Identifying progression predictors of breast ductal carcinoma in situ

Abstract

Ductal carcinoma in situ (DCIS) refers to neoplastic epithelial cells proliferating within the mammary ducts of the breast, which have not breached the basement membrane nor invaded surrounding tissues. Traditional thinking holds that DCIS represents an early step in a linear progression towards invasive ductal carcinoma (IDC). However, as only approximately half of DCIS cases progress to IDC, important questions around the key determinants of malignant progression need to be answered. Recent studies have revealed that molecular differences between DCIS and IDC cells are not found at the genomic level; instead, altered patterns of gene expression and post-translational regulation lead to distinct transcriptomic and proteomic profiles. Therefore, understanding malignant progression will require a different approach that takes into account the diverse tumour cell extrinsic factors driving changes in tumour cell gene expression necessary for the invasive phenotype. Here, we review the roles of the tumour stroma (including mesenchymal cells, immune cells and the extracellular matrix) and myoepithelial cells in malignant progression and make a case for a more integrated approach to the study and assessment of DCIS and its progression, or lack thereof, to invasive disease.

Dichotomous histopathological assessment of ductal carcinomain situof the breast results in substantial interobserver concordance

“…Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of non‐obligate preinvasive precursors of invasive carcinoma of no special type. The ability of DCIS to progress towards invasive cancer is likely to result from a complex interplay between intrinsic and extrinsic factors, such as genetic anomalies within the neoplastic cells, stromal remodelling, and stroma‐derived proinvasive signalling . Although DCIS has been the subject of intensive research during the past four decades, no robust prognostic markers have emerged that enable prediction of progression towards invasive cancer.…”

“…Ongoing clinical trials such as the COMET, LORD and LORIS trials, which are investigating watchful waiting strategies for low‐grade DCIS, might provide crucial information to fill this gap in our knowledge . The main motive for such trials is the increasing awareness that significant numbers of DCIS patients are currently overtreated, as not all DCIS cases will become invasive …”

“…The ability of DCIS to progress towards invasive cancer is likely to result from a complex interplay between intrinsic and extrinsic factors, such as genetic anomalies within the neoplastic cells, stromal remodelling, and stroma-derived proinvasive signalling. 1 Although DCIS has been the subject of intensive research during the past four decades, no robust prognostic markers have emerged that enable prediction of progression towards invasive cancer. Because surgery has always been the cornerstone of DCIS treatment, the natural biology of DCIS is poorly understood.…”

“…[2][3][4] The main motive for such trials is the increasing awareness that significant numbers of DCIS patients are currently overtreated, as not all DCIS cases will become invasive. 1,5 If these trials can prove that watchful waiting is not inferior to standard surgical treatment in a selected subgroup of patients, the search for proper prognostic markers is likely to be intensified. If DCIS is left untreated, adequate prognosticators are necessary to estimate the risk of upstaging of DCIS to invasive cancer on the initial biopsy, and to evaluate the risk of evolution towards invasion in the future.…”

Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer

“…Early events important to the genesis of human breast cancer are still limited and largely extrapolated from transgenic mouse models. Information derived from studies of human cancers has been largely limited to retrospective analyses of prevalent changes in established tumors (Futreal et al, 2004;Nik-Zainal et al, 2012), or a few analyses of preneoplastic mammary cells were obtained from carriers of BRCA1 mutations (Lim et al, 2009;Proia et al, 2011;Choudhury et al, 2013) or from samples of ductal carcinoma in situ (DCIS; Yeong et al, 2017). Events that accompany the acquisition of malignant properties by immortalized, but non-tumorigenic, human mammary cell lines have also been described (Debnath et al, 2003;Leung & Brugge, 2012).…”