Use of Circulating Tumor-Specific DNA as a Biomarker Predictive of Aggressive Disease and Early Recurrence
Abstract
Our proposal focuses on a novel technique for identifying clinically significant prostate cancer and distinguishing it from those prostate cancers that do not require medical, surgical, or radiological intervention. Specifically, we hypothesize that aggressive or metastatic tumor cells will shed their DNA (circulating tumor-specific DNA, or ctDNA) into the blood stream at a greater frequency than tumor cells with lower metastatic potential. We will measure ctDNA by sequencing DNA mutations that were originally discovered in the primary prostate tumor. Because prostate surgery is recommended for those men who are likely to have an aggressive (and potentially metastatic) tumor, men who are potentially low risk (such as low PSA [prostate specific antigen] and only low-grade Gleason 6 on biopsy) are often enrolled into an active surveillance program. This, in turn, delays the side effects associated with surgery and in many cases prevents an unnecessary surgery. However, concerns about potential disease progression over time leads many men to still seek prostate surgery as a treatment that may cure their cancer. In the first specific aim of our application, we propose that measuring ctDNA levels in the blood before surgery can serve as an additional indicator of disease severity. If our hypothesis is correct, this independent measurement may assist urologists in recommending treatment decisions for men who are "borderline" (between low and intermediate risk). In addition, for men who have already undergone one biopsy, measurement of ctDNA is a minimally invasive technique (requiring only a blood draw) for monitoring potential cancer progression over time. In the second specific aim of our application, we propose that measuring ctDNA after surgery may be an early indicator of relapse. Although most men who undergo prostate surgery are cured, approximately 30% of men experience relapse. Currently, the first indicator of potential relapse is a continuously rising PSA, at which time the urologist or oncologist may recommend radiation therapy (potentially in conjunction with hormone therapy). Because a rising PSA in these men is an indicator of a greater volume of tumor cells, the sooner the rising PSA is detected, the greater the chance that radiation therapy targeted to the pelvis is likely to be curative. With any radiation therapy, the side effects do not warrant its use without an indication of tumor progression. In our application, we provide preliminary data from two patients showing that ctDNA levels rise with PSA, and we show in one patient that ctDNA is more sensitive than PSA and preceded relapse. If our hypothesis is correct, ctDNA measurements may serve as a better marker than PSA to predict relapse, shorten the time until radiation therapy, and thus increase the chances that radiation therapy is curative. There is minimal (if any) potential risk to patients in our study. We will be performing this study retrospectively, so no changes to treatment decisions will be made. Ultimately, we hope that measuring ctDNA will prevent unnecessary surgeries and identify those men who would benefit from immediate surgery or radiation therapy. Immediately, however, measuring ctDNA levels is a research-use only application. Nonetheless, if our data from this study are promising (within 3 years), we will establish the feasibility of identifying ctDNA mutations from biopsy samples (rather than surgical specimens) and expand to a multicenter study for both applications to increase the statistical power of our observations while establishing a clinical (CLIA-certified) laboratory for performing these analyses. If we are successful (within 5-10 years), we can integrate ctDNA measurements into the diagnostic criteria for oncologists and urologists to recommend treatments, and patients will then begin to realize a benefit from this research. We will continuously publish our results during this time to publicize our d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510710
Entities
People
- Adam G Sowalsky
Organizations
- National Cancer Institute
- United States Army