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Myriad Sees Hopeful Reimbursement, Adoption Prospects for New Genetic 5-FU Toxicity Test

Myriad Genetics is hoping that the reimbursement and physician adoption of its newly launched genetic test, TheraGuide 5-FU, will be driven by the test’s potential to lower the high cost of treatment-related adverse reactions and prevent treatment-related deaths.
TheraGuide 5-FU uses DNA sequencing to identify variations in the DPYD and TYMS genes to predict whether patients will experience toxicities with 5-FU/capecitabine-based chemotherapy. The company launched the homebrew test last month.
“Our discussions with physicians have found a great interest in helping patients avoid toxicity due to the choice of chemotherapy,” William Hockett, Myriad vice president of corporate communications, told Pharmacogenomics Reporter this week. “Myriad has begun discussions with insurers and has very positive initial feedback. Because the test can save lives and avoid very costly toxicity, we anticipate widespread coverage.”
The test cost, which includes a comprehensive DNA sequence analysis of the DPYD gene and of variations in the TYMS gene, is $1,100.
The cost of treatment with 5-FU (fluorouracil) is approximately $5,000 per month and with Xeloda (capecitabine), an oral form of 5-FU, is approximately $8,000 per month. Although the cost of toxicity management depends on the type of adverse reaction the patient experiences, Hockett estimated that the price tag can range between $30,000 and $100,000.
Understanding the serious costs associated with treatment-related toxicities, physicians have not been apprehensive about incorporating this new technology into their practices, Hockett noted. “They sometimes expressed the belief that they could start all patients on a low dose, but that approach means that most patients will be left with a sub-optimal initial dose for efficacy,” he said.
5-FU is a chemotherapy drug indicated for the treatment of various types of cancer, including breast, bowel, stomach, and esophageal. Xeloda is indicated for the treatment of metastatic breast and colorectal cancers. According to Myriad, more than 500,000 people in the US use 5-FU each year to treat their cancers.
Approximately 30 percent of cancer patients treated with 5-FU have a toxic reaction that requires at least a dose adjustment. Within this group, however, approximately 1.5 percent to 2 percent of cancer patients treated with 5-FU experience fatal toxicities, and 60 percent have serious or life-threatening (grade 3/grade 4) adverse reactions.
“The balance are less severe, but still difficult and costly toxic reactions,” Hockett noted.
The majority of toxicities experienced by patients following 5-FU treatment are due to genetic variations in the DPYD and TYMS genes. The DPYD gene makes the enzyme responsible for metabolizing 5-FU and clearing it from the body quickly. Impaired DPYD enzyme activity means 5-FU will be cleared more slowly, patients will be exposed to 5-FU for longer, and therefore, their risk for having toxic reactions to the treatment will be higher.
According to Myriad, an estimated 9 million individuals in the US have low DPYD enzyme activity due to mutations in the DPYD gene.
The TYMS gene can have genetic variations altering patients’ ability to produce thymidylate synthase, an enzyme that is essential for DNA synthesis. When 5-FU binds to the TYMS enzyme, it stops DNA synthesis and causes cell death.
A genetic mutation in the TYMS gene that causes underproduction of the enzyme may cause the patient to receive too large a dose of 5-FU. Due to mutations in the TYMS gene, only a portion of the 5-FU dose will be used to bind to the TYMS enzyme and the remaining drug will cause greater toxicity in the patient. On the other hand, a genetic variation that causes the body to overproduce the TYMS enzyme will lead to underdosing and a loss of efficacy with 5-FU, since there will be not enough drug to bind to the excess enzyme.  
Reduced enzyme activity may induce in patients hand-foot syndrome, fever, mucositis, stomatitis, and severe diarrhea. Other adverse reactions from 5-FU include nausea, vomiting, rectal bleeding, skin changes, as well as neurological abnormalities such as cerebellar ataxia and changes in cognitive ability. “Elimination of 5-FU from the treatment regimen is usually sufficient to prevent additional unexpected toxicities,” the company reported.
TheraGuide 5-FU analyzes a patient blood sample using DNA sequencing to identify variations in the coding regions of the DPYD gene. According to Hockett, DNA sequencing is the gold standard for mutation detection and has 100 percent sensitivity and specificity.
“There are no typical false positive and false negative rates, because those rates are always in comparison to the gold standard,” he added. “The TYMS portion of the analysis detects tandem and triplet repeats in the promoter region of the gene, to determine whether too much or too little TYMS enzyme is being made.”

"TheraGuide 5-FU points the way to the future promise of personalized medicine, where tests can guide the therapeutic choice for improved patient care, while limiting the side effects of otherwise efficacious drugs."

Hockett acknowledged that the company may face some competition in the DPYD gene testing space. “There are a few labs offering a test for DPYD, but they typically only offer a test for one common mutation, leaving the test sensitivity at about 40 percent at best,” he said. “The addition of TYMS adds a great value to the physician.”
LabCorp offers pharmacogenetic testing for DPYD, which tests for the most common DPYD gene mutation, IVS14+1 G>A, also known as *2A.
Myriad licensed the base patent for the DPYD gene and the TYMS gene from the National Institutes of Health. Hockett said that Myriad has applied for several patents on mutations in the DPYD gene and has made discoveries improving the company’s ability to detect and interpret overproduction or underproduction of the TYMS enzyme.
Myriad will market the test with its 190-person oncology sales force. After Myriad receives samples, physicians receive the results within seven days.
“TheraGuide 5-FU is a new personalized medicine test that has the potential to save many cancer patients from serious toxic reactions to the medicine that is supposed to help them," said Myriad President Greg Critchfield in a statement. "TheraGuide 5-FU points the way to the future promise of personalized medicine, where tests can guide the therapeutic choice for improved patient care, while limiting the side effects of otherwise efficacious drugs."
The company said it is now accepting samples for testing with TheraGuide 5-FU.
TheraGuide 5-FU is Myriad's fifth molecular diagnostic product launch after the BRACAnalysis test for hereditary breast and ovarian cancer, the Melaris test for hereditary melanoma, the Colaris test for hereditary nonpolyposis colorectal cancer, and the Colaris AP test for hereditary melanoma.

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