Human Ductal Carcinoma In Situ: Advances and Future Perspectives

Abstract

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS outcomes remain unclear. A large fraction of human DCIS (>50%) may not need the multimodality treatment options currently offered to all DCIS patients. More importantly, while we may be overtreating many, we cannot identify those most at risk of invasion or metastasis following a DCIS diagnosis. This review summarizes the studies that have furthered our understanding of DCIS pathology and mechanisms of invasive progression by using advanced technologies including spatial genomics, transcriptomics, and multiplex proteomics. This review also highlights a need for rethinking DCIS with a more focused view on epithelial states and programs and their cross talk with the microenvironment.

Figure 1.

Not all ductal carcinoma in situ (DCIS) and recurrent breast cancers are clonally related. Eighty percent of breast cancer recurrences following a DCIS diagnosis are clonally related, while about 20% are unrelated (A). UMAP plots showing clonal distribution in two clonally unrelated breast cancer recurrences; P122 recurred as invasive while P110 recurred as pure DCIS. As shown, the clones were specific to either the primary (purple) or recurrent breast cancers (orange) (B). Muller plots confirming independent clonal lineages in the primary and recurrent breast cancers (C). UMAP plots showing clonal distribution in two clonally related breast cancer recurrences; both DCIS recurred as invasive lesions. As shown, many copy number alteration (CNA) events were shared between the primary and recurrent breast cancers (D). Muller plots showing subclones that harbored common CNAs in primary and recurrent breast cancers. As shown, some subclones expanded in the transition from DCIS to invasive breast cancer (E). (Figure reprinted from Lips et al. 2022 under the Creative Commons Attribution 4.0 International License.) (See facing page for legend.)

Figure 1.

Not all ductal carcinoma in situ (DCIS) and recurrent breast cancers are clonally related. Eighty percent of breast cancer recurrences following a DCIS diagnosis are clonally related, while about 20% are unrelated (A). UMAP plots showing clonal distribution in two clonally unrelated breast cancer recurrences; P122 recurred as invasive while P110 recurred as pure DCIS. As shown, the clones were specific to either the primary (purple) or recurrent breast cancers (orange) (B). Muller plots confirming independent clonal lineages in the primary and recurrent breast cancers (C). UMAP plots showing clonal distribution in two clonally related breast cancer recurrences; both DCIS recurred as invasive lesions. As shown, many copy number alteration (CNA) events were shared between the primary and recurrent breast cancers (D). Muller plots showing subclones that harbored common CNAs in primary and recurrent breast cancers. As shown, some subclones expanded in the transition from DCIS to invasive breast cancer (E). (Figure reprinted from Lips et al. 2022 under the Creative Commons Attribution 4.0 International License.) (See facing page for legend.)

Figure 2.

A hypothetical model of ductal carcinoma in situ (DCIS) progression. In human mammary epithelial cells with an intact cell-cycle pathway (human mammary epithelial cell [HMEC], green cells), cellular stress due to DNA damage/aneuploidy causes cell-cycle arrest. In contrast, the same type of insult in human mammary epithelial cells with a compromised cell-cycle pathway (i.e., DCIS; brown cells) induces uncontrolled proliferation, secretion of growth factors, and cytokines (i.e., Activin A, IL-6, IL-8, vascular endothelial growth factor [VEGF]) and up-regulation of biomarkers of cellular stress and stemness (i.e., ARCS⁺, ALDH1A, SIAH2, SOX11, BCL9). Fibroblasts adjacent to stressed DCIS epithelial cells and exposed to epithelial-derived secreted factors up-regulate a protumorigenic microenvironment, typified by altered extracellular matrix (ECM), angiogenesis, immune cell influx, and altered metabolism, among others. In turn, protumorigenic stroma secretes factors that further fuel cellular stress and stemness programs via epigenetic changes that induce a hybrid epithelial/mesenchymal (E/M) state. Stem-like (E/M) cells characterized by their plasticity and invasive capacity will ultimately promote DCIS cell invasion and potentially early epithelial cell dissemination, leading to metastasis. (Figure modified Fordyce et al. 2012 under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0.)