Even Low-level HER2 Expression May be Associated With Worse Outcome in Node-positive Breast Cancer

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
The American journal of surgical pathology (Impact Factor: 5.15). 02/2009; 33(5):759-67. DOI: 10.1097/PAS.0b013e31819437f9
Source: PubMed


HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients. Although standardized assays are used to help select patients for anti-HER2 therapy, there are no standardized criteria for assessing HER2 as a prognostic marker. Recent data using quantitative image analysis suggest that both high and low HER2 expression are associated with poor clinical outcome. Using the immunohistochemical scoring criteria currently recommended by the College of American Pathologists and American Society of Clinical Oncology to help select patients for trastuzumab, we evaluated HER2 protein expression in tumor tissue microarrays of 91 node-positive patients with invasive breast carcinoma treated with mastectomy and doxorubicin-based chemotherapy without trastuzumab and without irradiation with a median follow-up of 12.5 years. A wide range of HER2 expression (HER2 >or=1+) in the primary tumor was significantly associated with decreased locoregional recurrence-free survival (P=0.014), decreased disease-specific survival (P=0.001), and decreased overall survival (P=0.001). Even in the subset considered HER2 negative by current College of American Pathologists and American Society of Clinical Oncology guidelines, HER2=1+ was associated with worse outcome than HER2=0 in this patient cohort. The association between HER2 >or=1+ and worse outcome had the greatest statistical significance in the hormone receptor-positive subset of patients. These findings support the hypothesis that low-level HER2 expression may have significant clinical implications. Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy.

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    • "Some authors have illustrated that erbB-2 IHC tests generally reveal a correlation between an erbB-2 positive status and an aggressive phenotype [79], but other authors have proposed that normal levels of the erbB-2 protein could be associated with a similar aggressive phenotype [77], [80]. Additionally, even patients with low erbB-2 expression levels and worse outcome may confer important therapeutic potential being however ineligible for anti-HER2 therapy [80], [81]. This point of view is also in agreement with our results that indicated the presence of some association between low ERBB2 RNA and erbB-2 protein expression levels with a worse cat mammary lesion prognosis. "
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    ABSTRACT: Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%-59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10-15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "HER2 overexpression has been detected in many human tumor types, including breast, ovarian, endometrial, salivary gland, gastric, bladder and pancreatic cancers [9–13]. Its expression is normally associated with poor clinical outcome [14] even at a very low level. The use of Herceptin®, a humanized monoclonal antibody that binds the extracellular, juxtamembrane domain of HER2, has been proven to be an effective treatment for breast cancer in which HER2 overexpression is present [15,16]. "
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    ABSTRACT: Anti-HER2/neu antibody therapy has been reported to mediate tumor regression of HER2/ neu(+) tumors. Here we demonstrated the expression of HER2 in a wide range of human melanoma cells including a primary culture and seven cell lines, and we further investigated whether HER2 could be served as a target for T cell mediated immunotherapy of human melanoma. Specific cytolytic activity of activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi-Ab) against Malme-3M-luc cells was evaluated by bioluminescent signal generated by luciferase reporter which did not alter HER2 expression or proliferation ability of Malme-3M cells. Contrast with unarmed ATC, increased cytotoxic activity of HER2Bi-armed ATC against Malme-3M-luc cells was observed at effector/target (E/T) ratios of 1:1, 5:1, and 20:1. Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-γ than unarmed ATC counterpart at the E/T ratio of 20:1. In addition, compared with anti-HER2 mAb (Herceptin®) or unarmed ATC, HER2Bi-armed ATC showed remarkable suppression effect on Malme-3M-luc tumor cells. Furthermore, in melanoma tumor cell xenograft mice, infusion of HER2Bi-armed ATC successfully inhibited the growth of melanoma tumors. The anti-tumor effect of HER2Bi-armed ATC may provide a promising immunotherapy for melanoma in the future.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "In node-positive patients, HER2 amplification or protein overexpression has been shown to be a poor predictor of clinical outcome [21, 23–35]. A recent study by Gilcrease et al. has shown that any degree of HER2 overexpression (1+, 2+ or 3+) was associated with increased tumor recurrence and decreased patient survival in a node-positive cohort of breast cancer patients (n = 91) treated with doxorubicin-based chemotherapy without trastuzumab [36]. A different study showed a distinct, intermediate outcome in patients with low-level HER2 amplification by FISH, with a ratio of 1.5–2.2, "
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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%-20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin) a "humanized" monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls.
    Full-text · Article · Jan 2011 · Pathology Research International
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