Abstract 4991: Identifying a highly-aggressive DCIS subgroup by studying intra-individual DCIS heterogeneity among invasive breast cancer patients
Authors: Jiang Zhengyu , Pape-Zambito Dana , Devarajan Karthik , Wu Hong , Slater Carolyn , Dolinsky Lauren , Daly Mary , Chen Xiaowei 
Published: May 2015

Abstract
Background: Detection rates for ductal carcinoma in situ (DCIS) have dramatically increased because of the widespread use of mammographic screening. The heterogeneity among multiple DCIS lesions within the same patient, also diagnosed with invasive ductal carcinoma (IDC), has not been well evaluated, leaving clinical and research implications of this intra-individual heterogeneity of DCIS yet to be explored. In the study presented here, we tested the hypothesis that classification of heterogeneous DCIS based on adjacent IDC and normal terminal duct lobular units (TDLU) in patients concurrently diagnosed with IDC and DCIS helps to identify DCIS subgroups which have different degrees of “aggressiveness”.
Experimental Designs and Results: Ten DCIS lesions from each of 36 patients concurrently diagnosed with DCIS and IDC were randomly selected and scored with IHC biomarkers. Our results showed that expression of PR, HER2, Ki-67 and p16 varied significantly in DCIS lesions from a single patient (P &lt; 0.05 for PR; P &lt; 1 × 10-8 for HER2, Ki-67 and p16). In addition, seventy-two percent of the individuals had heterogeneous expression in at least 2/6 markers (P &lt; 10-18, vs. hypothesized homogeneity baseline, 10%). Importantly, by comparing the expression of promising DCIS risk biomarkers (Ki-67, p53 and p16) among different DCIS subgroups, we found that DCIS lesions in subgroup IIb, which had the same molecular subtypes as the adjacent IDC but not the same subtypes as the adjacent TDLU, had a higher Ki-67 index (P &lt; 10-7), a higher chance of positive p53 staining (P = 0.02), and less p16 staining (P = 0.08) than those in type I DCIS lesions with different molecular subtypes from the adjacent IDC. Further molecular characterization by microarray analysis identified that 246 annotated coding and non-coding genes were differentially expressed between DCIS subgroups Type I and IIb [FC (fold change)&gt;2.0, P&lt;0.05]. A majority of genes were upregulated in type IIb DCIS and more than 50% of genes are cancer-relevant (P &lt; 10-8∼-2). Importantly, a group of differentially expressed genes in subgroup IIb including CD44, IFIT1, STAT1, MLH1, PARP9 and BRIP1 were confirmed by qPCR validation and likely play important roles in DCIS progression based on previous findings, which further support that Type IIb DCIS may represent a highly aggressive subgroup.
Conclusions: By using a systematic approach, our results clearly demonstrate that intra-individual heterogeneity in DCIS is very common in patients concurrently diagnosed with IDC. Our novel findings of a DCIS subpopulation with high-aggressiveness will provide a new paradigm for mechanistic studies of breast tumor progression and also have broad implications for prevention research as heterogeneous pre-invasive lesions are present in many other cancer types.
This work was kindly supported by the Susan G. Komen for the Cure (KG100274), and Eileen Stein Jacoby Fund.
Citation Format: Zhengyu Jiang, Dana Pape-Zambito, Karthik Devarajan, Hong Wu, Carolyn Slater, Lauren Dolinsky, Mary Daly, Xiaowei Chen. Identifying a highly-aggressive DCIS subgroup by studying intra-individual DCIS heterogeneity among invasive breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4991. doi:10.1158/1538-7445.AM2014-4991