Abstract A29: Ductal Carcinoma in Situ Lesions Commonly Exhibit Heterogeneity within Individuals
Authors: Jiang Zhengyu , Pape-Zambito Dana , Wu Hong , Devarajan Karthik , Slater Carolyn M. , Cai Kathy Q. , Patchefsky Arthur , Daly Mary B. , Chen Xiaowei 
Published: January 2014

Background: Cellular heterogeneity of IHC biomarker expression between patients has been well documented in invasive ductal carcinoma (IDC) and its precursor lesion, ductal carcinoma in situ (DCIS). However, no studies have quantified the variations in the expression of standard prognostic or therapeutic response-monitoring markers within an individual patient's DCIS lesions. This intra-individual heterogeneity in DCIS likely hinders current personalized medicine strategies which largely rely on clinical results from single biopsy samples. More importantly, because current regimens are restricted to standardized IHC parameters, this bias could contribute to inadequate decision-making for risk assessment and therapeutic approaches in DCIS patients. Therefore, it is critical to quantitatively evaluate intra-individual heterogeneity of standard clinical markers in DCIS.

Experimental Design: Breast cancer cases were selected in which patients were concurrently diagnosed with DCIS. 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 throughout the entire tissue section derived from one or two multifocal-lesion blocks. Significant variations in IHC marker expressions were defined by a ≥20% of the lesions within an individual showing staining patterns that differ from the majority of lesions within that individual. Each case was considered to display heterogeneity among DCIS lesions when at least 2/6 of the IHC markers were classified as having significant variations in expression. Associations of case heterogeneity with clinical characteristics were examined by Fisher's exact tests.

Results: Over 2,100 scores were analyzed for 380 DCIS lesions among different patients. PR, HER-2, Ki-67, and p16 displayed significant expression variations in DCIS lesions within an individual patient 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). Seventy-one percent of individuals manifested various levels of expression of at least 2/6 markers, and 32% of patients had discordant expression of at least 3/6 markers tested. These percentages were statistically greater than a hypothesized level of 10% difference within an individual (p &lt; 1 × 10−18 and p &lt; 0.001, respectively). Patients exhibiting a higher extent of heterogeneity (3/6 markers displaying variations in expression) were also more likely to have nodal involvement (p &lt; 0.05). Furthermore, ER- lesions was positively correlated to PR- status and to a moderate or high Ki-67 proliferative index (p &lt; 1 × 10−23 and p &lt; 1 × 10−8, respectively).

Conclusions: This is the first study to quantitatively evaluate intra-individual heterogeneity of standard clinical markers in DCIS. Our results clearly support the hypothesis that intra-individual heterogeneity in multi-lesion DCIS is quite common. This is clinically relevant of basing the treatment regimen of a patient diagnosed with IDC or DCIS on these markers. A substantial amount of heterogeneity may signify that a patient is more likely to develop a resistant population of cells and to have subsequent relapse at a later date. 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: Zhengyu Jiang, Dana Pape-Zambito, Hong Wu, Karthik Devarajan, Carolyn M. Slater, Kathy Q. Cai, Arthur Patchefsky, Mary B. Daly, Xiaowei Chen. Ductal carcinoma in situ lesions commonly exhibit heterogeneity within individuals. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A29.