While there may be cost and time savings associated with the use of next-generation sequencing (NGS), panel-based testing for inherited colorectal cancer (CRC), questions remain as to whether the identification of moderate-penetrance genes currently enhances clinical care and management, according to a study published online March 20 in Clinical Genetics. This study is the largest to date to describe results found among clinical patients undergoing panel-based CRC testing and critically assesses the benefits and challenges associated with this testing method. While many tout the potential time and cost savings associated with NGS panel-based testing, these tests increase the complexity of interpreting results in part because of the higher rate of inconclusive results, which may result in lengthier counseling and unnecessary screening and follow-up. However, the hope is that by including moderate-risk genes along with continued analysis of variants of unknown significance (VUS), understanding of cancer risk and case management will improve over time. It is estimated that between 10 percent and 30 percent of patients with CRC have an inherited predisposition, making them prime targets for enhanced risk-based management. Patients who underwent hereditary CRC panel-based testing (ColoNext; Ambry Genetics [Mission Viejo, Calif.]) from March 2012 to March 2013 were identified […]
While there may be cost and time savings associated with the use of next-generation sequencing (NGS), panel-based testing for inherited colorectal cancer (CRC), questions remain as to whether the identification of moderate-penetrance genes currently enhances clinical care and management, according to a study published online March 20 in Clinical Genetics. This study is the largest to date to describe results found among clinical patients undergoing panel-based CRC testing and critically assesses the benefits and challenges associated with this testing method.
While many tout the potential time and cost savings associated with NGS panel-based testing, these tests increase the complexity of interpreting results in part because of the higher rate of inconclusive results, which may result in lengthier counseling and unnecessary screening and follow-up. However, the hope is that by including moderate-risk genes along with continued analysis of variants of unknown significance (VUS), understanding of cancer risk and case management will improve over time. It is estimated that between 10 percent and 30 percent of patients with CRC have an inherited predisposition, making them prime targets for enhanced risk-based management.
Patients who underwent hereditary CRC panel-based testing (ColoNext; Ambry Genetics [Mission Viejo, Calif.]) from March 2012 to March 2013 were identified from a comprehensive data repository. ColoNext includes analysis of 14 genes, a mix of mostly highly penetrant, actionable genes and some moderately penetrant genes with lower established clinical utility. The researchers estimated mutation and VUS rates and determined whether patients with a mutation met national genetic testing criteria (2013 National Cancer Center Network [NCCN] guidelines) for the respective cancer syndromes identified.
Based on demographic data stored in Ambry’s comprehensive repository, those tested tended to have a personal history of CRC (53 percent) and a positive family history of CRC or other cancers (54 percent). The researchers found that just over 10 percent of the 586 patients tested had a pathogenic mutation. When excluding the patients with CHEK2 mutations (n=8; clinical relevance remains uncertain) and patients with only one MUTYH mutation (n=11; MUTYH-associated polyposis are autosomal recessive, but monoallelic carriers may have a moderately increased CRC risk), the number of patients with actionable mutations decreased to 7.2 percent, primarily in Lynch syndrome genes. Just over 20 percent of all patients had a VUS. Nearly 12 percent of those with a VUS also had a pathogenic mutation.
The majority of the 42 patients with an actionable mutation (71 percent) met NCCN syndrome-based testing, screening, or diagnostic criteria. Twelve patients with actionable mutations did not clearly meet the testing criteria, including six in whom panel-based testing may have identified mutations otherwise missed because of limited medical or family history or an atypical presentation.
“On the basis of our findings, although there are scenarios where panel-based testing may have been more cost-efficient, [the] reality remains that syndrome-based testing would have been sufficient to identify the majority of patients with deleterious mutations. Consequently, the optimal and most cost-effective use of panel-based testing as a first-tier test vs a second-tier test (i.e. after syndrome-based testing is negative), remains to be determined,” write the authors, led by Deborah Cragun, from the H. Lee Moffitt Cancer Center (Tampa, Fla.). “Finally, it remains uncertain whether identification of moderate penetrance genes truly helps guide cancer screening decisions over and above what would be recommended based on comprehensive collection of family history without conducting testing.”
Several authors report financial ties to Ambry Genetics, which performs ColoNext testing.
Takeaway: While the expanded information profile and cost efficiencies made possible with panel-based CRC testing are appealing, it remains to be seen whether this can be translated into improved management of potentially higher-risk patients.
