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Levels of DNA in blood test correlated with ovarian cancer outcomes


Levels of circulating tumor DNA (ctDNA) detected in a blood test are correlated with the size of ovarian cancers and can predict a patient's response to treatment or time to disease progression, according to a retrospective study of cancer patients' blood samples published in PLOS Medicine by Nitzan Rosenfeld and James Brenton of Cancer Research UK Cambridge Institute and colleagues.

Blood levels of a protein called CA-125 are currently used to gauge treatment response in women receiving chemotherapy for high grade serous ovarian cancer (HGSOC). However, CA-125 levels don't change rapidly enough to guide treatment changes after one or two cycles of chemotherapy. In the new study, researchers measured levels of ctDNA carrying mutations in the gene TP53, which are detected in 99% of patients with HGSOC. 318 blood samples from 40 HGSOC patients, taken before, during, and after standard-of-care treatment were analyzed. CT images of the patients' tumors were collected, as well as data on the progression of their cancers.

The fraction of mutated TP53 in ctDNA (TP53MAF) was correlated with volume of disease as measured by CT scan (Pearson r=0.59, p<0.001), and--unlike CA-125--pre-treatment TP53MAF levels were also correlated with each patient's time to progression. While CA-125 took 84 days to reflect the full extent of changes after chemotherapy, changes were reflected in TP53MAF in a median of just 37 days. In patients being treated for a relapse, a decrease in TP53MAF of more than 60% was associated with a longer time to progression, while a decrease of 60% or less was associated with poor response to chemotherapy and a time to progression of less than 6 months. The study was limited by small sample size, heterogeneity of treatments, and its retrospective design; larger, prospective trials with uniform treatments are now needed to confirm the findings.

"These findings have strong potential for clinical utility owing to the ease of assaying DNA in plasma and the low cost and speed of ctDNA testing," the authors say. "Having very early information on response would empower patients and physicians to test alternative treatment options and have high utility in trials that link biomarkers to targeted therapy."


Funding: This work was supported by Cancer Research UK ( Grant numbers: A15601-JDB; A11906-NR; A20240-NR; A18072-JDB. JDB was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. CAP was supported in part by the Academy of Medical Sciences, the Wellcome Trust, British Heart Foundation and Arthritis Research UK. CAP, DG, AMP, HB, CH, HA, SF, PM, KH, IG, MJL, HME, WQ, NR and JDB are affiliated with Cancer Research UK but the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: DG, NR and JDB are co-founders, shareholders and officers/consultants of Inivata Ltd, a cancer genomics company that commercialises ctDNA analysis.

Citation: Parkinson CA, Gale D, Piskorz AM, Biggs H, Hodgkin C, Addley H, et al. (2016) Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study. PLoS Med 13(12): e1002198. doi:10.1371/journal.pmed.1002198

Author Affiliations: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Cancer Research UK Major Centre--Cambridge, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom


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