HER-2 therapy. HER-2/neu diagnostics in breast cancer

Abstract

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed. IntroductionFor many years estrogen receptor (ER) status has guided the administration of hormone therapy to patients with breast cancer. Positive ER status narrows the pool of patients eligible for hormone therapy and increases the likelihood of favorable response. However, ER status indicates that approximately 50% of patients will respond, but it does not predict which patients will respond to hormone therapy. Similarly, the HER-2/neu status of breast carcinoma narrows the pool of candidates eligible for HER-2/neu directed therapies, but it does not definitively select those who will or will not respond.The HER-2/neu oncoprotein continues to be an important target in the development of a variety of new cancer therapies, which include mAb-based therapy, small-molecule drugs directed at the internal tyrosine kinase portion of the HER-2/ neu oncoprotein, and vaccines. The most widely known HER-2/ neu-directed therapy is trastuzumab (Herceptin; Genentech, South San Francisco, CA, USA). Trastuzumab is a humanized recombinant mAb that specifically targets the HER-2/neu extracellular domain (ECD). [6]. Therefore, accurate determination of the HER-2/neu status is extremely important in guiding therapy, and the reliability of the diagnostic method used to determine HER-2/neu status is critical in selecting the most appropriate patients for HER-2/neu directed therapies.The present review is focused on HER-2/neu testing, and so we address reports concerning the tissue tests used to determine HER-2/neu status as well as tests to quantitate circulating levels of the HER-2/neu ECD. Although there is approximately 80% to 85% accuracy in determining HER-2/ neu status by tissue analysis, studies collectively show that the HER-2/neu status of the primary breast cancer (PBC) does not always accurately reflect the HER-2/neu status of the MBC. We highlight some of the factors that contribute to inaccurate assessment of HER-2/neu status by tissue testing, in the hope that this will improve assessment of HER-2/neu status. We also review reports on assays that have been used to quantitate circulating levels of the HER-2/neu ECD, and we present evidence that not all HER-2/neu assays have been adequately validated, which has resulted in inaccurate Review HER2 therapy HER-2/neu dia...

Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer

“…We demonstrated that coexpression of these molecules was associated with worse prognosis than high HER2/neu alone, indicating that Grb7 coexpression might be necessary for HER2/neu function. The importance of HER2/neu in breast cancer is well established [41]; HER2/neu is overexpressed in approximately 20%-30% of invasive breast cancers and is original article Annals of Oncology associated with poor prognosis, as reviewed previously [42]. Drugs that target HER2/neu have been shown to prolong survival, as reviewed previously [43][44][45].…”

Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

“…The serum HER-2 test using the ADVIA Centaur assay is approved by the Food and Drug Administration (FDA) for follow-up and monitoring of patients with metastatic breast cancer (MBC) whose initial serum HER-2 concentration is above 15 ng/mL (4).…”

Enhanced immuno-detection of shed extracellular domain of HER-2/neu

“…Measured levels of the sECD-HER 2/neu protein greater than 15 ng/ml were indicative of the potential presence and the associated progression of primary tumors to metastatic breast cancer [4,6,7]. Most commercially available assays use this concentration as a focal point leaving smaller amounts undetected.…”

“…The human epidermal growth factor HER-2 oncogene (cerbB-2) has been implicated in this disease [1][2][3][4]. The HER-2/neu oncoprotein is amplified and over-expressed in 25 to 30 percent of patients with aggressive breast cancer.…”