Abstract P2-03-11: The immune microenvironment of HER2-positive ductal carcinoma in situ of the breast
Authors: Ubago JM , Blanco LZ , Siziopikou KP 
Published: February 2018

Background: Ductal carcinoma in situ (DCIS) consists of a heterogeneous group of tumors that can be subclassified based on their molecular profile similar to invasive breast carcinomas. DCIS ducts are often surrounded by an inflammatory infiltrate, yet few studies have focused on this inflammatory response in the different subtypes of DCIS. The role of the immune microenvironment in tumor progression and response to therapy has led to a number of effective immune-based therapies, particularly targeting the PD-1/PD-L1 axis, and these approaches may extend to breast cancer subtypes and their precursor DCIS. In this study we evaluated the inflammatory response and PD-1/PD-L1 expression in both tumor-infiltrating lymphocytes (TILs) and tumor cells in HER2-positive (HER2+) and HER2-negative (HER2-) DCIS.

Design: Our population consisted of 85 cases of pure DCIS treated with surgical excision or mastectomy at our institution from 2008 to 2012. The molecular subtypes of DCIS were determined based on ER and HER2 expression. Tissue microarrays (TMAs) were constructed with 3 cores from each case to account for tumor heterogeneity. The presence of tumor-associated inflammation (TAI) was graded as absent, mild (&lt;10%), moderate (10-50%) or severe (&gt;50%) and the extent and intensity of PD1 and PD-L1 in the TILS and in the tumor cells were also assessed. A composite score was calculated by multiplying extent and intensity (range 0-12 with 9-12=strong).

Results: Of the 85 cases, 51 were classified as Luminal A (ER+/HER2-), 15 as Luminal B (ER+/HER2+), 13 as HER2+ (ER-/HER2+) and 6 as basal-like (ER-/HER2-). Moderate/severe inflammation around DCIS correlated with HER2 expression (20/28 HER2-expressing cases (71.4 %) compared to 21/36 HER2-non-expressing cases (58.3%), p=0.005). Of interest, severe inflammation was seen almost exclusively around HER2-expressing cases (7/28, 25% vs 1/57, 1.7 %, p=0.002). Furthermore, over half of the TILs around HER2+ cases expressed PD-L1 (7/13, 54%), while only 6% of Luminal A (3/47) and none of Luminal B (0/15) or basal-like (0/6) cases did (p=0.00001). In addition, about 1/3 of the TILs around HER2+ cases expressed PD-1 (4/13, 31%), while only 8% of Luminal A (4/49) and none of Luminal B (0/15) or basal-like (0/6) cases did (p=0.004). None of the DCIS tumor cells expressed PD-1. Of interest, 15% of HER2+ cases (2/13) and 7% of Luminal B cases (1/15) expressed PD-L1 in the DCIS tumor cells.

Conclusions: 1. Moderate/severe inflammation around DCIS foci correlates with HER2 expression. 2. PD-L1 expression in TILs is seen almost exclusively in HER2+ DCIS cases 3. About 1/3 of the TILs around HER2+ DCIS cases also express PD-1. 4. None of the DCIS tumor cells express PD-1. 5. Small subgroups of HER2+ and Luminal B DCIS cases show PD-L1 expression in the tumor cells themselves. The results of our study add to the understanding of the role of the immune microenvironment in DCIS, especially in the HER2+ subtype. The complex interactions between DCIS tumor cells and the local immune system may play a role in breast cancer progression and may be further exploited for immune-based therapeutic strategies.

Citation Format: Ubago JM, Blanco, Jr. LZ, Siziopikou KP. The immune microenvironment of HER2-positive ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-11.