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InVitae Poster Expands Data on Hereditary Cancer Panel Testing Compared to BRCA1/2 Alone

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NEW YORK (GenomeWeb) — In data presented earlier this month at the annual meeting of the Association for Molecular Pathology, genetic testing company InVitae expanded on earlier work evaluating the clinical performance of its next-generation sequencing-based test for determining hereditary cancer risk compared to more limited BRCA1/2-focused testing such as Myriad Genetics' BRACAnalysis.

Like the earlier data, the results indicated InVitae's approach is largely equal to BRCA1/2-specific testing in identifying variants in the BRCA genes alone, but can also find additional variants in other genes that increase the risk of developing cancers.

In an initial study, which appeared in the Journal of Clinical Oncology earlier this year, Invitae researchers partnered with researchers at Stanford University, recruiting 198 women that had been referred to Stanford for clinical BRCA1/2 testing between 2002 and 2012 to have their germline DNA assessed for variants in 42 cancer-risk associated genes — including the BRCA1/2 genes — and receive potentially actionable results.

That study found, overall, that of the 57 women who had tested positive for BRCA1/2 mutations via Myriad Genetics' clinical BRCA1/2 test, the InVitae assay detected 58 of 59 variants initially identified by Myriad. The variant the assay missed was a large insertion, which would have likely been picked up with deletion/duplication testing, which InVitae performs on its clinical samples.

At the AMP meeting this month, InVitae researchers shared a poster describing an expansion of this research with Stanford and Massachusetts General Hospital collaborators, which assessed the company's 215-gene NGS panel in more than 1,000 patients, most of whom had previously been tested separately for BRCA1/2.

Currently, InVitae offers a hereditary cancer diagnostic panel of 29 genes for $1,500. While the test sequences about 200 genes, the firm only interprets results from 29 with the most evidence for clinical utility. Additionally, the test can be customized depending on the physician's preference. For instance, a doctor can just order the genes involved in Lynch syndrome at the same price.

InVitae's Steve Lincoln previously described some of the individual cases assessed in the company's larger 1,000-patient study. But the new poster offers a much broader overview of the company's results in the cohort as a whole.

In the study, InVitae researchers recruited patients in several different ways. According to the authors, 735 patients were prospectively recruited following NCCN guidelines, and another 209 retrospective cases were added from a biobank specifically representing high-risk patients. Most of the subjects in both of these groups had had previous BRCA1/2 testing, though some had had testing of additional genes as well.

In addition, 118 subjects were referred for testing based on the presence of a known pathogenic variant in their family. The study also sequenced 36 reference samples known to be positive for specific variants, and another seven reference samples with high-quality whole genome data available.

According to the study authors, nine percent of the clinical referral subset of the cohort carried a pathogenic variant in either BRCA1 or BRCA2. Another four percent had a pathogenic variant in another cancer risk gene among 29 total that were analyzed, mainly in moderate penetrance genes or Lynch syndrome genes. Another 2.5 percent of the subjects were heterozygous MUTYH carriers.

To measure the method's sensitivity, the InVitae team looked at 750 of the total set of identified variants that fell into the 29-gene list that it analyzes for clinical test reporting, including all pathogenic variants, large indels, CNVs, and a sampling of VUS and benign variants, and then validated that against Sanger and qPCR results. The variants detected by the company's NGS analysis matched up perfectly with previously identified variants. There were no false positives and no false negatives.

The researchers then compared the BRCA1/2-specific results from within the larger NGS analysis to patients' previous BRCA1/2 test results from Myriad Genetics to establish their concordance. The two sets of results agreed 99.8 percent of the time. According to the authors, this strong concordance is especially notable in light of the fact that InVitae's variant classification relies only on public, non-proprietary data resources, while patients' previous Myriad results were informed by that company's large proprietary database, frequently cited by Myriad as a marker of the superiority of its testing. 

Lincoln, the first author of the poster, told GenomeWeb at the conference that the study, which is ongoing, is also tracking several clinical factors in the cohort, including patient phenotypes and physician decision making. The poster mentioned some initial results of this analysis, including the observation that in most cases — 80 percent, so far — patients' family history or cancer phenotype was consistent with their InVitae test results.

Interestingly, looking at the potential impact of the testing on clinical care, the group also concluded that for patients with non-BRCA findings, for example, Lynch-syndrome mutations, the results indicated a consideration of a change in care or treatment based on current medical guidelines about 70 percent of the time. The authors also reported that in patients who consented to receive their results in the study, genetic counseling has been both "feasible and appreciated by the patients."

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