Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy.
OBJECTIVE
1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5-FU) 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
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/m2/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 p53 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, cellulitis in 1, and patient choice in another. Objective clinical 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, p53 overexpression, and Her2/neu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at immunohistochemistry) significantly correlated with achievement of a pathological response to this regimen (p = 0.010).


CONCLUSIONS
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 the 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 preliminary data suggest that initial p53 status predicts for pathological response (pPR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer.
Formenti
S C
SC
Department of Radiation Oncology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Dunnington
G
G
Uzieli
B
B
Lenz
H
H
Keren-Rosenberg
S
S
Silberman
H
H
Spicer
D
D
Denk
M
M
Leichman
G
G
Groshen
S
S
Watkins
K
K
Muggia
F
F
Florentine
B
B
Press
M
M
Danenberg
K
K
Danenberg
P
P
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D015411:Mastectomy, Modified Radical; D008875:Middle Aged
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil