Journal
JOURNAL OF THORACIC ONCOLOGY
Volume 13, Issue 1, Pages 112-123Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jtho.2017.09.1951
Keywords
Small cell lung cancer; Cell-free tumor DNA; Liquid biopsy; Next-generation sequencing; Plasma
Categories
Funding
- Vanderbilt Ingram Cancer Center Young Ambassadors Award
- National Institutes of Health
- National Cancer Institute [R01CA121210]
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- V Foundation Scholar-in-Training Award
- American Association for Cancer Research-Genentech Career Development Award
- Ruth L. Kirschstein National Research Service Award Fellowship [T32HL094296]
- National Cancer Institute/National Institutes of Health Cancer Center Support Grant [2P30CA068485-19]
- [U10CA180864]
- NATIONAL CANCER INSTITUTE [R01CA121210, T32CA009592, U10CA180864, P30CA068485] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL094296] Funding Source: NIH RePORTER
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Introduction: Patients with SCLC have a poor prognosis and limited treatment options. Because access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden. Methods: We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including tumor protein p53 gene (TP53), retinoblastoma 1 gene (RB1), BRAF, KIT proto-oncogene receptor tyrosine kinase gene (KIT), notch 1 gene (NOTCH1), notch 2 gene (NOTCH2), notch 3 gene (NOTCH3), notch 4 gene (NOTCH4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), phosphatase and tensin homolog gene (PTEN), fibroblast growth factor receptor 1 gene (FGFR1), v-myc avian myelocytomatosis viral oncogene homolog gene (MYC), v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog gene (MYCL1), and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene (MYCIV). Results: Over the course of 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies ranging from 0.1% to 87%. In our cohort, 59% of the patients had extensive-stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1, NOTCH2, NOTCH3, NOTCH4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed allele frequencies and copy number alterations tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging. Conclusions: These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of response to treatment, and timely warning of disease relapse in patients with this disease. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
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