ORIGINAL P53 STATUS PREDICTS FOR PATHOLOGICAL RESPONSE IN LOCALLY ADVANCED BREAST CANCER PATIENTS TREATED PREOPERATIVELY WITH CONTINUOUS INFUSION 5FLUOROURACIL AND RADIATION THERAPY

Purpose/Objective: 1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5FU) and radiation (RT) in locally advanced breast cancer. 2) To study clinical and pathological response rates of 5-FU and radiation. 3) To attempt preliminary correlations between biological probes and pathological response. Methods and Materials: Previously untreated, locally advanced breast cancer patients were eligible: only patients who presented with T3/T4 tumors that could not be resected with primary wound closure were eligible, while inflammatory breast cancer patients were excluded. The protocol consisted of preoperative c.i. infusion 5-FU, 200 mg/m’/day with radiotherapy, 50 Gy at 2 Gy fractions to the breast and regional nodes. At mastectomy, pathological findings were classified based on persistence of invasive cancer: pathological complete response (PCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of microscopic foci of invasive cells in either the breast or nodal specimens; no pathological response (pNR) = pathological persistence of tumor. For each patient pretreatment breast cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR hormonal receptors, her2/neu and ~53 overexpression. Results: Thirty-five women have completed the protocol and are available for analysis. 5-FU was interrupted during radiation in 10 of 35 patients because- of oral mucositis in 8 patients, celhditis in 1, and patient choice in another. Objective cliical response rate before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35 patients tumor response was sufFicient to make them resectable with primary wound closure. Accordingly, all patients underwent modified radical mastectomy: primary wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%), 5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of cancer (pNR). Variables analyzed as potential predictors for pathological response (pPR and pCR) were: initial TNM clinical stage, clinical response, nuclear grade, hormonal receptor status, ~53 overexpression, and Her2Ineu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at hmnunohistochemistry) significantly correlated with achievement of a pathological response to this regimen @ = 0.010). Conclusion: The combination of c.i. 5-FU and radiation was well tolerated and generated objective clinical responses in 71% of the patients. With the limitation of tbe small sample size, the complete pathological response achieved (20%) compares favorably with that reported in other series of neoadjuvant therapy for similar stage breast cancer. These prelhninary data suggest that initial ~53 status predicts for pathological response @PR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer. 0 1997 Elsevier Science Inc. Locally advanced breast cancer, 5-Fluorouracil and radiation, ~53, Pathological response.