Abstract 3653: Intra-individual heterogeneity of DCIS lesions in patients concurrently diagnosed with invasive ductal carcinoma .
Authors: Pape-Zambito Dana , Jiang Zhengyu , Wu Hong , Devarajan Karthik , Slater Carolyn M. , Cai Kathy Q. , Patchefsky Arthur , Daly Mary B. , Chen Xiaowei 
Published: August 2014

Background: It has been well documented that several cancers exhibit a large amount of heterogeneity when evaluating cells from different patients. However, few studies have quantified the level of cellular heterogeneity observed within an individual patient. This is significant because patients are often treated based upon expression of certain protein biomarkers, yet heterogeneous expression of these markers may affect the success of current targeted drug strategies. The objective of this study was to quantitatively assess intra-individual heterogeneity of standard clinical markers in ductal carcinoma in situ (DCIS).

Experimental Design: Thirty-eight breast cancer cases in which patients were concurrently diagnosed with DCIS and invasive ductal carcinoma (IDC) were used. Sequential sections from paraffin embedded tissue blocks were cut and immunostained with anti-ER, -PR, -HER-2, -Ki-67, -p16, -p53, and -p63 antibodies. Ten DCIS lesions from each patient were randomly selected and scored. Significant variation in IHC marker expression was defined by ≥20% of the lesions within an individual showing staining patterns that differed from the majority of lesions within that individual. Individuals were considered to display heterogeneity among DCIS lesions when at least 2/6 markers were classified as having significant variations in expression. In order to determine if the proportion of cases exhibiting variable expression for a single marker was higher than our hypothesized value of 10%, a one-sided exact binomial test was done at the 5% significance level.

Results: Our results showed that PR, HER-2, Ki-67, and p16 displayed significant expression variations in DCIS lesions in individual patients in 21%, 58%, 47% and 61% of cases, respectively (P &lt; 0.05 for PR; P &lt; 1 × 10−8 for HER-2, Ki-67 and p16). In addition, seventy-one percent of individuals had heterogeneous expression in at least 2/6 markers (P &lt; 1 x 10−18). As previous studies indicated that DCIS displays four molecular subtypes, including luminal A, luminal B, HER2+, and basal-like, we further examined the heterogeneous status in regards to DCIS subtypes. As a result, 39.5% cases (15 out of 38) showed DCIS heterogeneity in molecular subtypes (P &lt; 0.001). Interestingly, DCIS/IDC concurrent patients exhibiting more heterogeneity in DCIS seem more likely to have nodal involvement (P &lt; 0.05).

Conclusions: Our results quantitatively demonstrate for the first time that intra-individual heterogeneity in multi-lesional DCIS is common. Given that these results were from patients concurrently diagnosed with invasive and in situ ductal carcinoma, this could indicate that heterogeneity itself could be a predictor of subsequent development of IDC.

This work was kindly supported by the FCCC Personalized Risk and Prevention Keystone, the Susan G. Komen for the Cure (KG100274), and Eileen Stein Jacoby Fund.

Citation Format: Dana Pape-Zambito, Zhengyu Jiang, Hong Wu, Karthik Devarajan, Carolyn M. Slater, Kathy Q. Cai, Arthur Patchefsky, Mary B. Daly, Xiaowei Chen. Intra-individual heterogeneity of DCIS lesions in patients concurrently diagnosed with invasive ductal carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3653. doi:10.1158/1538-7445.AM2013-3653