A tissue-free circulating tumor DNA (ctDNA) assay was strongly prognostic for recurrence in patients treated for triple-negative breast cancer and provided a lead time to recurrence comparable to that of a multivariant tumor-informed assay, according to findings from a prognostic study published by Cunningham et al in JAMA Oncology.
“These findings support tissue-free ctDNA detection in the molecular residual disease [MRD] setting, allowing testing when archival tissue is unavailable,” the investigators wrote.
Study Details
The investigators focused on patients treated for early triple-negative breast cancer at moderate to high risk of recurrence who were participating in the ctDNA surveillance period of the multicenter phase II c-TRAK TN trial. Following completion of adjuvant therapy, plasma samples were collected every 3 months for up to 2 years and prospectively analyzed by digital polymerase chain reaction (dPCR). A subsequent retrospective analysis used a whole-exome sequencing–powered multivariant tumor-informed assay, which detected MRD with a longer lead time to relapse than dPCR.
In this prognostic and exploratory analysis, the investigators retrospectively evaluated 1,026 samples from 159 patients (mean age = 51.4 years; 100% female) using a tissue-free ctDNA assay that leverages cancer differential methylation patterns to detect ctDNA without requiring sequencing of the primary tumor.
The primary objective was to assess the prognostic significance of tissue-free ctDNA detection for recurrence. Tissue-free assay results were also compared with the dPCR and whole-exome sequencing–powered multivariant tumor-informed assays.
Key Findings
A total of 54 (34%) patients had detectable ctDNA by the tissue-free assay; ctDNA detection was strongly associated with recurrence risk (hazard ratio [HR] = 27.2, 95% confidence interval [CI] = 13.7–54.2; P < .001), the investigators reported.
Of the 42 (26%) patients with ctDNA detected by both the tissue-free and dPCR assays, detection occurred concurrently with both assays in 28 (66.7%), whereas the tissue-free assay detected ctDNA earlier in 14 (33.3%). The median lead time to recurrence was longer with the tissue-free assay than with dPCR (7.9 [95% CI = 6.1–10.5 months] vs 5.8 [95% CI = 3.3–10.0 months] months; HR = 0.57, 95% CI = 0.34–0.95; P = .03).
The investigators described the concordance between the tissue-free and tumor-informed assays as good. Of 41 (30.8%) patients with ctDNA detected by both assays, detection occurred earlier with the tumor-informed assay in 12 (29.3%) and earlier with the tissue-free assay in 1 (2.4%). The median lead times to recurrence with the tissue-free and tumor-informed assays were 7.6 (95% CI = 4.6–10.5 months) and 7.1 (95% CI = 5.7–10.0 months) months, respectively (HR = 1.46, 95% CI = 0.87–2.44; P = .15).
“In this prognostic study, tissue-free ctDNA detection during surveillance was strongly prognostic for recurrence of triple-negative breast cancer, demonstrating clinical validity in this setting,” the investigators concluded. “The median lead time of the tissue-free ctDNA assay was similar to a multivariant tumor-informed assay, although the tumor-informed approach detected ctDNA at earlier time points in a greater proportion of patients.”
They continued, “These findings support the use of tissue-free assays as a practical alternative in patients for which a tumor-informed assay is not possible. However, the clinical benefit of early MRD detection and intervention remains uncertain, and prospective ctDNA-guided intervention studies are warranted to assess clinical utility of tissue-free assays.”
Nicholas C. Turner, MD, PhD, of the Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research, London, is the corresponding author of the article in JAMA Oncology.
DISCLOSURE: For full funding information and disclosures of the study authors, visit jamanetwork.com.
