Next-generation Sequencing

A Powerful Tool for the Discovery of Molecular Markers in Breast Ductal Carcinoma In Situ

Hitchintan Kaur; Shihong Mao; Seema Shah; David H Gorski; Stephen A Krawetz; Bonnie F Sloane; Raymond R Mattingly


Expert Rev Mol Diagn. 2013;13(2):151-165. 

In This Article

Breast Ductal Carcinoma in situ

Mortality from breast cancer has been declining for the past two decades.[1] This decline is thought to be due both to the introduction of widespread mammographic screening programs in the 1980s, resulting in earlier diagnosis and intervention,[2–4] and the development and optimization of chemotherapy[5] and targeted therapies,[6] although the relative contributions of each are hotly debated. Indeed, evidence now indicates that the contribution of screening to the decrease in death rates from breast cancer may be less than previously thought.[7,8] For example, a recent review in The Lancet[9] concludes that screening in the UK only modestly reduces mortality (decrease of 43 deaths in 10,000 women screened for 20 years) and recommends that this should be balanced against the significant risk of overdiagnosis, to allow women to make informed decisions regarding screening. In the USA, analysis of the Surveillance, Epidemiology and End Results database shows that as many as one-third of new breast cancer diagnoses (particularly that of ductal carcinoma in situ [DCIS]) could represent overdiagnosis with "at best, only a small effect on the rate of death from breast cancer".[10] This result is in line with a similar study using data from European countries, Canada and Australia.[11]

Overdiagnosis (Box 1) is a direct result of the use of mammography[7,8] and is manifested by a dramatic apparent increase in DCIS. The National Institutes of Health Office of Medical Applications of Research commissioned a review on the incidence, treatment and outcomes of DCIS to be used for the State of the Science Conference on the diagnosis and management of DCIS.[12] Their conclusions included that the incidence of DCIS has risen from 1.87 per 100,000 in 1973 to 32.5 per 100,000 in 2004, with the increase mostly accounted for by the introduction of screening mammography.[12] More recently, it was reported that the overall incidence of early-stage disease (DCIS and localized cancer combined) has doubled since 1976.[10] At the same time, there is an insufficient decrease in the incidence of late-stage disease to offset the increased detection of these early-stage cancers.[10] This result strongly implies that mammographic screening has led to significant overdiagnosis of subclinical and indolent disease. Another interpretation from long-term follow-up is that mammographic screening is detecting a significant number of lesions that would not only have remained indolent but would probably have spontaneously regressed.[13] According to analysis of a Swedish cohort, as many as one in five mammographically detected breast cancers could spontaneously regress.[13]

Any diagnosis of DCIS presents a challenge as we cannot yet distinguish cases that would remain indolent and not require aggressive treatment from cases that are likely to progress to life-threatening invasive ductal carcinoma (IDC).[14,15] A diagnosis of DCIS imposes a major burden, even in the absence of progression to IDC, as double mastectomy is an increasingly prevalent intervention.[16] A recent study presented at the 2012 American Society of Clinical Oncology Quality Care Symposium suggests that this major surgical procedure is almost certainly overused, particularly in the context of DCIS.[17] Molecular screening approaches are being considered, but so far only to inform decisions about postsurgery adjuvant treatments.[18,19] At the 2011 San Antonio Breast Cancer meeting, Solin et al. reported that a subset of markers in the 21-gene Oncotype DX® test can predict likelihood of progression.[20] If the use of these markers spares those at low risk of progression to IDC from adjuvant radiation, then it will make a significant impact. Nonetheless, we still do not have molecular screens that can predict whether DCIS will progress, nor do we understand the pathways that control progression to IDC and thus might serve as therapeutic targets.