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Objective: To evaluate whether adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care is clinically and economically beneficial. Method: A decision-analytic model was developed to compare reflex sgNIPT as first-line carrier screening to the traditional sequential carrier screening workflow (positive maternal carrier screen is followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and cost effectiveness between the two screening methods. Results: Reflex sgNIPT carrier screening detected 108 of 110 affected pregnancies per 100,000 births (sensitivity 98.5%). This is a 2.4-fold improvement compared to the traditional sequential carrier screening, which detected 46 of 110 affected pregnancies per 100,000 births (sensitivity 41.5%). The testing costs in reflex sgNIPT carrier screening to identify one affected birth were $ 0.65 million, reduced by 62% from $1.73 million in traditional sequential carrier screening. Adoption of reflex sgNIPT carrier screening translated to a cost savings of $90.6 million per 100,000 births. Conclusion: Using reflex sgNIPT as the first-line carrier screening method improved the detection of affected births by 2.4-fold and saved $906 in healthcare costs per pregnancy screened. A real-life experience will need to assess the clinical utility of carrier screen with reflex sgNIPT.

As novel cancer treatments become available, the need to quickly and accurately evaluate whether these treatments are effective remains unaddressed. Obtaining earlier feedback on the efficacy of a cancer therapy could prevent a poor treatment outcome by switching to a more effective therapy sooner. Levels of circulating tumor DNA (ctDNA) have been found to be prognostic of tumor progression, suggesting that a non-invasive liquid biopsy assay could provide longitudinal ctDNA measurements that accurately track tumor progression. However, while there is interest in using existing minimal residual disease (MRD) detection and treatment selection liquid biopsy assays for treatment monitoring applications, they both suffer from limitations in their ability to precisely and sensitively quantify trends in tumor progression over the course of treatment. In addition, tumor-informed MRD detection assays are often infeasible for treatment monitoring due to unavailability of the initial tissue sample. We have developed and validated a novel methylation-based liquid biopsy assay for pan-cancer treatment monitoring without the need to obtain a sample from the tumor itself. Methylation has long been shown to be a strong and consistent biomarker for cancer, and because tumor tissue has widespread differential methylation across the genome compared to normal tissue, we are able to overcome molecule sampling limitations. In analytical validation, our assay could detect as small changes as 0.05%, e.g., an elevation of tumor fraction from 0.5% to 0.55%, a level of precision that is an order-of-magnitude better than any available assays. Next, we tested our assay on clinical specimens by measuring ctDNA in serially collected blood samples from subjects with cancer. As would be expected from the high level of precision, we were able to successfully demonstrate the predictive power of ctDNA measurements for clinical outcomes. These results from our methylation-based liquid biopsy assay open the path to earlier and extremely precise treatment monitoring for oncologists and their patients. Citation Format: Patrick Peiyong Ye, Robb Viens, Xavier Bower, Shan Riku, David Tsao, Oguzhan Atay. Novel methylation-based, tissue-free ctDNA assay accurately quantifies longitudinal tumor burden changes for precision treatment monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 526.