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Prediction of Breast Tumor Progression by Integrity of Free Circulating DNA in Serum

Naoyuki Umetani, Armando E. Giuliano, Suzanne H. Hiramatsu, Farin Amersi, Taku Nakagawa, Silvana Martino, Dave S.B. Hoon

From the Department of Molecular Oncology and the Joyce Eisenberg Breast Center, John Wayne Cancer Institute; and The Angeles Clinic and Research Institute, Santa Monica, CA

Address reprint requests to Dave S.B. Hoon, PhD, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; e-mail: hoon{at}jwci.org

Purpose: Cell-free DNA circulating in serum is a candidate molecular biomarker for malignant tumors. Unlike uniformly truncated DNA released from apoptotic cells, DNA released from dead cancer cells varies in size. Serum DNA integrity, the ratio of longer fragments to total DNA, may be clinically useful for detecting breast cancer progression.

Patients and Methods: Serum samples from 51 healthy females and 83 females with primary breast cancers (eight American Joint Committee on Cancer stage 0, 24 stage I, 27 stage II, 21 stage III, and three stage IV) were assessed preoperatively. Serum DNA integrity was assessed by fragment length-dependent quantitative real-time polymerase chain reaction of ALU DNA repeats.

Results: Mean serum DNA integrity was significantly higher in patients with stage II, III, and IV breast cancers than in healthy females (P = .005, P < .0001, and P = .002, respectively). The receiver operating characteristic (ROC) curve for discriminating patients with stage II or more advanced breast cancers from healthy females had an area under the curve (AUC) of 0.79 (95% CI, 0.70 to 0.86). Mean serum DNA integrity was positively correlated to size of invasive cancers (r = 0.48; P < .0001) and significantly higher in the presence of lymphovascular invasion (LVI; 0.25 ± 0.02 v 0.17 ± 0.02; P < .0001) or lymph node (LN) metastasis (0.27 ± 0.02 v 0.14 ± 0.02; P < .0001). The ROC curve for discriminating LN metastasis had an AUC of 0.81 (95% CI, 0.72 to 0.89). Serum DNA integrity and LVI were significant for predicting LN metastasis in a multivariate analysis (P = .0002 and P < .0001, respectively).

Conclusion: Integrity of serum circulating DNA is a promising molecular biomarker for detecting breast cancer tumor progression and regional LN metastases.

Presented in part at the fourth International Conference on Circulating Nucleic Acids in Plasma/Serum, London, United Kingdom, September 4-6, 2005.

Supported in part by the Komen Breast Cancer Foundation, California Breast Cancer Research Program, and Avon Breast Foundation.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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