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Tumor sequencing superior to other methods of detecting Lynch syndrome in colorectal cancer
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Upfront tumor screening for Lynch syndrome appeared simpler and demonstrated superior sensitivity than the current multiple sequential test approach among patients with colorectal cancer, study data showed.
Lynch syndrome — which affects 3% of patients with colorectal cancer — also increases risk for endometrial, ovarian, gastric and other cancers. Identifying Lynch syndrome among patients with colorectal cancer and their relatives enables timely cancer surveillance, chemoprevention and prophylactic surgical procedures.
Although universal screening for Lynch syndrome is recommended for all patients with colorectal cancer, there are several screening practices that are used.
“Testing methods of the past would just point to a suspicion of Lynch syndrome, but they could not confirm the diagnosis without multiple additional tests, which slows down the diagnostic process and adds costs,” Heather Hampel, MS, CGC, associate director of the divisions of human genetics and biospecimen research and clinical professor of internal medicine at Ohio State University Comprehensive Cancer Center, said in a press release. “This new approach points to the exact mutation patients were born with and does so through a single test. The mutation will need to be confirmed using a blood test, but this requires a single mutation test which is less expensive than multigene panel testing. The previous method could sometimes require patients to get up to five individual tests before knowing if they had Lynch syndrome.”
The researchers compared the sensitivity of tumor sequencing with microsatellite instability testing and immunohistochemical staining for detecting Lynch syndrome.
For this comparison, Hampel and colleagues used DNA from a prospective cohort of 419 patients with colorectal cancer, as well as a validation cohort of 46 patients with colorectal cancer who were known to have Lynch syndrome as a result of a germline mutation in a mismatch repair gene.
Mean age at the time of diagnosis was 59.9 years, and 51.8% of patients were female.
Tumor sequencing correctly identified all 46 cases of Lynch syndrome from the validation cohort, as well was 12 cases from the prospective cohort. This appeared superior to microsatellite instability testing followed by BRAF V600E testing, which missed five cases, and immunohistochemical testing followed by BRAF V600E testing, which missed six.
Tumor sequencing demonstrated better sensitivity (100%; 95% CI, 93.8-100) than immunohistochemical testing plus BRAF testing (89.7%; 95% CI, 78.8-96.1) and microsatellite instability testing plus BRAF testing (91.4%; 95% CI, 81-97.1).
Further, tumor sequencing demonstrated specificity (95.3%; 95% CI, 92.6-97.2) equal to that of immunohistochemical testing plus BRAF testing (94.6%; 95% CI, 91.9-96.6) and microsatellite instability plus BRAF testing (94.8%; 95% CI, 92.2-96.8).
Tumor sequencing also avoided the need for another test by identifying 284 cases with KRAS, NRAS or BRAF mutations that could impact therapy for stage IV colorectal cancer, as well as identifying eight patients who had germline DPYD mutations that could increase toxicity 5-FU, the most common chemotherapy used to treat colorectal cancer.
“Knowing this type of information ahead of time might be useful for oncologists who can select another drug or use lower doses to avoid these bad reactions,” Hampel said. “In addition, this test can also identify other potential hereditary cancer syndromes by looking at other known cancer susceptibility genes at the same time.”
These results support upfront tumor testing for all patients with colorectal cancer, instead of reserving testing for advanced-stage patients for whom standard therapies are not working.
“Although this new test is more expensive, it will eliminate many other tests for a subset of patients so that it may be more cost-effective overall,” Hampel said. “If it is not now, it will certainly be in the future as the costs of tumor sequencing continue to decline.” – by Andy Polhamus
Disclosures: Hampel reports stock in Genome Medical and consultant/advisory roles with Genome Medical and Invitae. Please see the full study for all other authors’ relevant financial disclosures.
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