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TP53 Gene Mutations Predict the Response to Neoadjuvant Treatment with 5-Fluorouracil and Mitomycin in Locally Advanced Breast Cancer

¹ Department of Medicine, Section of Oncology, and
² Departments of Surgery and
³ Pathology, The Gades Institute, Haukeland University Hospital, Bergen; and
⁴ Department of Genetics, The Norwegian Radiumhospital, Oslo, Norway

Purpose: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer.

Experimental Design: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m² on days 1 and 2) and mitomycin (6 mg/m² on day 2), administered every 3 weeks for 2–10 cycles in the neoadjuvant setting.

Results: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by 25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen.

Conclusion: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.

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