Discordant Marker Expression Between Invasive Breast Carcinoma and Corresponding Synchronous and Preceding DCIS Lindy L. Visser, MSc,* Lotte E. Elshof, MD, PhD,*†‡ Koen Van de Vijver, MD, PhD,§ Emma J. Groen, MD,*§ Mathilde M. Almekinders, MD,*§ Joyce Sanders, MD,§ Carolien Bierman, BSc,§ Dennis Peters, BSc,∥ Ingrid Hofland, BSc,∥ Annegien Broeks, PhD,∥ Flora E. van Leeuwen, PhD,† Emiel J. Th Rutgers, MD, PhD,‡ Marjanka K. Schmidt, PhD,*† Michael Schaapveld, PhD,† Esther H. Lips, PhD,* and Jelle Wesseling, MD, PhD*§ Abstract: Ductal carcinoma in situ (DCIS) is considered a po- tential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared characteristics of IBC lesions with those of ad- jacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we com- pared both primary DCIS and synchronous DCIS with the as- sociated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were per- formed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields differ- ent results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS. Key Words: ductal carcinoma in situ, invasive breast carcinoma, local recurrence, synchronous lesions, immunohistochemistry (Am J Surg Pathol 2019;43:1574–1582) D uctal carcinoma in situ (DCIS) is generally accepted as a nonobligate precursor of invasive breast carcinoma (IBC). 1 This is because they are frequently found next to each other sharing the genetic alterations and risk factors (eg, age, family history of breast carcinoma, etc.). 2–6 While DCIS itself is not life threatening, it does increase a wom- an’s risk of developing IBC later in life, which subsequently could lead to breast cancer-specific death. 7 To prevent progression to invasive disease, almost all DCIS lesions are treated by mastectomy or breast-conserving surgery with or without adjuvant radiotherapy and/or endocrine therapy. If it holds true that DCIS directly progresses to IBC, one would expect that primary DCIS and subsequent ip- silateral IBC share multiple features, for example, hor- mone receptor and HER2 status. It has been shown that the histological grade of the DCIS component adjacent to invasive disease (synchronous DCIS) and the grade of the IBC lesion are significantly correlated, that is, well- differentiated DCIS relates to grade I IBC and poorly differentiated DCIS to grade III IBC. 8,9 Therefore, it is thought that, if progression occurs, well-differentiated DCIS will give rise to grade I IBC and poorly differ- entiated DCIS to grade III IBC. Nonetheless, comparison of marker expression shows conflicting results. Allred et al found that HER2 overexpression is more frequently From the *Division of Molecular Pathology; †Division of Psychosocial research and Epidemiology; ‡Department of Surgery; §Department of Pathology, Division of Diagnostic Oncology; and ∥Core Facility Molecular Pathology and Biobanking, Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. L.L.V., F.E.v.L., E.J.R., M.S., M.K.S., E.H.L., and J.W.: designed the study. L.L.V. and L.E.E.: collected the data. D.P., I.H., and A.B.: set up and performed IHC stains. L.L.V., K.v.d.V., E.J.G., M.M.A., J.W., J.S., and C.B.: did the pathology review and IHC assessment. L.L.V., F.E.v.L., E.J.R., M.S., M.K.S., E.H.L., and J.W.: analyzed and interpreted the data. L.L.V.: wrote the report. Conflicts of Interest and Source of Funding: This work was funded by Pink Ribbon (grant number 2013.WO29, to J.W.) and A Sister’s Hope (grant number 2011.WO19.C88, to J.W.), and it was jointly funded by Cancer Research UK and the Dutch Cancer Society (grant number C38317/A24043, to J.W.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jelle Wesseling, MD, PhD, Department of Pathology, Division of Diagnostic Oncology and Division of Molecular Pathol- ogy, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands (e-mail: j.wesseling@nki.nl). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.ajsp.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ORIGINAL ARTICLE 1574 | www.ajsp.com Am J Surg Pathol  Volume 43, Number 11, November 2019 Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.