posted on 2025-11-25, 13:05authored byLavanya Sivapalan, Wade T. Iams, Zineb Belcaid, Susan C. Scott, Noushin Niknafs, Archana Balan, James R. White, Prasad Kopparapu, Christopher Cann, Blair V. Landon, Gavin Pereira, Victor E. Velculescu, Christine L. Hann, Christine M. Lovly, Valsamo Anagnostou
<p>Schematic summarizing the branched logic used to determine the origin of sequence alterations identified in plasma NGS. Variants representing lung cancer hotspots were classified as tumor-derived, independent of their presence in matched WBC DNA NGS. Variants with a variant allele fraction (VAF) >25% in all WBC DNA and plasma samples from a patient were classified as germline. Alterations that were detected in matched WBC DNA sequencing or in the canonical clonal hematopoiesis (CH) gene DNMT3A were classified as CH-derived. For all variants detected in plasma using TEC-Seq but not in matched WBC DNA samples (based on a threshold of >3 supermutants), we performed an additional evaluation of their supermutant counts in the WBC DNA sequence data to exclude potential CH origin. Plasma variants with a supermutant count of >1 in matched WBC DNA TEC-Seq data were classified as CH-derived and alterations with a matched WBC DNA supermutant count of 0 were assigned a tumor-derived origin.</p>
Funding
National Institutes of Health (NIH)
The Bloomberg-Kimmel Institute for Cancer Immunotherapy
U.S. Department of Defense (DOD)
ECOG ACRIN Thoracic Malignancies Integrated Translational Science Center
V Foundation for Cancer Research (VFCR)
LUNGevity Foundation (LUNGevity)
Vanderbilt-Ingram Cancer Center Young Ambassadors Award
Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response.
We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy.
Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging.
ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring.See related commentary by Pellini and Chaudhuri, p. 2176