Abstract
Simple SummaryTumor-infiltrating lymphocytes (TILs) are likely to play a role in the biological behavior of HER2+ ductal carcinoma in situ (DCIS). To prevent invasiveness, the potential of targeted immune-modulating treatment of HER2+ DCIS has been explored. We identified a 29-gene expression profile that was associated with the density of TILs. These genes included CCND3, DUSP10 and RAP1GAP, which may guide towards more rationalized choices with respect to immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy.The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation. The Ion AmpliSeq Transcriptome Human Gene Expression Kit was used for RNA sequencing. After normalization, a Mann–Whitney rank sum test was used to analyze differentially expressed genes between TIL-poor and TIL-rich HER2+ DCIS. Whole tissue sections were immunostained for validation of protein expression. We identified a 29-gene expression profile that differentiated TIL-rich from TIL-poor HER2+ DCIS. These genes included CCND3, DUSP10 and RAP1GAP, which were previously described in breast cancer and cancer immunity and were more highly expressed in TIL-rich DCIS. Using immunohistochemistry, we found lower protein expression in TIL-rich DCIS. This suggests regulation of protein expression at the posttranslational level. We identified a gene expression profile of HER2+ DCIS cells that was associated with the density of TILs. This classifier may guide towards more rationalized choices regarding immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy.
Highlights
Ductal carcinoma in situ (DCIS) of the breast is characterized by a proliferation of neoplastic cells confined within the duct [1,2]
We identified 29 differentially expressed genes potentially playing a role in the density of TILS in human epidermal growth factor receptor 2 (HER2)+ DCIS, of which many were involved in the cell cycle or protein transportation
Similar to CCND3, we found higher DUSP10 gene expression levels in tumor-infiltrating lymphocytes (TILs)-rich DCIS compared to TIL-poor cases, while the opposite was found at the protein level
Summary
Ductal carcinoma in situ (DCIS) of the breast is characterized by a proliferation of neoplastic cells confined within the duct [1,2]. DCIS can progress into invasive breast cancer (IBC) [3,4]. Several markers for progression have been proposed, including high nuclear grade, large DCIS size and the overexpression of human epidermal growth factor receptor 2 (HER2) [4–8]. HER2+ DCIS accounts for 23–37% of all DCIS cases and is associated with high nuclear grade, large diameter and comedonecrosis [9,10]. HER2 overexpression in DCIS has been reported as a biomarker for local recurrence and upstaging to IBC in the final excision specimen after a biopsy diagnosis [10–13]. Since HER2+ IBC has an aggressive biological behavior, optimal early treatment is needed to minimize the risk of DCIS progression to IBC. Previous studies reported the potential of targeted treatment of HER2-enriched DCIS, including vaccine therapy, to prevent invasive disease [14–18]
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