Nitzan Rosenfeld, PhD

Nitzan Rosenfeld, PhD, Senior Group Leader,
Cancer Research UK, Cambridge Institute

The identification of circulating tumor DNA (ctDNA) following initial treatment among patients with early non-small cell lung cancer (NSCLC) using sensitive, patient-specific assays may inform which patients would benefit from additional treatment, according to a study published in Annals of Oncology.

Identifying residual disease among patients with localized NSCLC who have been treated with curative intent may enable the identification of those at risk for relapse, according to the study results. Specifically, novel tools can identify ctDNA in plasma at fractional concentrations—as low as a few parts per million—but clinical evidence is needed to guide the use of such tools.

Nitzan Rosenfeld, PhD, of the Cancer Research UK Cambridge Institute, and colleagues examined 363 serial plasma samples from 88 patients with early-stage NSCLC, mainly adenocarcinomas (62.5%). Treatment included surgery with curative intent (N=61), chemoradiotherapy (N=19), and surgery with adjuvant chemotherapy/radiotherapy (N=8). Exome sequencing of the primary tumor was employed to develop personalized assays targeting 48 variants specific to each patient. Dr. Rosenfeld and colleagues followed patients for a median of 3 years (range, 42 days to 5 years) and recorded clinical outcomes.

ctDNA Associated With Worse Survival Outcomes

The researchers identified ctDNA before the start of treatment in 24%, 77%, and 87% of patients with stage 1, 2, and 3 disease, respectively, and in 26% of all longitudinal samples. The median tumor fraction reported was 0.042%, with 63% of samples at less than 0.1% and 36% at less than 0.01%. Clinical specificity for identification of ctDNA was greater than 98.5% and preceded clinical recognition of primary tumor recurrence by a median of 212.5 days. Additionally, ctDNA was identified following treatment in 18/28 (64.3%) of patients with clinical recurrence of the primary tumor.

“Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients and was associated with shorter recurrence-free survival (HR, 14.8; P<0.00001) and overall survival (HR, 5.48; P<0.0003),” Dr. Rosenfeld and colleagues wrote. “ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HRs, 2.97 and 3.14; P values, 0.01 and 0.003, respectively).”

Using ctDNA to Guide Treatment & Monitor Patients

What the researchers described as “ctDNA detection in a landmark window,” within 2 weeks to 4 months after treatment, was associated with a 5.5-fold greater risk for death and a 14.8-fold greater risk for recurrence of the primary tumor. Patients in whom ctDNA was identified before, but not after, treatment experienced “excellent” outcomes, with recurrence occurring in only two of 16 patients, indicating the potential for de-escalating adjuvant treatment, Dr. Rosenfeld and colleagues noted.

The study’s primary limitation was that routine sampling was conducted for only 9 months after the end of treatment, Dr. Rosenfeld and colleagues explained, but the assay used identified ctDNA in plasma at fractional concentrations as low as 0.0011%. Such detection was seen in patients with no obvious or radiological signs of disease who went on to experience recurrence.

“Our study adds to the accumulating evidence that supports the utility of ctDNA testing for detection of residual disease and recurrence,” the researchers wrote. “This may be used as a sensitive tool for identifying patients at high risk of relapse who may benefit from additional adjuvant therapy or may be eligible for enrollment [in] clinical trials. In the future, ctDNA testing may allow identification of patients at lower risk of relapse, for whom it may be possible to consider less intensive or shorter treatment courses.”