Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer

Abstract

To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification. 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 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). 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; = 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 ( = 0.002 and < 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; = 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%, = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, = 0.005; and ypT0/is: 87.5% vs. 28.0%, < 0.001), and was largely absent in HR-negative tumors. 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. .

Relationship between <em>HER2</em> gene status and selected potential biological features related to trastuzumab resistance and its influence on survival of breast cancer patients undergoing trastuzumab adjuvant treatment

“…One of the problems is the variety of treatment schedules (neoadjuvant/adjuvant) and of breast cancer stage (early/metastatic). It appears that in neoadjuvant setting HER2 amplification is positively correlated with more frequent pathological response to trastuzumab treatment, 10 , 37 but not necessarily to higher survival rate. 37 In case of metastatic breast cancer, most of the studies noted relationship between higher values of HER2/CEP17 ratio and longer time to progression 9 , 11 , 12 or overall survival 9 or higher probability of an objective response.…”

The differences of clinicopathologic characteristics among subgroups of reclassified HER2 fluorescence in situ hybridization (FISH) according to the ASCO/CAP 2018 breast cancer HER2 testing guidelines

“…Patients who had low amplified HER2 status could also benefit from HER2 targeted therapy 21. However, low-amplified HER2 status may indicate lower sensitivity to HER2 targeted therapy than high-amplified HER2 status 14 15…”

“…The aim of this retrospective study was to compare clinicopathologic features among the reclassified FISH subgroups with updates of 2018 guidelines in a large cohort of breast carcinoma cases. With suggestions of other studies that HER2 amplified cases with higher average HER2 copy numbers have higher sensitivity to targeted therapy,14 15 we also divided HER2 amplified cases ( HER2 / CEP17 ratio ≥2.0, HER2 copy number ≥4.0) into a high-amplified group ( HER2 copy number ≥6.0) and a low-amplified group ( HER2 copy number ≥4.0 and<6.0) to determine whether there were any differences between these two groups.…”

Micromolecular methods for diagnosis and therapeutic strategy: a case study

“…In the absence of lymph-node involvement, adjuvant chemotherapy is not fully recommended for HER2-overexpressing breast cancers of less than 5 mm (pT1mi and pT1a) [ 10 , 11 ]. Here, for decision treatment, we considered two biological characteristics: the high metastatic potential of this micro-invasive primary tumor since the patient already had a lymph node micrometastasis at diagnosis (pN1mi), and the level of HER2 amplification, since a ratio HER2/CEP17 over 5 is associated with a higher complete response rate to trastuzumab-based chemotherapy [ 12 ]. We finally took into account the patient's own preference to maximally decrease her relapse-risk.…”