TY - JOUR
T1 - Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease
AU - Lak, Nathalie S M
AU - Voormanns, Timon L
AU - Zappeij-Kannegieter, Lily
AU - van Zogchel, Lieke M J
AU - Fiocco, Marta
AU - van Noesel, Max M
AU - Merks, Johannes H M
AU - van der Schoot, C Ellen
AU - Tytgat, Godelieve A M
AU - Stutterheim, Janine
N1 - Funding Information:
N. Lak, L. Zappeij-Kannegieter and J. Stutterheim were supported by KiKa (Children Cancer Free), grant number 312. N. Lak, L. Zappeij-Kannegieter and J. Stutterheim were supported by the Children Cancer-Free Foundation (KiKa), project number 312. The cell line CW9019 was kindly provided by dr. F. Barr, National Cancer Institute, Bethesda, USA.
Funding Information:
N. Lak, L. Zappeij-Kannegieter and J. Stutterheim were supported by the Children Cancer-Free Foundation (KiKa), project number 312. The cell line CW9019 was kindly provided by dr. F. Barr, National Cancer Institute, Bethesda, USA.
Funding Information:
N. Lak, L. Zappeij-Kannegieter and J. Stutterheim were supported by KiKa (Children Cancer Free), grant number 312.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - Background Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase quantitative PCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR. Methods Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematological tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the EpSSG RMS2005 protocol. Findings We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year EFS was 35.5% (95%CI 17.5-53.5%) for the 33/99 RNA-positive patients, versus 88.0% (95%CI 78.9-97.2%) for the 66/99 RNA-negative patients (p<0.0001). Five-year OS was 54.8% (95%CI 36.2-73.4%) and 93.7% (95%CI 86.6-100.0%), respectively (p<0.0001). RNA panel-positivity was negatively associated with EFS (Hazard Ratio 9.52 95%CI (3.23-28.02), while the RMS2005 risk group stratification was not, in the multivariate Cox regression model. Interpretation This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared to conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
AB - Background Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase quantitative PCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR. Methods Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematological tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the EpSSG RMS2005 protocol. Findings We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year EFS was 35.5% (95%CI 17.5-53.5%) for the 33/99 RNA-positive patients, versus 88.0% (95%CI 78.9-97.2%) for the 66/99 RNA-negative patients (p<0.0001). Five-year OS was 54.8% (95%CI 36.2-73.4%) and 93.7% (95%CI 86.6-100.0%), respectively (p<0.0001). RNA panel-positivity was negatively associated with EFS (Hazard Ratio 9.52 95%CI (3.23-28.02), while the RMS2005 risk group stratification was not, in the multivariate Cox regression model. Interpretation This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared to conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
KW - Child
KW - Child, Preschool
KW - Female
KW - Humans
KW - Infant
KW - Male
KW - Prospective Studies
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Rhabdomyosarcoma/diagnosis
KW - Risk Assessment
UR - http://www.scopus.com/inward/record.url?scp=85117390520&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-1083
DO - 10.1158/1078-0432.CCR-21-1083
M3 - Article
C2 - 34285060
SN - 1078-0432
VL - 27
SP - 5576
EP - 5585
JO - Clinical cancer research : an official journal of the American Association for Cancer Research
JF - Clinical cancer research : an official journal of the American Association for Cancer Research
IS - 20
ER -