At a recent cancer research meeting, experts predicted that liquid biopsies are “the future.” Jean-Charles Soria, MD, chair of the scientific committee for the EORTC-NCI-AACR symposium and director of the Site de Recherche Intégrée sur le Cancer (SIRIC) Socrate project at Gustave Roussy Cancer Campus, Paris, said that liquid biopsies are going to “completely change the rules of engagement” for patient management and clinical practice.
Dr Soria continued: “I really think ― and I’m ready to bet ― that this is the most transformational thing that’s going to happen in oncology in terms of how it’s going to impact cancer clinical trials and cancer daily management for the next 5 years.”
The latest study, conducted by researchers from Cancer Research UK Cambridge Institute, was published online December 20 in PLOS Medicine. The researchers found that ctDNA test results correlated with the size of ovarian cancers and was predictive of response to treatment or time to disease progression.
“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,” write the authors, led by Nitzan Rosenfeld, PhD, and James Brenton, MD, PhD, both of Cancer Research UK. “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.”
The standard clinical blood test used in ovarian cancer is the serum protein cancer antigen 125 (CA-125), which is sensitive but lacks specificity for detecting ovarian cancer, note the authors. In addition, CA-125 levels do not change quickly enough following treatment to inform decisions regarding changes in chemotherapy after one or two cycles in cases in which the patient is not responding.
Therefore, there is a need for better tumor markers, and ctDNA is a promising candidate, the authors suggest.
Sensitive to Treatment Response
Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). Dr Rosenfeld, Dr Brenton, and colleagues evaluated the use of these mutations as personalized markers to monitor tumor burden, early response to treatment, and time to progression.
They conducted a retrospective analysis using 318 blood samples that had been obtained from 40 HGSOC patients. Patient-specific TP53 assays were designed and used to quantify the amount of ctDNA in the samples that were collected before, during, and after chemotherapy.
Of these samples, 261 were collected during treatment of relapsed disease. Treatment included 54 courses of chemotherapy (n = 32 patients). An additional 57 specimens were collected from 12 patients during first-line treatment with chemotherapy.
The findings showed that the fraction of mutated TP53 in ctDNA (TP53MAF) had a significant correlation with disease volume, as measured by CT scan (Pearson r = 0.59; P < .001). Pretreatment TP53MAF levels correlated with the time to progression.
These findings are consistent with previous studies across a range of tumor types, note the authors, which found that ctDNA levels increase as stage increases.
Patient response to chemotherapy was seen much earlier with ctDNA, with a median time of 37 days, as compared to 84 days with CA-125.
The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04%/cm3) as compared to patients who were untreated (0.0008%/cm3; P = .004).
In 49 treatment courses for relapsed disease, pretreatment TP53MAF concentration, but not CA-125, was associated with time to progression.
Among patients being treated for relapsed disease, a decrease in TP53MAF of >60% was an independent predictor of longer time to progression (hazard ratio, 0.22; P = .008), whereas a decrease in TP53MAF of ≤60% was associated with poor response and could identify patients for whom time to progression was less than 6 months (sensitivity, 71%; specificity, 88%).
“TP53 ctDNA has the potential to be a clinically useful blood test to assess prognosis and response to treatment in women with HGSOC,” they conclude.
These findings need to be confirmed in larger, prospective studies with patients receiving uniform treatment, the authors comment. If the findings do hold up, then “TP53 ctDNA could be used in HGSOC clinical trials and routine practice to identify earlier whether treatment is effective,” the authors add.
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