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Next-generation sequencing cost-effective for evaluation of inherited colorectal cancer, polyposis syndromes
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The use of next-generation sequencing panels that included highly penetrant genes associated with colorectal cancer and polyposis syndromes in addition to Lynch syndrome genes appeared to be cost-effective for the evaluation of colon cancer in patients’ relatives, according to study results.
“Despite the promise of next-generation sequencing, the utility of testing multiple genes with different modes of inheritance and with varying levels of disease penetrance has been questioned based on the argument that costs of increased surveillance and unnecessary treatments may outweigh the benefits of cancer prevention, as well as the uncertain consequences of the identification of variants of unknown significance,” David L. Veenstra, PharmD, PhD, of the University of Washington, and colleagues wrote. “The colorectal cancer and polyposis syndromes phenotype is an ideal model to study the cost-effectiveness of next-generation sequencing panels because … there are multiple genes associated with the overlapping clinical picture and testing under the current standard of care has unacceptable sensitivity.”
Veenstra and colleagues created a model to compare next-generation sequencing with the current standard of care for individuals referred to a cancer genetic clinic based on a personal or family history of colon cancer. They used the model to evaluate financial and health benefits of identifying relatives with pathogenic variants — in life-years and quality-adjusted life-years (QALY) — based on the occurrence of genetic mutations. Researchers categorized colorectal cancer and polyposis syndromes by inheritance type and penetrance of colorectal cancer.
The base-case test presumed that first-, second- and third-degree relatives would be contacted, but only first-degree relatives would be approached. Relatives who hypothetically accepted counseling and testing were presumed to undergo targeted analysis for pathogenic mutations. The model assumed relatives positive for mutations would be offered colorectal cancer surveillance with colonoscopy.
The researchers developed four hypothetical sequencing panels:
- Panel 1 included only the Lynch syndrome genes;
- panel 2 included panel 1 plus genes associated with autosomal dominant colorectal cancer and polyposis syndromes with high penetrance of colorectal cancer;
- panel 3 included panel 2 plus genes associated with autosomal recessive colorectal cancer and polyposis syndromes with high penetrance of colorectal cancer; and
- panel 4 included panel 3 plus genes associated with autosomal dominant colorectal cancer and polyposis syndromes with low penetrance of colorectal cancer.
The use of a next-generation sequencing panel that included both Lynch syndrome genes and highly penetrant genes (panel 3) resulted in a 0.151-year life expectancy increase, 0.128 QALY gained and a benefit of $4,650 per person compared with the current standard of care. These data equated to an incremental cost-effectiveness ratio of $36,508 per QALY.
Sequencing only the Lynch genes (panel 1) resulted in a $144,235 cost per QALY, which researchers noted is much higher than the contemporary threshold of $100,000 per QALY.
Next-generation sequencing that included genes with a low penetrance of colorectal cancer (panel 4) was associated with 0.01 life-years gained and a cost-effectiveness ratio of $77,300 per QALY compared with panel 3.
Results of the probabilistic sensitivity analysis indicated there was a 74% probability that panel 3 was cost-effective at a threshold of $50,000 per QALY and a 99% probability of being cost-effective at $100,000 per QALY compared with the current standard of care.
The assumption that disease penetrance for colorectal cancer and polyposis syndromes was similar to disease penetrance of associated conditions based on a literature review was identified as a limitation of the study.
“If the conditions modeled here hold true in practice, the use of a [next-generation sequencing] panel that includes genes associated with highly penetrant syndromes in addition to Lynch syndrome genes likely provides important clinical benefit and good value for the health care system,” Veenstra and colleagues concluded. “Additional studies are needed to determine whether these findings are applicable to other common phenotypes and to other, more comprehensive [next-generation sequencing applications], including universal [next-generation sequencing] screening of all patients with colorectal cancer.” – by Cameron Kelsall
Disclosure: Veenstra reports travel expenses from Genentech and consultant roles with Abbott Diabetes, Genentech and Jazz Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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David H. Ilson, MD, PhD
Familial and heritable causes of colorectal cancer are relatively rare and account for less than 5% of cases in the United States. The most common familial cause of colorectal cancer — Lynch syndrome or hereditary nonpolyposis colorectal cancer — is now routinely screened for in resected primary cancers. Immunohistochemistry (IHC) is readily available to study the presence of DNA mismatch repair proteins, which are lost in Lynch syndrome due to autosomal dominant mutations in the genes coding for these proteins. The more common sporadic loss of these proteins, not due to gene mutation but to gene silencing by promoter hypermethylation, also is tested for with the application of IHC, and it has potential prognostic and therapeutic implications, particularly in stage II disease. Recent analyses have suggested that routine IHC testing for DNA mismatch repair proteins is cost-effective and support universal testing.Investigators now report an analysis of the cost-effectiveness of applying the emerging technology of genomic next-generation sequencing to resected colon cancer, in the diagnosis of polyposis and nonpolyposis colorectal cancer syndromes. The authors report that, if this screening is only applied to Lynch screening, cost-effectiveness is not reached. However, if screening includes testing for genes leading to the rarer but highly penetrant hereditary polyposis colorectal cancer syndromes, then the threshold for cost-effectiveness is met. The results support next-generation testing as a screening tool in resected colorectal cancer.
Increasingly, next-generation sequencing is being applied more universally both in earlier-stage resected colorectal cancer, and in metastatic disease, as genomic sequencing has now identified prognostic and predictive biomarkers. The identification of molecular subsets of colorectal cancers will likely lead to the investigation of therapies and approaches designed specifically to impact on these specific subsets. We are now moving beyond the era of one therapy fitting all patients.
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