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Fig S7 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer

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posted on 2023-06-13, 08:25 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

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

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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

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