Clinically Used Breast Cancer Markers Such As Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Are Unstable Throughout Tumor Progression

Department of Surgery, University of California at San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2012; 30(21):2601-8. DOI: 10.1200/JCO.2011.37.2482
Source: PubMed


PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemar's test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log-rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER-positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival.

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Available from: Ulla Wilking, May 04, 2015
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    • "Up to 30% to 40% of metastases from hormone receptor-positive primary breast cancer do not respond to endocrine therapy [9]. Moreover , some patients with ERα-positive tumors will relapse with a metastatic disease no longer expressing ER [10] or is endocrine resistant in spite of ER-expression due to acquired mutations [11]. The orchestrating mechanism behind endocrine resistance in tumors retaining ERα remains partly elusive. "
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    ABSTRACT: Breast cancer cells with stem cell characteristics (CSC) are a distinct cell population with phenotypic similarities to mammary stem cells. CSCs are important drivers of tumorigenesis and the metastatic process. Tamoxifen is the most widely used hormonal therapy for estrogen receptor (ER) positive cancers. In our study, tamoxifen was effective in reducing proliferation of ER + adherent cancer cells, but not their CSC population. We isolated, expanded and incubated CSC from seven breast cancers with or without tamoxifen. By genome-wide transcriptional analysis we identified tamoxifen-induced transcriptional pathways associated with ribosomal biogenesis and mRNA translation, both regulated by the mTOR-pathway. We observed induction of the key mTOR downstream targets S6K1, S6RP and 4E-BP1 in-patient derived CSCs by tamoxifen on protein level. Using the mTOR inhibitors rapamycin, everolimus and PF-04691502 (a dual PI3K/mTOR inhibitor) and in combination with tamoxifen, significant reduction in mammosphere formation was observed. Hence, we suggest that the CSC population play a significant role during endocrine resistance through activity of the mTOR pathway. In addition, tamoxifen further stimulates the mTOR-pathway but can be antagonized using mTOR-inhibitors. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters 07/2015; 367(1). DOI:10.1016/j.canlet.2015.07.017 · 5.62 Impact Factor
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    • "Cells fit to metastasize have departed already early in the evolution of the tumor, keeping the fitness to remain plastic and adaptive to the new environment. This is substantiated by recent findings showing that molecular markers for guiding treatment are not necessarily conserved between primary tumor and metastatic lesion [29] [30]. To our knowledge, we are unaware of any cancer treatment regiment that takes in consideration this evident difference between the primary tumor and metastatic lesion. "
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    • "In terms of the firmly established triplet of biomarkers used in the clinical management of breast cancer patients, namely ER/PgR/HER2, multiple lines of evidence indicate relevant rates of discordance between primary tumour and subsequent metastatic disease (Cardoso et al, 2001; Liedtke et al, 2009; Amir et al, 2012; Lindström et al, 2012). In terms of more recently recognised genomic aberrations observed in breast cancer, even for the most common ones such as PIK3CA mutations, only a few studies have interrogated their prevalence in metastatic disease in comparison to what is observed in primary tumours (Dupont Jensen et al, 2010; Gonzalez-Angulo et al, 2011; Kalinsky et al, 2011; Fumagalli et al, 2013). "
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