Editors' ChoiceDIAGNOSIS AND PROGNOSIS

A Liquid Solution for Solid Tumors

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Science Translational Medicine  10 Apr 2013:
Vol. 5, Issue 180, pp. 180ec62
DOI: 10.1126/scitranslmed.3006268

Few things are certain in science, but most biomedical researchers agree that DNA can reveal secrets of biology—and pathobiology. Next-generation genomic sequencing of patient tumors in parallel with adjacent noncancerous tissue is now a common research tool in cancer genomics. This approach has revolutionized the ability to identify new somatic variations that underlie cancer biology. At the same time, circulating tumor DNA (ctDNA) detected in plasma from patients with solid-tumor malignancies is a promising biomarker of tumor dynamics. However, combining these two approaches and comparing them with existing biomarkers has not yet been performed in breast cancer. Now, Dawson et al. describe a proof-of-principle study in women with metastatic breast cancer designed to assess the diagnostic and prognostic characteristics of ctDNA.

The authors made use of an data set in which 52 women with metastatic breast cancer had archival DNA from their primary tumor, serial, banked plasma samples, serial imaging studies, and 2-year survival data. To identify patient-specific somatic mutations in primary tumors, the authors performed either whole-genome sequencing or targeted sequencing of two genes, PIK3CA and TP53, which are frequently mutated in breast cancer. In those women in which a mutation could be identified (30 of 52), the authors then designed personalized assays to detect this variation in the circulating DNA of each woman’s banked cell-free plasma. As a comparator, the authors measured two circulating biomarkers, CA 15-3 and circulating tumor cells (CTC), and performed serial medical imaging of the metastatic tumors, the current standards of care for breast cancer monitoring.

Compared with currently available biomarkers, personalized assays to detect ctDNA were more sensitive, correlated with tumor response to chemotherapy by medical imaging, and were strong predictors of survival. ctDNA appeared to have a wide dynamic range, so that many women with disease otherwise undetectable with CA 15-3 or CTC monitoring were readily identified through ctDNA. In some women, serial monitoring revealed the emergence of new mutations not present in the primary tumor.

Even with a small patient sample, these findings demonstrate the superior diagnostic and prognostic capacity of ctDNA as compared with the standard of care. In addition, these findings open the possibility of monitoring the evolution of breast cancer in real-time, during and after treatment. Such a strategy may allow for the earlier detection of emerging resistance or tumor subclones that either were not present in the primary tumor or were not accessible by biopsy. As the authors note, ctDNA may serve as a cumulative “liquid biopsy” of the entire tumor burden within an individual over time. With such information, oncologists may tailor treatment with the hope of reducing toxicity and enhancing efficacy.

S. J. Dawson et al., Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013). [Abstract]

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