Abstract 751: Ductal carcinoma in situ of the breast: Cancer precursor or not
Authors: Visser Lindy , Hoogstraat Marlous , Bismeijer Tycho , Elshof Lotte , Vijver Koen van de , Groen Emilie , Almekinders Mathilde , Sanders Joyce , Bierman Carolien , Peters Dennis , Hofland Ingrid , Nieboer Frank , Maaker Michiel de , Kristel Petra , Mulder Lennart , Broeks Annegien , Schaapveld Michael , Schmidt Marjanka , Wessels Lodewyk , Lips Esther , Wesseling Jelle ,   On behalf of the PRECISION team
Published: August 2019

Abstract
Background. Ductal carcinoma in situ (DCIS) is a potential precursor of invasive breast cancer (IBC). However, the natural course of a particular DCIS lesion is unknown, because almost all women with DCIS are treated. Furthermore, most studies are biased because these comprise DCIS adjacent to IBC, also known as synchronous DCIS and IBC, indicating that such DCIS lesions already have the capacity to progress to IBC. It is still unknown which proportion and type of subsequent ipsilateral IBCs (iIBC) are related to the initial primary “pure” DCIS lesion. Therefore, we performed an extensive molecular characterization of DCIS and matched subsequent iIBC, to better understand the natural course of DCIS.
Patients and methods. We used a unique series of 78 women diagnosed with DCIS and treated by breast conserving surgery (BCS) alone, which subsequently developed iIBC. Mean time to iIBC event was 6.3 years (range 0.5-17.0). These 78 women are a representative sample of a case-control series, nested in a nation-wide, population-based cohort including all patients diagnosed with DCIS between 1989 and 2005 in the Netherlands (Visser, et al Clin Can Res 2018). Data on tumor location (ICD-10) was available for all lesions. DNA and RNA was simultaneously extracted for 78 DCIS lesions and 78 matched subsequent iIBC (DNA &gt;20ng; RNA &gt;100ng), and RNA sequencing (RNAseq) and low coverage whole genome sequencing (CNVseq) was performed. Panel sequencing (PanelSeq), using a custom panel of 53 breast cancer driver genes, was performed with the remaining DNA of 42 DCIS and iIBC matched pairs. We determined if the iIBC lesion and DCIS lesion were related, by comparing tumor location and genomic features.
Results. Based on tumor location and histological grade, &gt;95% of the subsequent iIBC reflected outgrowth of residual disease. Based on RNAseq data, 77% of all DCIS and IBC lesions classified into the same PAM50 subtypes. The CNVseq data showed that the DCIS lesions contained copy number aberrations on typical breast cancer-associated loci, such as 1q gain, 8q gain, 16q loss, 20q gain. However, when we compared DCIS with their matched iIBC, we observed in 41% of the cases very distinct copy number profiles, indicating either outgrow of a different tumor (minority) subclone or a second primary tumor. Analysis of PanelSeq mutation data supported this clonal or independent origin of the subsequent iIBC.
Conclusion. To our knowledge, our study is the first to investigate if subsequent iIBC is likely to originate from the initial primary “pure” DCIS in a large series with long-term follow-up.
Surprisingly, our CNVseq and PanelSeq results indicate that more than one third of the subsequent iIBCs after BCS alone treated primary DCIS are likely to be second primary tumors or represent selective outgrowth of a minority DCIS subclone.
Citation Format: Lindy Visser, Marlous Hoogstraat, Tycho Bismeijer, Lotte Elshof, Koen van de Vijver, Emilie Groen, Mathilde Almekinders, Joyce Sanders, Carolien Bierman, Dennis Peters, Ingrid Hofland, Frank Nieboer, Michiel de Maaker, Petra Kristel, Lennart Mulder, Annegien Broeks, Michael Schaapveld, Marjanka Schmidt, Lodewyk Wessels, Esther Lips, Jelle Wesseling, On behalf of the PRECISION team. Ductal carcinoma in situ of the breast: Cancer precursor or not [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 751.