Article

Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

and the Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia (S.-J.D.).
New England Journal of Medicine (Impact Factor: 55.87). 03/2013; 368(13). DOI: 10.1056/NEJMoa1213261
Source: PubMed

ABSTRACT

Background:
The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.

Methods:
We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

Results:
Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

Conclusions:
This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).

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    • "However, due to the above limitations, circulating cell-free DNA (cfDNA) is now actively being investigated as a potential source for a more comprehensive picture of the tumor genomic profile, as cfDNA captures genomic mutations from the primary tumor, circulating tumor cells, and metastatic lesions[2]. Therefore, plasma-isolated cfDNA is potentially an invaluable and non-invasive source, obtained as a liquid biopsy, and may aid in monitoring changes in tumor burden over time and in identifying new cancer-specific mutations that arise during the course of treatment[5,12]. Cell-free nucleic acids, including cfDNA, were first isolated from human blood in 1948[1]. "
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    ABSTRACT: Due to the spatial and temporal genomic heterogeneity of breast cancer, genomic sequencing obtained from a single biopsy may not capture the complete genomic profile of tumors. Thus, we propose that cell-free DNA (cfDNA) in plasma may be an alternate source of genomic information to provide comprehensive data throughout a patient's clinical course. We performed a retrospective chart review of 100 patients with stage 4 or high-risk stage 3 breast cancer. The degree of agreement between genomic alterations found in tumor DNA (tDNA) and cfDNA was determined by Cohen's Kappa. Clinical disease progression was compared to mutant allele frequency using a two-sided Fisher's exact test. The presence of mutations and mutant allele frequency was correlated with progression-free survival (PFS) using a Cox proportional hazards model and a log-rank test. The most commonly found genomic alterations were mutations in TP53 and PIK3CA, and amplification of EGFR and ERBB2. PIK3CA mutation and ERBB2 amplification demonstrated robust agreement between tDNA and cfDNA (Cohen's kappa = 0.64 and 0.77, respectively). TP53 mutation and EGFR amplification demonstrated poor agreement between tDNA and cfDNA (Cohen's kappa = 0.18 and 0.33, respectively). The directional changes of TP53 and PIK3CA mutant allele frequency were closely associated with response to therapy (p = 0.002). The presence of TP53 mutation (p = 0.0004) and PIK3CA mutant allele frequency [p = 0.01, HR 1.074 (95 % CI 1.018-1.134)] was excellent predictors of PFS. Identification of selected cancer-specific genomic alterations from cfDNA may be a noninvasive way to monitor disease progression, predict PFS, and offer targeted therapy.
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    • "In order to overcome limitations of tissue acquisition, the use of blood-based liquid biopsies has been suggested (Alix-Panabiè res et al., 2012; Crowley et al., 2013; Haber and Velculescu, 2014). Several blood-based biosources are currently being evaluated as liquid biopsies, including plasma DNA (Bettegowda et al., 2014; Chan et al., 2013; Diehl et al., 2008; Murtaza et al., 2013; Newman et al., 2014; Thierry et al., 2014) and circulating tumor cells (Bidard et al., 2014; Dawson et al., 2013; Maheswaran et al., 2008; Rack et al., 2014). So far, implementation of liquid biopsies for early detection of cancer has been hampered by non-specificity of these biosources to pinpoint the nature of the primary tumor (Alix-Panabiè res and Pantel, 2014; Bettegowda et al., 2014). "
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    • "Genome sequencing will be integrated into clinical care in many ways. It is already demonstrating clinical utility for the diagnosis and treatment of certain cancers [5,19] and rare diseases [2,3,20-22] and shows promise for use in infectious disease outbreaks [23-25] and fetal diagnosis in prenatal medicine [7,26]. The design of the MedSeq Project models two archetypal scenarios for how WGS could be integrated into clinical care. "
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