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

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.

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) model¹ 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.

In a cohort of 3.7 million newborns, the model estimated 1584 newborns (95% UI, 1230-2026) and 792 siblings (95% UI, 615-1013) would carry variants. An estimated 116 siblings (95% UI, 98-139) carrying variants would develop cancer before age 20 years. If these siblings underwent surveillance, 15 cancer deaths (95% UI, 11-20) would be averted, representing a 52% reduction (95% UI, 45%-59%) (Table 1). Compared with usual care, sibling cascade testing had an incremental cost-effectiveness ratio (ICER) of $16 910 per LY gained (95% UI, $7060-$31 440). ICERs for individual genes ranged from cost-saving (eg, WT1, SUFU) to $52 100 per LY gained (TP53), and scenario analyses on the frequency of de novo variants did not substantially change ICER estimates (Table 2). ICERs were robust in sensitivity analyses on sequencing and initial visit costs ($16 650-$17 160 per LY gained) and surveillance costs ($10 040-$24 380 per LY gained).

In this study, we estimated that sibling cascade testing would identify approximately 800 siblings with variants, avert half of projected cancer deaths before age 20 years among these individuals, and would have high value.⁵ Results align with adult studies that find relatives’ genetic testing cost-effective compared with standard screening.²

Limitations to our work included consideration of only 11 genes, exclusion of costs and benefits of parental cascade testing, entry of siblings into the model at birth, and omission of impact on adult-onset cancer outcomes. Benefits assumed full adherence to surveillance and previously used assumptions regarding early detection resulting in improved outcomes.¹ We did not consider how siblings of variant carriers who developed cancer may already undergo surveillance or genetic testing. Notably, the most cancer deaths averted (ie, 80%-89%) accrued among siblings of healthy newborns. Findings demonstrate how sibling cascade testing would enhance newborn screening efforts and how targeted screening approaches may be more efficient than universal screening to achieve population-level benefits.⁶

Accepted for Publication: August 12, 2021.

Published: October 18, 2021. doi:10.1001/jamanetworkopen.2021.29742

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 O’Brien G et al. JAMA Network Open.

Corresponding Author: Ann C. Wu, MD, MPH, Department of Population Medicine, Landmark Center, 401 Park Dr, Ste 401 E, Boston, MA 02215 (ann.wu@childrens.harvard.edu).

Author Contributions: Dr Wu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ms O’Brien and Dr Christensen contributed equally as co-first authors. Drs Yeh and Wu contributed equally as co-senior authors.

Concept and design: Christensen, Sullivan, Diller, Yeh, Wu.

Acquisition, analysis, or interpretation of data: O'Brien, Christensen, Stout, Diller, Yeh, Wu.

Drafting of the manuscript: O'Brien, Yeh, Wu.

Critical revision of the manuscript for important intellectual content: O'Brien, Christensen, Sullivan, Stout, Diller, Yeh.

Statistical analysis: O'Brien, Sullivan, Yeh.

Obtained funding: Wu.

Administrative, technical, or material support: O'Brien, Christensen, Yeh.

Supervision: Christensen, Diller, Yeh, Wu.

Conflict of Interest Disclosures: Dr Christensen reported receiving grants from Sanford Health outside the submitted work. Dr Wu reported receiving grants from GSK outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grant R01-HD090019 from the NIH. Dr Christensen was supported by grant K01-HG009173 from the NIH.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.