary breast cancer treatment, contemporary trend has been to treat these tumors more aggressively. High-dose therapy involving stem cell support is not advocated, as this has not been shown to improve long-term survival in early breast cancer. However, the attitude in general has been toward a more aggressive approach within the frame of "conventional" therapy.

Based on theoretical modeling, an alternative approach, "dose-dense" therapy, has been advocated. Recently, that concept was brought to the test in two adjuvant trials. Thus, Citron et al applying doxorubicin, paclitaxel and cyclofosfamide revealed an improved outcome for dose-dense (2-weekly) administration compared to regular 3-weekly scheduling. In contrast, the German GEPARDUO study reported doxorubicin plus cyclophosphamide and docetaxel, given in sequence on a 3-weekly basis (8 cycles), to be superior to doxorubicin and docetaxel given in concert on a 2-weekly basis for 4 cycles. However, the doses administered (doxorubicin 50 versus 60 mg/m2; docetaxel 75 versus 100 mg/m2) was unequal, meaning total drug dose exposure differed between the two treatment arms. While more data are warranted, a reasonable interpretation of available data suggest sequential administration of different compounds in a dose-density approach to be a suitable regimen provided adequate total doses are given.

Rationale for regimen Considering anthracyclines, most regimens today combine either epirubicin or doxorubicin in concert with 5-fluorouracil and cyclophosphamide. However, based on the evidence in the literature, it is not clear what the contribution of 5-FU or cyclophosphamide is to the effectiveness of such regimens, in particular not when a taxane is administered in sequence or concert. Thus, the NSABP-group has abandoned use of 5-FU from their adjuvant regimen. Considering cyclophosphamide, this compound seems to add to the carcinogenetic effect of anthracyclines enhancing the risk of secondary leukemia, while the contribution to the antitumor efficacy of the regimen remains uncertain. The taxanes are known to have significant antitumor effects in breast cancer when administered as monotherapy. Considering docetaxel, the dose generally advocated for monotherapy is 100 mg/m2, while a dose of 75mg/m2 is recommended for combined use. Thus, the potential exists that the dose for combined use may be sub-optimal in some patients.