TY - JOUR
T1 - Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse
AU - Almodovar, Karinna
AU - Iams, Wade T.
AU - Meador, Catherine B.
AU - Zhao, Zhiguo
AU - York, Sally
AU - Horn, Leora
AU - Yan, Yingjun
AU - Hernandez, Jennifer
AU - Chen, Heidi
AU - Shyr, Yu
AU - Lim, Lee P.
AU - Raymond, Christopher K.
AU - Lovly, Christine M.
N1 - Funding Information:
This study was supported in part by a Vanderbilt Ingram Cancer Center Young Ambassadors Award and by the National Institutes of Health and National Cancer Institute R01CA121210 (to Dr. Lovly). Dr. Lovly was also supported by a Damon Runyon Clinical Investigator Award, a LUNGevity Career Development Award, a V Foundation Scholar-in-Training Award, an American Association for Cancer Research–Genentech Career Development Award, and grant U10CA180864 . Dr. Almodovar was supported by a Ruth L. Kirschstein National Research Service Award Fellowship ( T32HL094296 ). Mr. Zhao was supported in part by National Cancer Institute/ National Institutes of Health Cancer Center Support Grant 2P30CA068485-19 . We first and foremost would like to thank the patients and their families. We are extremely grateful to the Vanderbilt Ingram Cancer Center Young Ambassadors Award for their generous support of this pilot project; to Anel Muterspaugh, Hina Chowdhry, and Brandon Winston for their assistance in obtaining consent from patients and collecting patient samples; to Dr. Adam Seegmiller for providing the bone marrow biopsy images, and to the entire Lovly laboratory and Darren Tyson for their thoughtful and critical review of the manuscript. Drs. Almodovar, Iams, Lim, Raymond, and Lovly designed the experiments. Drs. Almodovar, Yan, Hernandez, Lim, and Raymond performed the experiments. Drs. Almodovar, Iams, Meador, Hernandez, Lim, Raymond, Lovly generated and analyzed data. Drs. Horn, York provided direct patient care. Drs. Almodovar, Iams, and Lovly wrote the manuscript. Drs. Zhao, Chen, Shyr performed the statistical analysis. Drs. Almodovar, Iams, Meador, Zhao, Horn, Lim, Raymond, and Lovly reviewed the data and the final manuscript.
Publisher Copyright:
© 2017 International Association for the Study of Lung Cancer
PY - 2018/1
Y1 - 2018/1
N2 - 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 (MYCN). 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.
AB - 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 (MYCN). 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.
UR - http://www.scopus.com/inward/record.url?scp=85034735357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034735357&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2017.09.1951
DO - 10.1016/j.jtho.2017.09.1951
M3 - Article
C2 - 28951314
AN - SCOPUS:85034735357
VL - 13
SP - 112
EP - 123
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
IS - 1
ER -