Estimated Cost-effectiveness of Genetic Testing in Siblings of Newborns With Cancer Susceptibility Gene Variants

Introduction Newborn population-based genetic screening may reduce pediatric cancer deaths and could be cost-effective. 1 Testing siblings of newborns with variants (ie, cascade testing) could further improve population health. 2 Economic studies of cascade testing have focused on adults, although evidence suggests that cost-effectiveness improves for some cancer syndromes when surveillance is initiated in younger individuals. 3 Our objective was to estimate the benefits and costs of cascade testing of siblings of newborns with cancer susceptibility gene variants.


Introduction
Newborn population-based genetic screening may reduce pediatric cancer deaths and could be cost-effective. 1Testing siblings of newborns with variants (ie, cascade testing) could further improve population health. 2 Economic studies of cascade testing have focused on adults, although evidence suggests that cost-effectiveness improves for some cancer syndromes when surveillance is initiated in younger individuals. 3Our objective was to estimate the benefits and costs of cascade testing of siblings of newborns with cancer susceptibility gene variants.

Methods
This economic evaluation study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.This study was deemed exempt from review, and informed consent was not required because the institutional review board at Harvard Pilgrim Health Care determined the project did not meet the definition of human participant research.
Using the Precision Medicine Policy and Treatment (PreEMPT) model 1 created in 2020, we estimated outcomes in siblings of newborns who were born with pathogenic or likely pathogenic variants in 1 of 11 pediatric cancer genes (ie, RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, or PHOX2B).Genes were selected based on associations with increased risk of very early onset malignant neoplasm and available surveillance guidelines.Children with variants were assumed to have 1 newborn sibling, based on US Census Bureau data.In the base case, we assumed de novo variants were rare, and siblings had 50% likelihoods of having the same germline variants as probands.Because of the variation and uncertainty in de novo variant rates by gene, 4 we then varied assumptions about having the same germline variants to 5% (ie, very high de novo rate) and 25% (ie, moderate rate) in scenario analyses.Model outcomes included lifetime cancer deaths averted and cost-effectiveness relative to no cascade testing, calculated from a societal perspective with 3% discounting for costs and life-years (LYs).Cascade testing costs included Sanger sequencing (ie, $200) and clinical visits (ie, $188) before initiating surveillance.Surveillance costs were based on 2018 Medicare reimbursement rates.Sensitivity analyses varied costs of sequencing, clinical visits, and surveillance by 25%.To capture uncertainty, we conducted 1000 simulations where we sampled model parameters from their underlying distributions.We report means and 95% uncertainty intervals (UIs), defined as the 2.5 and 97.5 percentiles of estimates from 1000 simulations.Analyses were conducted in 2021 using R version 4.1.0(R Project for Statistical Computing).Statistical tests were not conducted, given estimates were derived from simulation modeling rather that population sampling.

Results
In a cohort of 3.7 million newborns, the model estimated 1584 newborns (95% Abbreviations: LYs, life-years; P/LP, pathogenic or likely pathogenic; UI, uncertainty intervals.
a Cancer cases for the 11-gene panel include all medullary thyroid carcinoma, retinoblastoma, adrenocortical carcinoma, choroid plexus, rhabdomyosarcoma, osteosarcoma, rhabdoid tumors, pleuropulmonary blastoma, medulloblastoma, neuroblastoma, Wilms tumor, and hepatoblastoma, including those not attributable to 1 of the 11 genes.Siblings were only at risk for developing the cancer associated with the gene for which they were assumed to undergo genetic screening.
b Calculated as the ratio of expected incremental costs divided by the expected incremental life years among 1000 simulations.Abbreviations: ICER, incremental cost-effectiveness ratio; UI, uncertainty intervals.
a Assumes a 50% likelihood siblings carry the same variant as probands.
b Number of siblings based on variant carriers identified via newborn screening of a birth cohort of 3.7 million individuals with a 11-gene panel.
c Sibling cascade testing compared with usual care.
d Calculated as the ratio of expected incremental costs divided by the expected incremental life-years among 1000 simulations.95% UI is based on ICERs calculated for each simulation.ICERs were defined as cost-saving if sibling cascade testing had higher incremental LYs and lower incremental costs compared with usual care.
e Assumes a 25% likelihood siblings carry the same variant as probands.
f Assumes a 5% likelihood siblings carry the same variants as probands.
g Excludes 4 simulations (out of 1000) which included no cases of PHOX2B.

JAMA Network Open | Genetics and Genomics
Cost-effectiveness of Genetic Testing in Siblings of Newborns With Cancer Susceptibility Gene Variants

Table 2 .
Cost-eff ectiveness of Sibling Cascade Testing Compared With Usual Care