Abstract
Purpose: To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.Experimental Design: 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by in situ hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is).Results: In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; P = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P = 0.002 and P < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90; P = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, P = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, P = 0.005; and ypT0/is: 87.5% vs. 28.0%, P < 0.001), and was largely absent in HR-negative tumors.Conclusions: An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. Clin Cancer Res; 23(14); 3676-83. ©2017 AACR.
Highlights
HER2 is amplified in 18% to 20% of human breast carcinomas and has been intensively evaluated as a therapeutic target in recent years [1,2,3,4]
PCR to Trastuzumab Is Dependent on HER2/CEP17 Ratio in BC
At least one of the two steroid hormone receptors (HR-positive/luminal HER-amplified) was detected in 62 samples (54.4%) whereas both estrogen receptor (ER) and progesterone receptor (PR) were absent in 52 tumors (45.6%, HER2-amplified, nonluminal; Table 1 and Fig. 1)
Summary
HER2 is amplified in 18% to 20% of human breast carcinomas and has been intensively evaluated as a therapeutic target in recent years [1,2,3,4]. Several randomized trials have investigated its efficacy in the neoadjuvant setting, using pathologic complete response (pCR) as primary endpoint, and consistently found that 4–8 cycles of preoperative trastuzumab improved pCR rate [7,8,9,10,11]. Our study is the first to determine the optimum HER2/ CEP17 ratio cut-off value for tumor response (pathologic complete response, pCR), commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is, for HER2-positive breast cancer patients treated with neoadjuvant trastuzumab. Results from our study show convincingly that a HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, in HER2/hormone receptor copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab-based therapy is initiated. Our findings have significant implications for the treatment and clinical management of this subgroup of breast cancer patients
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