Cost effectiveness of adding genes to next generation sequencing panels for evaluation of colorectal cancer and polyposis syndromes. C. J. Gallego1, B. S. Shirts3, C. C. Pritchard3, G. P. Jarvik1, D. L. Veenstra2 1) Division of Medical Genetics, University of Washington, Seattle, WA; 2) Pharmaceutical Outcomes and Research Policy Program, University of Washington, Seattle, WA; 3) Department of Laboratory Medicine, University of Washington, Seattle, WA.

   Background: Next generation sequencing (NGS) panels are increasingly used in the evaluation of inherited colorectal cancer and polyposis (CRCP) syndromes. However, the added value incorporating additional genes into these panels has not been studied. This study evaluates the cost-benefit of adding groups of genes, based on their inheritance mode and penetrance. Methods: We developed a decision model comparing evaluation of CRCP syndromes with NCCN guidelines with four increasingly comprehensive NGS panels with the following groups of genes: (1) genes associated with Lynch syndrome alone, (2) adding genes associated with other autosomal dominant conditions with high colorectal cancer (CRC) penetrance, (3) adding genes associated with autosomal recessive conditions with high CRC penetrance, and (4) further adding autosomal dominant, low CRC penetrance genes. Empiric variant frequencies were obtained from a large clinical NGS laboratory. Outcomes were quality adjusted life years (QALY) and costs associated with intensive surveillance of colorectal cancer in relatives of probands identified with a CRCP syndrome. We calculated Incremental Cost-Effectiveness Ratios (ICER) of each panel compared to guidelines and compared to the next panel. Sensitivity analyses were conducted. Results: The use of a panel testing only for Lynch associated genes resulted in ICER between $125,000 and $260,000 per QALY, while the addition of high penetrance autosomal dominant genes associated with high CRC resulted in ICER of $38,000 to $69,000 per QALY. Adding high penetrance autosomal recessive genes associated with CRC had an ICER of $14,000 to $15,000 per QALY and the addition of low penetrance autosomal dominant genes yielded an ICER between $84,000 and $85,000 per QALY. Overall, the use of NGS panels for the evaluation of CRCP compared to current guidelines added costs as low as $40,000 per QALY. Sensitivity analysis did not markedly change these results. Conclusion: Incorporating autosomal dominant high penetrance genes associated with CRC to NGS panels is more cost effective than sequencing only Lynch syndrome genes. Addition of autosomal recessive high penetrance genes is also cost effective. Finally, adding low penetrance genes associated with CRC yields less benefit, but may still be cost-effective. These findings support the use of NGS panels for evaluation of CRCP syndromes and the addition of new genes to these panels, even when penetrance is modest.

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