Biomarkers ER, PR, HER-2 En Topoisomerase II alpha in Correlation with Response to Neoadjuvant Chemotherapy for Primary Breast Cancer.
Authors: Lambein K. , Pauwels P. , Buijsrogge M. , Denys H. , Van den Broecke R. , Depypere H. , Van Belle S. , Dochy E. , Cocquyt V. 
Published: December 2010

Background: Neoadjuvant chemotherapy (CT) is widely accepted for patients with primary breast cancer (BC) not eligible for breast conservative surgery (BCS). Docetaxel, when used in combination with or when sequentially added to an anthracycline-based regimen, is active in the adjuvant setting. The objectives of this trial were to assess the activity of sequential anthracycline-docetaxel chemotherapy in the neo-adjuvant setting and to evaluate these markers as predictors of response.Patients and methods: Patients with unilateral BC &gt; 2 cm (with or without positive sentinel lymph node (LN)), adequate liver, kidney and bone marrow function and no evidence of distant metastasis were eligible for enrolment. Patients with stage T4d or inflammatory BC were excluded. Treatment prior to surgery consisted of 4 cycles of Adriamycin (60 mg/m²) plus cyclophosphamide (600 mg/m²) (AC) administered intravenously every 3 weeks (q3wk), followed by 4 cycles of docetaxel (D) (100mg/m²) q3wk. Patients were clinically evaluated after 4 cycles of AC and again after 4 cycles of D. Pathological evaluation was performed after definitive surgery. Hormonal receptor, HER2 and topoisomerase II alpha (topoII) status and tumor grade were evaluated for their ability to predict response to treatment.Results: Fifty-three patients with a mean age of 49 years (range 31-69), were included in this analysis. Mean largest tumor diameter before treatment was 49.1 mm (range 25-90 mm). There were 12 grade 2 and 30 grade 3 tumours representing 46 ductal carcinomas, 5 lobular carcinomas and 2 mixed tumors. Eleven tumors (21%) were not evaluable (NE). LNs were positive in 62% of patients. Forty patients were evaluable for HER-2 and topoII. Thirteen patients (33%) were HER2-positive by immunohistochemistry (IHC) and 11 of these 13 were also HER2-positive by fluorescence in situ hybridization (FISH), 4 patients were topoII positive by FISH. The mean topoII level for FISH-positive patients was 1.83 (CI, 95%, 1.49 to 2.16). There was no increase in the topoII level without HER2 amplification by FISH. Forty-three percent of patients were oestrogen (E) and progesterone (P) receptor (R) positive, 28% were ER and PR negative, and 15% of patients were triple negative. After 4 cycles of AC, a complete reponse (CR) was seen in 17% of patients, partial response (PR) in 53% stable disease (SD) in 26%, and progressive disease (PD) in 4%. After 4 cycles of D the corresponding figures were 30%, 45%, 11% and 2% respectively. Eleven percent of patients were NE. Forty patients (75.5%) had BCS and 13 (24.5%) underwent mastectomy. A correlation was found between HER2 amplification by FISH and topoII amplification: r=0.576 (95% CI, 0.290 to 0.767). ER, PR, tumor grade, HER2 and topoII failed to predict response.Conclusions: Sequential AC followed by D is a highly effective neoadjuvant treatment and permits BCS in more than 75% of patients. There is a significant correlation between HER2 amplification by FISH and topoII levels. Tumor grade, ER, PR, HER2 or topoII were no predictors of response to AC nor D.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2045.