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      Serum HER2 extra-cellular domain, S100ß and CA 15-3 levels are independent prognostic factors in metastatic breast cancer patients

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          Metastatic breast cancer (MBC) prognosis is highly variable, depending on various factors such as the biological subtype, the performance status, disease extension…. A better evaluation of a patient’s prognostic factors could allow for a more accurate choice of treatments. The role of serum tumor markers remains, however, unclear in this population. Considering the recent interest in phenotypic changes and tumor heterogeneity during breast cancer progression, additional tumor markers could be interesting in this setting.


          Two hundred fifty MBC patients treated at the Montpellier Cancer Institute (2008–2015) were retrospectively selected, based on the availability of frozen serum samples. The usual MBC clinical and pathological variables were collected, altogether with Cancer Antigen 15-3 (CA15-3), Carcinoembryonic Antigen (CEA), HER2 extra-cellular domain (ECD), Neuron Specific Enolase (NSE), S100ß protein and Matrix Metalloproteinase 9 (MMP-9) serum levels in order to determine their prognostic value.


          With a median follow-up of 40.8 months, median overall survival was 16.2 months (95 % CI 12.4–20.6). In multivariate analysis, the performance status, brain or subcutaneous metastases, the number of previous metastatic chemotherapy lines and the tumor biological subtype were independent prognostic factors. Elevated CA 15-3 (HR = 1.95, IC 95 % 1.31–2.93, p = 0.001), HER2 ECD (regardless of tumor HER2 status, HR = 2.51, IC 95 % 1.53–4.12, p < 0.001) and S100ß (HR = 1.93, IC 95 % 1.05–3.54, p = 0.033) serum levels were independently associated with a poor outcome.


          Serum CA 15-3, HER2 ECD and S100ß could represent useful independent prognostic factors in MBC. Of particular interest is the independent value of serum HER2 ECD levels, regardless of the tumor HER2 status, possibly linked to metastatic tumor heterogeneity.

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          Most cited references 43

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          Metastatic behavior of breast cancer subtypes.

          Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected. Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression. Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases. Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.
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            Functions of S100 proteins.

            The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.
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              Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review.

              PURPOSE The purpose of this study was to determine whether trastuzumab improves prognosis of women with metastatic human epidermal growth factor receptor 2 (HER2)/neu -positive breast cancer beyond that of women with HER2/neu-negative disease. PATIENTS AND METHODS Two thousand ninety-one women with metastatic breast cancer diagnosed from 1991 to 2007, with known HER2/neu status and who had not received trastuzumab in the adjuvant setting, were identified. Disease was classified into the following three groups: HER2/neu negative, HER2/neu positive without first-line trastuzumab treatment, and HER2/neu positive with first-line trastuzumab treatment. Overall survival (OS) was estimated using the Kaplan-Meier product-limit method and compared between groups with the log-rank test. Cox proportional hazards models were used to determine associations between OS and HER2/neu status after controlling for patient characteristics. Results One hundred eighteen patients (5.6%) had HER2/neu-positive disease without trastuzumab treatment, 191 (9.1%) had HER2/neu-positive disease and received trastuzumab treatment, and 1,782 (85.3%) had HER2/neu-negative disease. Median-follow-up was 16.9 months. One-year survival rates among patients with HER2/neu-negative disease, HER2/neu-positive disease and trastuzumab treatment, and HER2/neu-positive disease and no trastuzumab treatment were 75.1% (95% CI, 72.9% to 77.2%), 86.6% (95% CI, 80.8% to 90.8%), and 70.2% (95% CI, 60.3% to 78.1%), respectively. In a multivariable model, women with HER2/neu-positive disease who received trastuzumab had a 44% reduction in the risk of death compared with women with HER2/neu-negative disease (hazard ratio [HR] = 0.56; 95% CI, 0.45 to 0.69; P < .0001). This HR varied with time and was significant for the first 24 months and not significant after 24 months. CONCLUSION Our results show that women with HER2/neu-positive disease who received trastuzumab had improved prognosis compared with women with HER2/neu-negative disease.

                Author and article information

                [ ]Department of Medical Oncology, Institut régional du Cancer de Montpellier, 208 rue des apothicaires, 34298 Montpellier, France
                [ ]Department of Clinical Research, Clinique Beausoleil, 19 Avenue de Lodève, 34070 Montpellier, France
                [ ]Department of Biology and Oncogenetic, Institut régional du Cancer de Montpellier, 208 rue des apothicaires, 34298 Montpellier, France
                [ ]Translational Research Unit, Institut régional du Cancer de Montpellier, 208 rue des apothicaires, 34298 Montpellier, France
                [ ]Centre Azuréen de Cancérologie, 1 place du Docteur Jean Luc Broquerie, 06250 Mougins, France
                [ ]Biometrics unit, Institut régional du Cancer de Montpellier, 208 rue des apothicaires, 34298 Montpellier, France
                +33-4-67-61-25-57 ,
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                7 July 2016
                7 July 2016
                : 16
                27387327 4937557 2448 10.1186/s12885-016-2448-1
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

                Funded by: GEFLUC (Groupement des Entreprises Françaises dans la Lutte contre le Cancer) Languedoc-Roussillon
                Funded by: SIRIC Montpellier Cancer
                Award ID: INCa-DGOS-Inserm 6045
                Award Recipient :
                Research Article
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                © The Author(s) 2016


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