Cell free DNA and oncology


cfDNA gives insight into the pathogenesis of serious disease and early information about benign conditions.



Dr. Levine is Clinical Fellow, Reproductive Endocrinology & Infertility, Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York.



Dr. Goldschlag is Assistant Professor of Clinical Obstetrics and Gynecology and Assistant Professor of Clinical Reproductive Medicine, Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York.



In September’s installment of Tech Tools, Noninvasive prenatal testing: A new standard of care? we discussed the utility of cell-free fetal DNA in prenatal diagnosis and the capabilities of the 4 commercially available noninvasive prenatal testing technologies. In this continuation of our cell-free DNA series, we discuss the role of cell-free nucleic acids as noninvasive biomarkers in oncology.

Colorectal screening

In August 2014, the FDA approved Cologuard, the first stool-based colorectal screening test. Cologuard assesses the presence of colorectal neoplasia-associated DNA markers and occult hemoglobin in stool.1 The test takes advantage of the fact that the gastrointestinal tract is constantly regenerating and shedding epithelial cells. As these cells are sloughed, they release their DNA and are removed through the stool stream, making them an ideal noninvasive target.2

A recently published study found that the multi-target stool DNA testing (targeting methylation and mutation biomarkers that are associated with cancer and precancer) detected significantly more cancers than the American College of Gastroenterology-recommended fecal immunochemical test (FIT), although there were more false-positive results (Cologuard detected 86.6% true negatives for a false-positive rate of 13.4%, whereas FIT detected 94.9% of true-negative patients, for a false-positive rate of 5.1%).3 While many may be concerned about this relatively high risk of false-positives, others may argue that it is more desirable for a screening test to catch as many affected cases as possible (ie, to have high sensitivity) even if it means that some unaffected individuals may be misclassified as at-risk (lower specificity).

The US Preventive Services Task Force (USPSTF) recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults, beginning at age 50 and continuing until age 75.4 According to the Centers for Disease Control and Prevention (CDC), if everyone age 50 years or older had regular screening tests as recommended, at least 60% of colorectal cancer deaths could be avoided.1 However, barriers to adherence with these screening recommendations include lack of access to a provider, the cumbersome nature of the sigmoidoscopy/colonoscopy’s required bowel prep, and incomplete adherence to the pretest dietary restrictions. Cologuard eliminates all those barriers: it only requires the patient to collect a stool sample at home and mail it to the Exact Sciences laboratory.



‘Liquid biopsy’

While mailing a stool sample is a prime example of noninvasive testing, blood-based cancer screening and monitoring takes this even further. Quite frequently cell-free DNA is referred to as a “liquid biopsy” because it can be a serum surrogate for tumor sampling. As opposed to cell-free fetal DNA, the source of cell-free tumor DNA in cancer patients is unclear. It has been hypothesized that a large proportion originates from malignant cells that are constantly going through growth/remodeling/apoptosis/necrosis and subsequently releasing digested or possibly metastatic/pathogenic nucleic acids into the blood.5 Although its etiology is not clear, we have known for more than 30 years that circulating serum cell-free DNA concentration is markedly elevated in malignancy (nearly 4 times), and moderately elevated in benign disease, as compared to controls.6

In May 2012 the USPSTF updated its position and recommended against prostate-specific antigen (PSA)-based screening for prostate cancer, stating that there is inadequate evidence of the benefit of PSA screening and early treatment.7 While it may seem that serum prostate cancer screening is a thing of the past, it is important to recognize that prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States, with a lifetime risk for diagnosis currently estimated at 15.9%.5

When the plasma-based DNA integrity assay, which measures cell-free DNA of a length characteristic of that shed by necrotic malignant cells, was employed as a screening tool for the detection of prostate cancer, it achieved a sensitivity of nearly 70% while maintaining an overall specificity of 68.2% to 92%, which is far superior to the PSA 60%–70% range of specificity.8

The advent of better tests using new technology in molecular medicine may result in the revision of current screening guidelines.

NEXT: Ovarian cancer detection >>



Ovarian cancer detection

One of the most promising uses of cell-free DNA is in the identification of early-stage epithelial ovarian cancer, the deadliest of gynecologic cancers, with a lifetime risk of approximately 1 in 80. A recent study demonstrated that after choosing a handful of candidate genes that are associated with gynecologic malignancies and have a high frequency of methylation, a PCR-based assay achieved a sensitivity of 85.3% and a specificity of 90.5% for stage I epithelial ovarian cancer.9 This is much higher than the sensitivity and specificity rates of a single CA125 (56.1% sensitivity and 64.15% specificity).9

Furthermore, cell-free DNA has been shown to be a potential marker of not only tumor treatment response, but also prognosis. A paper published in October 2014 reported a significant and independent association between elevated cell-free DNA and outcome in multiresistant ovarian cancer patients undergoing last-line treatment with a specific chemotherapy regimen.10

It seems undeniable that cell-free DNA testing will play an important role in the future of medicine: The technology is becoming increasingly affordable and constantly improving in both sensitivity and specificity. Regardless of your practice area, it is only a matter of time until you will be counseling your patients about the benefits of cell-free DNA testing and its ability to offer unique insight into the pathogenesis of serious disease as well as critical early information about benign conditions.



1. FDA approves first non-invasive DNA screening test for colorectal cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409021.htm

2. Ahlquist DA, Skoletsky JE, Boynton KA et al. Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology. 2000;119(5):1219-1227.

3. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1987-1997.

4. U.S. Preventive Services Task Force- Colorectal Cancer: Screening http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectal-cancer-screening

5. Stroun M, Maurice P, Vasioukhin V et al. The origin and mechanism of circulating DNA. Ann N Y Acad Sci. 2000;906:161-168.

6. Shapiro B, Chakrabarty M, Cohn EM, Leon SA. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer. 1983;51(11):2116-2120.

7. U.S. Preventive Services Task Force- Prostate Cancer: Screening http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening

8. Hanley R, Rieger-Christ KM, Canes D et al. DNA integrity assay: a plasma-based screening tool for the detection of prostate cancer. Clin Cancer Res. 2006;12(15):4569-4574.

9. Zhang Q, Hu G, Yang Q, Dong R, Xie X, Ma D, Shen K, Kong B. A multiplex methylation-specific PCR assay for the detection of early-stage ovarian cancer using cell-free serum DNA. Gynecol Oncol. 2013;130(1):132-139. 

10. Steffensen KD, Madsen CV, Andersen RF et al. Prognostic importance of cell-free DNA in chemotherapy resistant ovarian cancer treated with bevacizumab. Eur J Cancer. 2014;50(15):2611-8. doi: 10.1016/j.ejca.2014.06.022. Epub 2014 Jul 30.

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