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Fig S6 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

(A) Comparison between ctDNA molecular responses and clinical benefit determined through radiographic imaging for patients treated with immunotherapy-containing regimens revealed concordance between each assessment (p = 0.019, Fisher’s exact test). For these comparisons, durable clinical benefit (DCB) was defined as a lack of progression or death within 6 months of treatment initiation; non-durable benefit (NDB) was defined as progression or death within 6 months of treatment initiation. Comparison between ctDNA molecular responses and radiographic assessments (PR/CR vs SD/PD/MR) for the determination of (B) overall survival (OS) at 64 months (maximum OS observed in patients with date of death recorded) and progression-free survival (PFS) at (C) 6 months, (D) 9 months and (E) 14 months (maximum PFS observed in patients with clinically documented progression following systemic treatment), is shown for all 33 patients included in the study cohort.

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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