Wyndham Wilson, MD, PhD
Patients with diffuse large B-cell lymphoma (DLBCL) who developed detectable circulating tumor DNA (ctDNA) during surveillance were more than 200 times more likely to have their disease progress than those who did not have detectable ctDNA, according to an NCI study recently published in The Lancet Oncology
The researchers also found that measurement of ctDNA enabled the detection of cancer recurrence at a median of 3.5 months before clinical evidence of disease. In addition, the ctDNA test was able to predict which patients would not respond to therapy as early as the second cycle of treatment.
“Interim ctDNA is therefore a promising biomarker to identify patients at high risk of not responding to treatment for their disease,” said lead NCI investigator Wyndham Wilson, MD, PhD, Center for Cancer Research.
Researchers analyzed serum from 126 patients with DLBCL for the presence of ctDNA. Patients were examined from May 1993 to June 2013 with a medium follow-up of 11 years (IQR, 6.8-14.2).
Interim monitoring of ctDNA at the end of two treatment cycles in 108 patients showed a 5-year time lapse to progression of 41.7% (95% CI, 22.2-60.1) in patients with detectable ctDNA and 80.2% (69.6-87.3) in those without detectable ctDNA (P
<.0001). Detectable ctDNA had a positive predictive value of 62.5% (95% CI, 40.6-81.2) and a negative predictive value of 79.8% (69.6–87.8). Surveillance monitoring of ctDNA was done in 107 patients whose ctDNA had a positive predictive value of 88.2% (95% CI, 63.6–98.5) and a negative predictive value of 97.8% (92.2-99.7) and identified risk of recurrence at a median of 3.5 months (range, 0-200) before evidence of clinical disease.
To detect ctDNA in serum, the researchers used a quantitative method that assesses gene segments with advanced sequencing techniques. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum ctDNA encoding the VDJ rearrangements was quantitated.
Eligible patients had DLBCL, no evidence of indolent lymphoma, and were previously untreated. All patients received therapy involving the drugs etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH), with or without rituximab. Serum samples were collected before treatment, during treatment, and for many years after therapy. The patients also had CT scans done at the same time as the blood testing as part of standard surveillance.
Most people with DLBCL show no signs of disease after their initial therapy, but, because of the risk of recurrence, they currently undergo imaging by CT scanning or interim PET (iPET) scans on a regular basis for up to 5 years after their initial disease remission. The disease reoccurs in up to 40% of patients and is then often incurable, particularly in those who progress early and/or have significant levels of tumor cells in their blood.
However, these methods are often imprecise, as DLBCL is most likely to occur with a residual disease level below that which can be detected by imaging. Repeat radiation can also impose potential health risks and unnecessary financial burdens. Surveillance of ctDNA may be a promising alternative.
“Even with frequent CT imaging, administered for a median of 11 times per patient in our study, early-disease detection was suboptimal,” said Wilson. “Indeed, a recent study suggested that surveillance CT scans might be no better than an up-to-date patient history and physical exams, supporting the need for more effective monitoring technologies.”
The patients in this study did not undergo iPET scanning, but the researchers noted that it would be of interest to compare interim ctDNA monitoring and iPET in future clinical studies.
Roschewski M, Dunleavy K, Pittaluga S. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study [published online April 1, 2015]. Lancet Oncology. doi:10.1016/S1470-2045(15)70106-3.