Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Dawson, Sarah-Jane; Tsui, Dana; Murtaza, Muhammed; Biggs, Heather; Rueda, Oscar M.; Chin, Suet-Feung; Dunning, Mark J.; Gale, Davina; Forshew, Tim; Mahler–Araujo, Betania; Rajan, Sabrina; Humphray, Sean; Becq, Jennifer; Halsall, David; Wallis, Matthew; Bentley, David; Caldas, Carlos; Rosenfeld, Nitzan

doi:10.1056/nejmoa1213261

Cited by 1,966 publications

(1,712 citation statements)

References 39 publications

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“…This study confirmed independent prognostic value of CTC detection but lack to show difference between primary tumor-based molecular subgroups and impact of CTC status on survival (Wallwiener et al, 2013). Circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has been investigated and compared with cancer antigen 15-3 (CA 15-3) and circulating tumor cells in a recent study (Dawson et, al., 2013). They concluded that 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.…”

Section: Introductionsupporting

confidence: 71%

Detection of Circulating Tumor Cells in Breast Cancer Patients: Prognostic Predictive Role

Türker¹,

Üyetürk²,

Sönmez³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Section: Introductionsupporting

confidence: 71%

Detection of Circulating Tumor Cells in Breast Cancer Patients: Prognostic Predictive Role

Türker¹,

Üyetürk²,

Sönmez³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…And although most protein biomarkers stay in the blood for weeks, ctDNA has a half-life of less than two hours, so it gives a clearer view of a tumour's present, rather than its past. The Cambridge and Johns Hopkins teams have found that ctDNA is more sensitive than protein biomarkers when it comes to detecting breast 10 and bowel 9 cancers, respectively, and it is more accurate at tracking tumour disappearance, spread and recurrence.…”

Section: Better Biomarkersmentioning

confidence: 99%

Cancer biomarkers: Written in blood

Yong

2014

Nature

143

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“…6,7 Recent studies have consequently focused on the multipurpose utility of cfDNA for molecular characterization to aid in diagnosis, treatment selection and monitoring of cancer patients during therapy. 8 Recent focus has been dedicated to detection of tumor specific mutations from the circulating tumor DNA, whereas the clinical implications of measuring the total cfDNA is somehow controversial. The level of circulating tumor DNA as identified by tumor specific genetic alterations is expected to correlate directly to tumor volume, but the total level of circulating free DNA include both tumor specific DNA and nucleic acids origining from surrounding tissue and peripheral cells.…”

mentioning

confidence: 99%

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

et al. 2014

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The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with secondline chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second-line irinotecan for metastatic CRC (n 5 100), a cohort of healthy controls with and without comorbidity (n 5 70 and 100, respectively) were included. cfDNA was quantified by an in-house developed quantitative polymerase chain reaction from plasma samples drawn prior to the first cycle of chemotherapy and at time of progression. cfDNA levels were significantly higher in CRC compared to controls, with a clear capability for discriminating between the groups (receiver operation curve analysis; area under the curve 0.82, p < 0.0001). Patients with high levels had a shorter survival from irinotecan compared to those with lover levels. The cohort independent upper normal limit divided patients into high and low risk groups. The progression-free survival (PFS) was 2.1 months [95% confidence interval (CI) 2.0-3.4] and 6.5 (95% CI 4.2-7.2) months [hazard ratio (HR) 2.53; 95% CI 1.57-4.06, p < 0.0001] and overall survival (OS) 7.4 months (95% CI 4.3-8.7) and 13.8 months (95% CI 11.9-18.9; HR 2.52; 95% CI 1.54-4.13, p < 0.0000), respectively. Cox regression multivariate analysis showed a PFS HR of 1.4 (95% CI 1.1-1.7) for each increase in cfDNA quartile, p 5 0.03 and 1.6 (1.3-2.0) for OS, p < 0.0001, respectively. A combined marker analysis with plasma KRAS mutations added further prognostic impact, which was consistent when performed on the samples drawn at time of progression. In conclusion, cfDNA measurement holds important clinical information and could become a useful tool for prediction of outcome from chemotherapy in mCRC.Despite the availability of several effective cytotoxic drugs and new biological agents the prognosis of metastatic colorectal cancer (mCRC) is still poor and the curative options are limited to a subgroup of patients with resectable metastasis. Consequently, the majority of patients will be offered several lines of palliative chemotherapy, which imply a high level of side effects and careful selection of patients and monitoring during therapy is therefore essential. Irinotecan (a semisynthetic analog of camptothecin) is widely used in combination with flouropyrimidines or as monotherapy for mCRC. 1 The major dose limitating toxicities include diarrhea and myelosupression. 2,3 Better selection criteria in terms of predictive and prognostic markers to optimize treatment are needed.The presence of circulating nucleic acids in peripheral circulation was discovered more than 60 years ago by Mandel and Metais 4 followed by Leon et al. 5 in 1971 who later described the importance of circulating tumor DNA in cancer development. A substantial proportion of the circulating cell-free DNA (cfDNA) in cancer patients is believed to originate from tumor cells. 6,7 Recent studies have consequently focused on the multipurpose utility of cfDNA for molecular characterization to aid in...

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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Abstract: 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.).

Cited by 1,966 publications

References 39 publications

Detection of Circulating Tumor Cells in Breast Cancer Patients: Prognostic Predictive Role

Detection of Circulating Tumor Cells in Breast Cancer Patients: Prognostic Predictive Role

Cancer biomarkers: Written in blood

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

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