Relationship between thymidylate synthase expression and p53 levels with the treatment of cyclophosphamide, methotrexate, 5-fluorouracil chemotherapy(CMF) versus docetaxel (TXT) in locally advanced carcinoma of the breast

Abstract

10546 Background: Adjuvant chemotherapy is used in the treatment of breast carcinoma independently of axillar node involvement. Different drug combinations such as CMF, FAC, FEC are still used; recently new drugs such as TXT (NEJM 332:1004,1997) show activity and are used also in adjuvant chemotherapy. 5 Fluorouracil (5Fu), a drug involved in main therapeutic regimens, blocks Thymidylate Synthase (TS), an enzyme involved in the DNA synthesis. TS not only links its own mRNA, but also p53 mRNA, inhibiting post transcriptional p53 protein synthesis. TS protein overexpression (Cancer Res 55:1407,1995), and/or its absence (Cancer Res 61:1421,2001) are some of the main mechanisms of 5-Fu drug resistance; moreover TS protein could inhibit p53 protein synthesis. Many clinical studies demonstrate that tumours with mutations of p53 are resistant to anthracyclines chemotherapy, 5Fu and radiotherapy (Carcinogenesis 17:1417,1996). Other studies show that the relationship between p53 and taxanes chemosensitivity seems to be more complex, because p53 mutations are associated with better taxanes drug response (Nature Med 2:255,1996). Aim of the study is to find association between TS and p53 levels, and relation with CMF or TXT treatment. Methods: We detected TS and p53 protein levels with immunohistochemistry assay in 84 paraffin embedded tumour samples from untreated patients (pts) who underwent surgery for primary breast cancer. Stage was T2N2M0 and pts were divided into two groups depending on the drug treatment received. One group (44 pts) was treated by 6 cycles of adjuvant CMF chemotherapy, the other by 4 cycles TXT alone. Results: 30% of pts showed lower TS and higher p53 levels, and had better TXT, while worse CMF treatment response; 30% of pts showed higher TS and lower p53 levels and all had worse response to all treatments; 40% of pts showed intermediate TS and p53 levels and different response to both CMF or TXT. Conclusions: On the basis of these results we identified a sub-group of pts showing lower TS and higher p53 levels that could be treated by a first line therapeutic regimen including Taxanes, not by drug combinations including 5 FU. No significant financial relationships to disclose.