journal contribution
posted on 2025-11-25, 13:05 authored by Lavanya 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>Longitudinal changes in cfTL were re-analyzed for each patient, considering all plasma variants independent of origin. Survival analyses revealed that CH-unfiltered ctDNA responses were not associated with either (A) overall survival-OS or (B) progression-free survival-PFS. Comparison between CH-unfiltered ctDNA responses and radiographic assessments (PR/CR vs SD/PD/MR) in these patients revealed that CH-unfiltered responses we not predictive of (C) OS at 12 and (D) 36 months, and PFS at (E) 3 and (F) 12 months, compared to best overall radiographic responses.</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
Lung Cancer Foundation of America
NCCN Young Investigator Award
International Lung Cancer Foundation
History
ARTICLE ABSTRACT
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
