Progression from ductal carcinoma in situ to invasive breast cancer: revisited

Abstract

Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an 'evolutionary bottleneck', resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.

Keywords: Breast cancer; Darwinian evolution; Genomics; Intra-tumor genetic heterogeneity; Intraductal.

Figure 1

Heterogeneous expression of HER2 in breast cancer. (A) Heterogeneous expression of HER2 in neoplastic cells of a ductal carcinoma in situ; note that only a subpopulation of the cancer cells in one duct display strong, membranous expression of HER2. (B) Representative micrograph illustrating a ductal carcinoma in situ composed of cells displaying HER2 membranous expression associated with a HER2‐negative invasive ductal carcinoma.

Figure 2

Hypothetical models of progression from in situ to invasive breast cancer. (A) Progression from DCIS to IBC as a convergent phenotype, where several combinations of somatic genetic and/or epigenetic aberrations result in the acquisition of the biological properties required for cancer cells to progress from in situ to invasive disease (i.e. the genetic/epigenetic aberrations selected for are distinct between patients but all result in the progression to invasive disease). (B) Progression from DCIS to IBC as an evolutionary bottleneck. As DCIS develops, cells accumulate somatic mutations and copy number aberrations (depicted by color) to generate a heterogeneous lesion with distinct subclones harboring private mutations in addition to the founder genetic aberrations present in all neoplastic cells. Only subclones harboring a specific repertoire of genetic aberrations are selected and pass through the evolutionary bottleneck of progression to IBC. DCIS: ductal carcinoma in situ; IBC: invasive breast cancer.

Figure 3

Schematic of a potential approach for the identification of founder genetic events in DCIS and genetic aberrations that drive progression from DCIS to IBC. DCIS: ductal carcinoma in situ; IBC: invasive breast cancer.