Myriad Genetics Says myRisk Cancer Test Highly Accurate in Key Validation Study

Myriad Genetics, Inc.

today announced it will present data this week at the American Society of Human Genetics (ASHG) annual meeting in Boston showing that the Myriad myRisk Hereditary Cancer test meets rigorous quality standards and provides clinical sequencing results equivalent to 99.99 percent accuracy. Myriad myRisk Hereditary Cancer is a new diagnostic test that provides patients with information about their hereditary risk for eight major cancers including breast, colorectal, ovarian, endometrial, pancreatic, prostate, gastric cancers and melanoma. "Next-generation DNA sequencing offers the ability to test many genes at once, but it must be optimized to ensure clinical accuracy. We've invested three years of research to optimize our Myriad myRisk Hereditary Cancer test, and the validation data show that Myriad myRisk Hereditary Cancer offers 99.99 specificity and sensitivity which means it provides unprecedented quality and accuracy equal to the gold standard Sanger sequencing," said Richard J. Wenstrup, M.D., chief medical officer of Myriad. "As next-generation technology advances, mutation classification techniques also must evolve to ensure high quality data interpretation for clinical decision making. Myriad has developed a robust variant classification program called Myriad myVision™ to achieve highly accurate, clinically-actionable, genetic test results for patients and healthcare providers." The five studies being presented at the ASHG annual meeting include: Development of a Next Generation Sequencing Panel to Assess Hereditary Cancer Risk that Includes Clinical Diagnostic Analysis of the BRCA1 and BRCA2 Genes.  [Roa et al., Poster: Oct. 24, 2013, 11:30 a.m. – 12:30 p.m. ET] This study validated the myRisk Hereditary Cancer test, which is a 25-gene panel that uses next generation sequencing (NGS) technology. The study compared the myRisk Hereditary Cancer test to the gold standard Sanger sequencing for evaluation of BRCA1 and BRCA2 mutations in 1,864 patient samples. myRisk Hereditary Cancer detected 15,877 variants compared to 15,878 variants using Sanger sequencing, resulting in an analytic sensitivity > 99.99 percent.  These data show that a NGS gene panel designed to meet rigorous quality standards can provide clinical sequencing results that are equivalent to those obtained from Sanger DNA sequencing analysis (i.e., greater sensitivity without loss of specificity). In this validation study, Myriad's myRisk Hereditary Cancer test was shown to be highly effective and provided high quality, accurate results for clinical decision-making purposes.  A Clinical History Weighting Algorithm Accurately Classifies BRCA1 and BRCA2 Variants. [Bowles et al., Poster: Oct. 25, 2013, 10:30 – 11:30 a.m. ET] This study evaluated a clinical history weighting algorithm designed to provide highly accurate classifications for BRCA1 and BRCA2 variants of uncertain significance and which is integral to Myriad's proprietary myVision™ Variant Classification Program. The algorithm is based on the premise that disease-associated mutations will be observed more often in individuals at high risk for carrying a mutation, as determined by personal and family history.  Statistical analysis weights the family histories of each patient carrying a variant of interest and compares those histories to control patients carrying variants known to be benign or deleterious. Data from more than 400,000 patients were used to develop the algorithm, which was validated against 6,000 BRCA1 and BRCA2 variants. The results showed that the clinical history weighting algorithm accurately classified well-documented variants associated with BRCA1 and BRCA2 and allowed classification with fewer observations than other techniques, providing timely and accurate classifications to guide clinical care. Importantly, this clinical history weighting algorithm facilitated the accurate reclassification of BRCA1 and BRCA2 variants of uncertain significance, which will improve the clinical management of patients at risk for hereditary cancer. Frequencies of BRCA1, BRCA2, PALB2, and CDKN2A Germline Mutations in Familial Pancreatic Cancer (FPC): A PACGENE study. [Zhen/Petersen et al., Poster: Oct. 24, 2013, 10:30 – 11:30 a.m. ET] This study assessed the frequency of germline mutations in four of the genes in the myRisk Hereditary Cancer panel – BRCA1, BRCA2, PALB2, and CDKN2A – in patients with familial pancreatic cancer. Using samples from a large pancreatic cancer registry, the DNA from 80 patients who met familial pancreatic cancer criteria was tested.  The frequencies for deleterious or suspected deleterious mutations and variants of uncertain significance (VUS) among the patients tested totaled 13.8 percent: BRCA1 (2.9 percent), no VUS; BRCA2 (4.4 percent), no VUS; PALB2 (1.3 percent), no VUS; CDKN2A (5.2 percent), 3 VUS.  These data show the genetic heterogeneity of germline mutations in patients with familial pancreatic cancer and strongly suggest that these patients are appropriate candidates for genetic testing using a hereditary cancer panel that tests for multiple genes to prevent a misdiagnosis. Detection of Large Rearrangements in PMS2. [Mancini-DiNardo et al., Podium: Oct. 25, 2013, 3:15 p.m. ET] This study evaluated the frequency of large rearrangements (LR) in the PMS2 gene, which are associated with hereditary colon cancer.  While inactivation of PMS2 is caused largely by sequencing mutations, a significant proportion of all PMS2 mutations have been reported to be large rearrangements. In this study, the analysis of data from patients who received full gene sequencing and LR analysis of MLH1, MSH2, MSH6 and PMS2, demonstrated that deleterious and suspected deleterious mutations in PMS2 comprise 14.3 percent of all mutations detected in these hereditary colon cancer predisposing genes (108/755). Among the PMS2 mutation-positive patients, 25 percent of the mutations were LR compared with 75 percent that were sequencing mutations. This study showed that LR are a significant portion of PMS2 mutations. Since mutations within PMS2 alone are clinically actionable, it is critically important to accurately assess patients' PMS2 large rearrangement status. The multifaceted process used in this study provided patients with an accurate diagnosis. Clinical Presentation of Patients with Mutations in the APC Regions Associated with AFAP. [Kaushik et al., Poster: Oct. 25, 2013, 11:30 a.m. – 12:30 p.m. ET] This study evaluated the polyp history of patients with mutations in three areas of the APC gene associated with Attenuated Familial Adenomatous Polyposis (AFAP) compared to mutations elsewhere in the gene. AFAP is a subtype of familial adenomatous polyposis (FAP) and people with FAP/AFAP are at increased risk of hereditary colorectal cancer.  A total of 1,534 individuals with mutations in the APC genes were included in this study. APC mutations in the three gene regions associated with AFAP were identified in 30.1 percent of patients. Of these, 65.7 percent developed less than 100 colorectal adenomas. A total of 69.9 percent were found to carry an APC mutation in the remainder of the gene not associated with AFAP. Of these, 25 percent developed less than 100 polyps. The majority of patients with an APC mutation in the three regions associated with AFAP were over the age of 40 (72.7 percent), while the majority of patients with mutations elsewhere in the APC gene were aged 20 to 40 (57.1 percent). This data showed a trend of less severe polyps and later age of testing among patients with a mutation in the three main regions of APC associated with AFAP.  However, a substantial number of patients were found to have more than 100 colorectal adenomas regardless of the region the mutation was found in, suggesting that there is no definitive genotype/phenotype correlation between APC mutations and AFAP/FAP. This study supports expanding the use of genetic testing earlier in life for patients with AFAP.