Molecular Markers for the Diagnosis and Management of Ductal Carcinoma In Situ

Abstract

Cancer is an evolution of a population of cancer cells with diverse hereditary characteristics. With rare exceptions, tumors are derived from a single initiated cell and the progressive accumulation of genetic, epigenetic, and phenotypic features combined with selection drives cancer progression. The currently accepted stepwise model of breast tumorigenesis assumes a gradual transition from epithelial hyperproliferation to ductal carcinoma in situ (DCIS), to invasive and metastatic carcinomas (1,2). This progression model is strongly supported by human clinical and epidemiological data and by molecular clonality studies addressing the relationships between in situ and invasive areas of the same tumor and between DCIS and its local invasive recurrence. Until 1980, DCIS was diagnosed very rarely and represented less than 1% of all breast cancer cases. All of this changed dramatically with the increased utilization of mammography during the 1980s, and DCIS became the most rapidly increasing subset of breast cancers. Currently, DCIS accounts for 15%-25% of newly diagnosed breast cancer cases in the United States (3). In contrast to the dramatic improvement in our ability to detect DCIS, our understanding of the pathophysiology of this disease and factors involved in its progression to invasive carcinoma are still poorly defined. Numerous studies compared the gene expression, genetic, and epigenetic profiles of DCIS and invasive breast carcinomas, but a molecular alteration differentiating in situ and invasive tumors has not been identified (2). A dramatic change occurs during the normal to DCIS transition, but surprisingly in situ and invasive breast carcinomas of the same histological subtype essentially share the same genetic and epigenetic alterations and expression patterns. In contrast, the molecular profiles of breast tumors of distinct subtypes (ie, luminal, HER2+, and basal-like) are dramatically different. Emerging data also suggest a critical role for microenvironmental changes in the regulation of tumor progression, particularly that of the in situ to invasive breast cancer transition (4). Here, I summarize the results of molecular studies aiming to identify diagnostic markers that differentiate in situ and invasive tumors and predictive markers that correlate with the risk of invasive progression. Candidate Molecular Markers in DCISThe expression and mutation status of numerous tumor suppressor and oncogenes have been analyzed in DCIS and invasive ductal carcinoma (IDC) including TP53, PTEN, PIK3CA, ERBB2, MYC, and differences in the frequency of these changes have been found according to the tumor subtype but not histological stage (2). Thus, mutations in TP53 are more frequent in basal-like and HER2+ compared with luminal tumors; in basal-like cases, PIK3CA is rarely mutated but PTEN is frequently lost, and amplification of ERBB2 is specific for the HER2+ subtype.The expression of several candidate genes selected based on their biological function has also been analyzed in DCIS (5). Two recent studies ...

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

“…Our data also suggest that the final signal triggering invasion and local dissemination can be provided by changes in the ECM microenvironment rather than by genetic changes in the cancer cell. This suggestion is consistent with recent sequencing efforts that identified similar gene expression and mutations within in situ and invasive breast tumors (38,43). Additionally, central fibrosis, which is characterized by high levels of collagen I, independently correlates negatively with patient outcome even among the most aggressive types of breast cancers (44).…”

“…However, all our transcriptome experiments compared RNA extracted from whole cultures, so our experimental design cannot exclude gene-expression or signaling changes in the cells directly in contact with the ECM. Comparable molecular profiling studies comparing in situ and invasive breast cancer at the tissue level also have failed to define a gene signature predictive of invasion (38).…”

An epigenetically distinct breast cancer cell subpopulation promotes collective invasion

“…Once out of the epithelial niche, invasive tumor cells can intravasate into blood vessels, disseminate throughout the body, and form macrometastases that are responsible for patient deaths (2). Determining how tumor cells initiate and sustain invasive behavior may help improve patient diagnosis (3) and lead to the development of new intervention modalities (4). Given the key role of tumor cell invasion in the progression to metastasis, we sought to determine how alterations to the tumor cell-autonomous signaling circuitry promote invasive behavior.…”

Serum Autoantibody Signature of Ductal Carcinoma In Situ Progression to Invasive Breast Cancer

“…In contrast to the dramatic improvement in our ability to detect ductal carcinoma in situ (DCIS), our understanding of the pathophysiology of this disease and the factors involved in its progression to invasive breast carcinoma (IBC) is limited (1). Clinicohistologic features, such as a younger age, positive surgical margins, tumor size, comedo necrosis and, notably, tumor grade have consistently been correlated with DCIS recurrence.…”