Survival analyses of 31 patients with evaluable baseline plasma samples revealed that ctDNA molecular responses were significantly associated with both (A) overall survival-OS and (B) progression-free survival-PFS. Patients classified as molecular responders had a significantly longer OS and PFS compared to patients who were assigned a classification of molecular response f/b recrudescence or molecular progression. Comparison between molecular responses and radiographic assessments (PR/CR vs SD/PD/MR) in these patients revealed that ctDNA molecular responses were a stronger predictor of (C) OS at 12 and (D) 36 months and PFS at (E) 3 and (F) 12 months, compared to best overall radiographic responses.
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
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
