Abstract P5-17-09: Biomarkers to distinguish hazardous from harmless ductal carcinoma in situ (DCIS) of the breast
Authors: Visser L , Elshof L , Groen E , van de Vijver K , Lips E , de Maaker M , Nieboer F , Schaapveld M , Rutgers E , Wesseling J 
Published: May 2016

Abstract
Background. The incidence of DCIS has increased since the introduction of population-based screening. This has not resulted in a decrease in invasive breast cancer incidence, implying overdiagnosis exists. All women with DCIS are still intensively treated, by surgery, radiotherapy, and/or hormonal treatment, although only a minority will develop a subsequent invasive breast cancer. As we cannot discriminate such hazardous from harmless DCIS lesions, accurate prognostic biomarkers are urgently needed. In the current study we aim to identify molecular markers for DCIS aggressiveness, using a large population-based cohort.
Patients and methods. We used a population-based, nation-wide cohort consisting of 10,090 women treated for primary DCIS between 1989 and 2004 with a median follow-up time of 10.7 years. Within this cohort, a case-control study was set up to analyse which markers are associated with progression to invasive breast cancer. Formalin-fixed paraffin embedded (FFPE) tissue blocks were retrieved from 1580 DCIS patients who were treated by breast conserving surgery without radiotherapy (316 DCIS patients with a subsequent ipsilateral invasive breast cancer (iiBC): i.e. the "cases"; and 1264 DCIS patients without subsequent invasive breast cancer: i.e. the "controls"). A first study using this population-based cohort will involve immunohistochemistry (IHC) on 200 "cases" and 500 "controls" for an 8-marker IHC panel (ER, PR, HER2, Ki67, p16, p53, COX-2, and Annexin A1). Molecular subtypes of the DCIS and invasive breast cancer lesions will be determined and intra-individual heterogeneity will be assessed. IHC marker expression will be both compared between "cases" and " controls" as well as between DCIS lesions and its subsequent invasive breast cancer. In a second study, DNA and RNA will be isolated from these specimens, using laser microdissection, and extensive molecular profiling will be performed.
Results. We have collected FFPE tissue blocks of 287 "cases" and 1149 "controls" (86% of requested material) from 56 participating hospitals. At present, the specimens of 223 "cases" (matched DCIS and iiBC specimen) and 103 "controls" have been centrally revised for extensive morphological characteristics. Only a small part (14%) of the specimens had to be excluded from the study population. IHC staining of the tissue specimens, using the 8-marker IHC panel is ongoing.
Conclusion. Within a nation-wide cohort of 10,090 patients diagnosed with primary DCIS, we were able to collect tissue material of a representative case-control series of 200 "cases" with subsequent invasive breast cancer and 500 invasive breast cancer-free "controls". This is the first time such a large unique, unbiased DCIS series, with long-term follow-up is analysed integrating clinical, histological, and immunohistochemical data. The results will be presented at SABCS 2015.
Citation Format: Visser L, Elshof L, Groen E, van de Vijver K, Lips E, de Maaker M, Nieboer F, Schaapveld M, Rutgers E, Wesseling J. Biomarkers to distinguish hazardous from harmless ductal carcinoma in situ (DCIS) of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-17-09.