Biomarkers Predicting Progression and Prognosis of Ductal Carcinoma In Situ (DCIS).

Abstract

This review describes the histopathological and molecular features distinguishing high-risk ductal carcinoma in situ (DCIS) from low-risk DCIS and their progression to invasive breast cancer (IBC). We summarize key alterations that occur in various compartments of the breast tissue such as myoepithelial cells, luminal epithelial cells, and the immune environment. Evidence suggests that DCIS and IBC share a largely similar genome, with comparable transcriptomes across various grades of DCIS and IBC. However, some studies report transcriptional up-regulation of multiple genes in luminal epithelial cells of high-risk DCIS. High-risk DCIS is also characterized by loss of genes that are crucial for maintaining the integrity of the myoepithelium, a physical barrier that keeps the cancer cells from invading surrounding tissue. High-grade DCIS is also characterized by global hypomethylation, but hypermethylation of select gene promoters also occurs. Immune environment changes that correlate with high-risk DCIS include overall increased T cell, B cell, and macrophage infiltration. Despite the active immune environment, these immune cells are in suppressed state and are characterized by increased presence of immunosuppressive Tregs, immunosuppressive M2, tumor-associated macrophages (TAMs), an immunophenotypic switch of fibroblasts into cancer-associated fibroblasts (CAFs) and lesser amounts of protective cytotoxic T cells. Several long noncoding RNAs also play a role in driving the premalignant phenotypic changes in normal breast epithelial and DCIS cells. Further validating the ability of these prognostic biomarkers for predicting DCIS progression will help reduce overtreatment while effectively managing the patients with DCIS that are at high risk of progression to IBC.