New Markers and Drug Therapies Being Examined in DCIS Trials
Saraswati Sukumar, PhD;
Johns Hopkins University School of Medicine
Early detection assays must be minimally invasive, possess diagnostic value, be observer independent, specific (i.e., low number of false positives), and low cost. Methylation-specific polymerase chain reaction (MSP) is currently being used to detect cancer cells. It is a qualitative test that has a sensitivity of 1:1,000. However, it requires an abundance of DNA template, and difficulties sometimes arise in interpreting genes with low levels of methylation.
Quantitative multiplex (QM)-MSP answers these challenges by providing a quantitative, absolute method of detection with high sensitivity that allows for the detection of methylated DNA in the presence of a large excess of unmethylated DNA, provides simultaneous assessment of multigene promoter hypermethylation status from limited amounts of DNA, and simultaneously detects up to four genes in the same well using multiple fluorogenic probes.
Sampling method still remains a challenge for breast cancer detection. Although QM-MSP can provide a valuable adjunct to cytology in the clinic, ductal lavage is not an effective way to sample the breast for early detection because not all ducts are lavaged. Random periareolar fine needle aspiration (RPFNA) and serum are being investigated as alternatives to ductal lavage.
Any panel of markers developed to detect DCIS will need to be able to identify 100 percent of invasive carcinomas and at least 95 percent of DCIS cases. The panel should use markers that are frequently methylated in breast cancer but that have no or low methylation in white blood cells and normal breast tissue. The panel must have high sensitivity and specificity. In terms of cell-free DNA in plasma or serum, genes silenced by promoter methylation are promising markers for detection of cancer specific DNA. Serial analysis of gene expression (SAGE) and microarray analyses reveal multiple changes leading to invasive breast cancer, and underexpressed genes provide a rich source of information to identify genes that are silenced by methylation.
Treatment of DCIS needs to include a prevention arm. Studies of intraductal instillation of anticancer agents (DOXIL®) for treatment and prevention of DCIS found that, in HER-2/neu transgenic mice, DOXIL® administered intraductally achieves longer tumor-free survival and lower tumor incidence compared to intravenously administered drug. These findings have led to the initiation of Phase I trials, the results of which will help determine feasibility of this concept. Based on the outcome, the next step is to determine in the optimal platforms that intraductal administration of drugs can be tested.