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Cost-Effectiveness Analysis Can Determine Which Colorectal Cancer Patients Should Not be Sequenced

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By Monica Heger

Intermountain Healthcare has devised a cost-effectiveness analysis that can help determine whether colorectal patients should have a select number of genes sequenced in order to determine whether members of their family are at high risk of colorectal, endometrial, and ovarian cancer.

The team is now working with ARUP laboratories, which performs the testing, to validate the findings of a recent study and determine whether the laboratory should change its current testing protocol, Jim Gudgeon, lead author of the paper and senior policy and outcomes analyst for the Clinical Genetics Institute at Intermountain, told Clinical Sequencing News.

"We hope in the near future to have this screening [protocol] available at all our hospitals," added Marc Williams, director of Intermountain's Clinical Genetics Institute.

While the analysis concerns just the sequencing of four genes using Sanger sequencing, Williams said it could eventually serve as a framework to analyze the cost effectiveness of using next-generation sequencing on more genes.

Researchers at Intermountain Healthcare sought to implement a screening protocol to identify colorectal patients who also had Lynch syndrome, which is characterized by mutations to any of the four so-called mismatch repair genes, because the information can inform whether family members are at a high risk of developing colorectal cancer as well.

Individuals with Lynch syndrome are at high risk of developing colorectal cancer — some 70 percent to 80 percent of individuals with the syndrome will develop the disease, often before the age of 50. These individuals also have an increased risk of developing endometrial and ovarian cancer and also other kinds of malignancies.

While only 2 percent to 5 percent of colorectal cancer patients also have Lynch syndrome, among those that do, around half of all their first-degree family members will also have Lynch syndrome — and with it the risk of developing colorectal cancer. So, identifying family members early on could encourage more frequent monitoring and lessen the chances of developing cancer.

Sequencing the individual genes involved is effective at identifying Lynch syndrome-causing mutations, but, at a price of between $4,000 and $6,000 per test, the method is cost-prohibitive.

Therefore, the Intermountain Healthcare team wanted to devise a cost-effectiveness protocol to determine which patients were most likely to have Lynch syndrome, and should therefore be sequenced.

The resulting study, published online this month in the American Journal of Managed Care, found that the most cost-effective way to screen patients for Lynch syndrome is to first use immunohistochemistry staining of the four mismatch repair proteins.

If that test yields abnormal results, it should be followed by BRAF mutation testing and methylation analysis. And only if those tests are also abnormal should the patients undergo sequencing.

Sequencing the MMR genes of all patients with an abnormal IHC test resulted in identifying the most patients with Lynch syndrome, but was also the most expensive.

That protocol had 92.9-percent sensitivity, but cost on average $13,355 per case detected, and the cost to detect one additional case was over $1.5 million. The most cost-effective protocol, meantime, had a sensitivity only slightly lower, at 91.26 percent, and cost an average of $10,369 per case detected.

Incorporating BRAF and methylation analysis was critical for making the protocol more cost effective because IHC staining of the MMR genes has a high false positive rate, which results in unnecessary sequencing.

"Most of the time when you get an abnormal result from the IHC staining, it's due to an abnormality in the MLH1 gene," said Gudgeon. However, in about 90 percent of the cases, the abnormality is caused by a hypermethylation of the MLH1 promoter, not the gene, and does not result in Lynch syndrome.

"It's a false positive, because the MLH1 protein is still produced," Gudgeon said.

Following up the IHC staining with BRAF-mutation and methylation testing can help eliminate those false positives.

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Gudgeon said the team is now working with researchers at ARUP to verify the results of the paper and potentially change the lab's protocol. Currently, ARUP's protocol calls for IHC staining followed by BRAF mutation testing and then methylation testing, which the team found to be less efficient than performing methylation testing before BRAF testing. In addition, it costs an extra $216,498 to detect one additional case of Lynch syndrome.

Applied to Next-Gen Sequencing

While the model assumes that the genes will be sequenced with Sanger sequencing, the same model could be applied to determine the price point at which it would be cost effective to use next-gen sequencing, Williams said.

"The models that we've built, we could build [a similar] model and tell exactly when it would be more efficient to do a next-gen sequencing approach," he said.

The model could be tested for whole-genome sequencing and also for targeted sequencing of the genes involved in Lynch syndrome and other high-penetrance genes.

"If next-gen sequencing is applied to the subset of colorectal cancer genes — the four mismatch repair genes [as well as] TP53, APC, MYH, [and] PTEN — you could imagine a price point where it would be more efficient to do next-gen sequencing," as opposed to other screening methods, on all patients, said Williams.

Before such a model could be built for a next-gen sequencing-based assay, a number of questions about next-gen sequencing would first have to be answered, such as its sensitivity, specificity, and the false positive rate. "All of those costs would have to be factored in," said Williams

Additionally, a next-gen sequencing-based test would add the additional barrier data interpretation. According to Williams, if IHC yields abnormal results, "we know that the protein is abnormal."

But in a next-gen sequencing-based test, not every variant will be understood, and a major cost would be incurred in trying to determine whether variants of unknown significance actually affected the protein.

Despite these hurdles, Williams said that using next-gen sequencing in a clinical setting is something that he will look to do in the future.

"Once it starts to get to the point where it looks like it's going to be emerging in the clinic, then that's something we'd do," he said. "The issue for us is that we are a clinical center, not academic, so we have to be practical on where we concentrate our resources."

A number of organizations and even companies, including researchers at the Dana Farber Cancer Institute, Foundation Medicine, and even the UK and Canadian governments, are betting that next-gen sequencing will be implemented in a clinical setting, particularly for cancer care, and are developing targeted sequencing panels for cancer diagnostics and to help guide treatment (CSN 8/17/2011).

Additionally, there have been a few cases where whole-genome sequencing of a cancer patient has informed treatment decisions, such as at the Genome Institute of Washington University (CSN 4/26/2011).

Though he acknowledged that there have been some successes at implementing next-gen sequencing in a clinical setting, Williams said he doesn't think that it will make its way into general practice for at least a couple of years.

"But, we'll continue to monitor the field," he said.


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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