Cancer. 2013 Aug 1;119(15):2675-82.

Soluble human epidermal growth factor receptor 2 (HER2) levels in patients with HER2-positive breast cancer receiving chemotherapy with or without trastuzumab: results from North Central Cancer Treatment Group adjuvant trial N9831.

Moreno-Aspitia A, Hillman DW, Dyar SH, Tenner KS, Gralow J, Kaufman PA, Davidson NE, Lafky JM, Reinholz MM, Lingle WL, Kutteh LA, Carney WP, Dueck AC, Perez EA.

Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL 32224, USA. morenoaspitia.alvaro@mayo.edu

 

ABSTRACT

Purpose: IncreasedsHER2 is an indicator of poor prognosisin HER2+ metastatic breast cancer. This study evaluated the levels of sHER2 during treatment and at time of recurrence in the adjuvant N9831 clinical trial.

Patients and Methods: Aims were to describe sHER2 levels during treatment and at time of recurrence in patients randomized to Arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab) and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available for 2318 patients. Serial samples were available from 105 patients and recurrence samples were available from 124 patients. Cutoff for this assay was 15ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models.

Results: Differences between groups existed by age, menopausal status and hormone receptor status. Within Arms A, B and C, patients with baseline sHER2 ≥15ng/mL were found to have worse DFS than patients with baseline sHER2 <15ng/mL (A: HR=1.81, p=0.0014; B: HR=2.08, p=0.0015; C: HR=1.96, p =0.01). Among the 124 patients with disease recurrence, sHER2 levels increased from baseline to time of recurrence in Arm A and Arm B while it remained unchanged in Arm C. Patients with recurrence sHER2 levels ≥15ng/mL had shorter survival time following recurrence with 3-year OS of 51% compared to 77% for the <15ng/mL sHER2 group (HR=2.36; 95% CI: 1.19-4.70, p=0.01).

Conclusions: In early stage HER2-positive breast cancer, high baseline sHER2 level is a prognostic marker associated with shorter DFS and high sHER2 level at recurrence and is predictive of shorter survival.

Keywords: Breast cancer, HER2, soluble HER2, adjuvant trial

PMID: 23744760

 

SUPPLEMENT

Breast carcinoma is a significant health problem worldwide, with an estimated 1.38 million women diagnosed annually. The discovery of amplification and/or overexpression of the tyrosine kinase human epidermal growth factor receptor 2 (HER2) in 15-20% of invasive breast cancers, and the correlation of HER2 overexpression with worse prognosis in both locoregional and advanced disease, has revolutionized the understanding of prognosis and therapeutic management of breast cancer patients. In addition to evaluating HER2 and other molecular markers in tissue specimens, there has been great interest in serologic-based testing for circulating HER2 due to the accessibility of serologic testing and the possibility of serial monitoring for tumor response to therapy. HER2 is a 185 kDa protein composed of an intracellular domain, a transmembrane, and an extracellular domain (ECD). The ECD is occasionally cleaved by matrix metalloproteinases and released into the peripheral circulation as soluble HER2 (sHER2). Previous studies in the metastatic setting suggested that high circulating sHER2 levels are a prognostic factor of inferior progression-free survival (PFS) and overall survival (OS), and a predictive factor of poor response to endocrine therapy and some chemotherapy regimens. This study explored the role of sHER2 as a potential prognostic or predictive marker, in a large prospective study of chemotherapy alone or with trastuzumab for patients with HER2-positive resected breast cancer (N9831).

Serum samples were scheduled to be obtained at baseline in all patients (study entry; all patients were post primary surgical resection of tumors), throughout treatment in a subset of 35 patients per arm (every 3 months for the first year then every 6 months from year 2 to year 5), and when available, at time of tumor recurrence for all patients with recurrent disease. The cutoff for the assay used for normal and high levels was 15 ng/mL per FDA-approved ADVIA Centaur® HER-2/neu assay recommendation. Baseline samples were available for 2318 patients participating in Arms A (795), B (814) and C (709). 1187 patients were excluded from the statistical analysis for various reasons. Serial samples were available from 105 patients and recurrence samples were available from 124 patients for analyses.

Differences between groups existed by age, menopausal status and hormone receptor status. Within Arms A, B and C, patients with baseline sHER2 ≥15ng/mL were found to have worse DFS than patients with baseline sHER2 <15ng/mL (A: HR=1.81, p=0.0014; B: HR=2.08, p=0.0015; C: HR=1.96, p =0.01). Among the 124 patients with disease recurrence, sHER2 levels increased from baseline to time of recurrence in Arm A and Arm B while it remained unchanged in Arm C. Patients with recurrence sHER2 levels ≥15ng/mL had shorter survival time following recurrence with 3-year OS of 51% compared to 77% for the <15ng/mL sHER2 group (HR=2.36; 95% CI: 1.19-4.70, p=0.01).

Although the clinical importance of soluble HER2 has been studied extensively in metastatic breast cancer, with no consensus as of yet, there are little available data regarding the use of sHER2 in locoregional breast cancer or in the era of multiple anti-HER2 therapies. In this adjuvant study, N9831 phase III trial, 12% (289) of the 2318 women who enrolled in the study after undergoing breast cancer resection were noted to have baseline elevation of sHER2. Patients with high baseline levels of sHER2 demonstrated significantly worse DFS in Arm A (standard chemotherapy without trastuzumab) compared to those with normal levels, confirming a prognostic relevance of this marker in HER2-positive breast cancer not treated with trastuzumab. There was also a correlation of elevated baseline sHER2 with worse DFS in patients on Arm C (standard chemotherapy plus concurrent trastuzumab) who had an elevated baseline sHER2 level (HR=1.96; p=0.01). Again, this is in keeping with some of the data published in the metastatic setting, suggesting that patients with elevated sHER2 levels at baseline have inferior outcomes, in this case even when treated with trastuzumab. A number of other biomarkers that have shown promise in preclinical models are being evaluated in many of the already completed large adjuvant HER2 clinical trials for their potential to prognosticate risk of disease recurrence and predict response to anti-HER2-based therapies. To date, none of them have reliably been found to be of clinical significance, including p95 HER2, PTEN, PI3-kinase, topoisomerase IIα, C-MYC, and IGF-1R. Additional prospective studies are needed to further evaluate the role of soluble HER2 testing in the neoadjuvant, adjuvant and metastatic settings, especially within the context of trials using newer HER2-directed therapies such as lapatinib, pertuzumab, and trastuzumab-emtansine.

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