Pathologic Complete Response and Survival after Trastuzumab-Based Neoadjuvant Therapy According to the Level of HER2-Amplification.

Abstract

Abstract Purpose: Fluorescence in situ hybridization (FISH) is used to determine human epidermal growth factor receptor (HER-2) status and patient eligibility for trastuzumab therapy. We analysed whether the level of HER-2 amplification significantly influenced pathological complete response (pCR), disease-free survival and overall survival in patients with a locally advanced breast cancer treated with trastuzumab-based neoadjuvant therapy.Patients and methods: Breast biopsies from 116 HER-2-positive (3+ in immunohistochemistry, or 2+ and amplified by FISH) patients treated with trastuzumab-based neoadjuvant therapy were retrospectively analysed for HER-2 amplification using FISH. Tumors were classified as no (<6 gene copies number per nuclei), low (6-10/nuclei) or high amplification (>10/nuclei). According to ASCO guidelines, in case of low amplification, the ratio of HER2 copies on centromeric region chromosome 17 (CEP17) was analyzed and the tumor was confirmed as amplified if the ratio was > to 2.2. Pathologic response was assessed according to Chevallier's classification. Pathologic complete response was considered if no invasive carcinoma was found either in the breast or in the lymph nodes. Median follow-up lasted 46.3 [43.9-49.6] months. Response rates were compared using Chi2-tests. Survivals were calculated according to Kaplan-Meier and compared using log-rank tests.Results: The distribution of the 116 patients according to the level of amplification in FISH was the following: 17 (15%) no amplification, 33 (28%) low amplification and 66 (57%) high amplification. In the group of tumors with 6-10 copies of HER2 genes, they were no cases with a ratio HER2/CEP17 between 1.8 and 2.2 (borderline cases). Trastuzumab-based neoadjuvant therapy achieved pCR in 45 of 116 (38.8%) tumors. Pathologic complete response rate in low- and high- amplification tumors was significantly higher compared with no-amplification tumors (44% versus 6%; p=0.003). In the subgroup of amplified tumors (low and high), pCR rate in high-amplification tumors was significantly higher than in low-amplification tumors (54% versus 24%; p=0.004).In this subgroup of patients with amplification (low and high), there was no significant difference in disease-free survival (p=0.17) and in overall survival (p=0.22) according to the degree of HER2-amplification. However, among the 55 patients with a partial response in this subgroup (low- and high-amplification), disease-free survival and overall survival tend to be better in patients with low amplification tumor (p=0.08 and p=0.05 respectively).Conclusion: This study confirms a positive correlation between the level of HER-2 amplification assessed by FISH and the rate of pCR after trastuzumab-based neoadjuvant therapy. However, this benefit in term of pCR was not associated with a benefit in term of disease-free survival or overall survival. Indeed, as it was reported in metastatic or adjuvant settings, the level of HER-2 amplification assessed by FISH does not seem to influence survival for patients treated with trastuzumab-based therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1089.