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Review Breast Cancer Molecular Diagnostics in Breast Cancer Routine Practice Natalie D ter Hoeve, Cathy B Moelans, Willemijne AME Schrijver, Wendy de Leng and Paul J van Diest Department of Pathology, University Medical Center Utrecht, The Netherlands T he portfolio of adjuvant systemic treatment of breast cancer nowadays contains novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules that are only effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand, and costs and side effects on the other. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. Keywords Breast cancer, pathology, molecular biomarkers Disclosure: Natalie D ter Hoeve, Cathy B Moelans, Willemijne AME Schrijver, Wendy de Leng and Paul J van Diest have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. No funding was received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 12 October 2016 Adjuvant systemic treatment of breast cancer is moving away from the limited portfolio of traditional hormonal drugs and chemotherapy, towards a gamma of novel anti-hormonal and chemotherapeutic drugs, immunotherapeutic approaches and small molecules. All these therapeutic approaches are unfortunately effective in a limited number of patients and are often associated with high costs and significant side effects. Therefore, the traditional “one size fits all” approach can no longer be upheld, and a personalised approach based on individual tumour biomarkers is required to arrive at the optimal balance between effectiveness on the one hand and costs and side effects on the other. Over recent years, progress in molecular techniques has made it possible to analyse formalin fixed paraffin embedded (FFPE) tumour material of larger cohorts of patients. This has incentivised many translational studies relating molecular tumour biomarkers to diagnosis, prognosis and/or response to therapy, yielding many relevant molecular biomarkers that have rather quickly made it to clinical pathology practice. The aim of this paper is to provide an overview of the molecular biomarkers and associated molecular tests that are currently relevant in pathology of invasive breast cancer. Accepted: 13 February 2017 Citation: European Oncology & Haematology, 2017;13(1):74–9 Corresponding Author: Paul J van Diest, Department of Pathology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht. E: p.j.vandiest@umcutrecht.nl Diagnostic markers Hereditary breast cancers About 5–10% of breast cancer cases are due to a hereditary predisposition. 1 In most of these cases, mutations are found in well-characterised, medium to high-risk genes, such as BRCA1, BRCA2, CHEK2, TP53, PALB2, or BRIP1, 2 of which BRCA1 and BRCA2 are the most important ones. Promotor hypermethylation of BRCA1 and BRCA2 seems to be very infrequent in BRCA1/2 germline mutation related breast cancers, and significantly more frequent in sporadic cancers [data unpublished, submitted for publication]. BRCA1/2 promoter methylation testing, pointing to sporadic cancers when present, may grow out to be clinically useful once the diagnostically optimal CpG islands have been identified. 3 Copy number analysis by array comparative genomic hybridisation (CGH) showed frequently occurring gains of 3q, 7p, 8q 10p, 12p, 16p and 17q, and loss of 2q, 3p, 4p, 4q, 5q, 12q, 16p and 18q in BRCA1 germline mutation related cancers. BRCA2 related breast cancers show more frequently gains of 8q, 17q22–q24 and 20q13, and loss of 8p, 6q, 11q and 13q compared to BRCA1 related cancers. 4,5 A multiplex ligation-dependent probe amplification (MLPA) kit ® (MRC Holland, Amsterdam, The Netherlands) for copy number testing pointing to BRCA1 related cancers is commercially available. Molecular (intrinsic) typing Several gene expression studies have revealed the existence of five molecular subtypes of breast cancer: a “basal-like” subgroup with low oestrogen receptor (ER)/progesterone receptor(PR)/ human epidermal growth factor receptor 2 (HER2) and expression of basal cytokeratins; a subgroup mainly driven by HER2 amplification and overexpression while being ER/PR low; 74 TOU C H ME D ICA L ME D IA