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
AU - Merks, Johannes H M
AU - van der Schoot, C Ellen
AU - Tytgat, Godelieve A M
AU - Stutterheim, Janine
N1 - ©2021 The Authors; Published by the American Association for Cancer Research.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - PURPOSE: 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 qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.EXPERIMENTAL DESIGN: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic 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 European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.RESULTS: We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (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 overall survival (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), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.CONCLUSIONS: 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 with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
AB - PURPOSE: 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 qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.EXPERIMENTAL DESIGN: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic 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 European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.RESULTS: We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (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 overall survival (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), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.CONCLUSIONS: 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 with 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 - Clin Cancer Res
JF - Clin Cancer Res
IS - 20
ER -