The use of universal tumor screening in conjunction with multigene panel testing led to an improvement in the identification of hereditary cancer syndromes in patients with colorectal cancer.
The use of universal tumor screening in conjunction with multigene panel testing led to an improvement in the identification of hereditary cancer syndromes in patients with colorectal cancer (CRC), according to findings from the Ohio Colorectal Cancer Prevention Initiative study (NCT01850654) that were published in JCO Precision Oncology. The data suggest that universal tumor screening alone is an inadequate screening method for cancer susceptibility gene mutations.
The results showed that 525 patients (15.9%) had mismatch repair (MMR) deficiency. A total of 234 of 3310 patients (7.1%, 95% CI, 6.2%-8.0%; 16% of the 1462 patients who received multigene panel testing, 95% CI, 14.2%-18.0%) had 248 pathogenic germline variants in cancer susceptibility genes. A total of 142 patients (4.3%, 95% CI, 3.6%-5.1%) had a pathogenic germline variant in an MMR gene, and 101 patients (3.1%, 95% CI, 2.5%-3.7%) had a pathogenic germline variant in a non-MMR gene. Ten patients with Lynch syndrome also had a non-MMR pathogenic germline variant and were included in both groups.
“[Universal tumor testing] alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with [Lynch syndrome]. At a minimum, 7.1% of individuals with CRC have a [pathogenic germline variant] and pan-cancer [multigene panel testing] should be considered for all patients with CRC,” wrote lead study author, Rachel Pearlman, MS, of The Ohio State University Comprehensive Cancer Center, in the study publication.
Hereditary cancer syndromes are associated with high cancer risks and require heavy surveillance. To improve the identification of high-risk patients with CRC, investigators provided universal tumor screening for Lynch syndrome and germline pan-cancer multigene panel testing to patients with CRC to assess the frequency and variation of cancer susceptibility gene mutations across the state of Ohio.
A total of 3310 unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016.
All patients underwent universal tumor screening for MMR deficiency, and pathogenic germline variants were identified with multigene panel testing in those who had at least one inclusion criterion: MMR deficiency; a diagnosis before the age of 50 years; multiple primary tumors––CRC or endometrial cancer––or a first-degree relative with CRC or endometrial cancer.
A total of 125 patients were excluded from analysis because of ineligibility (n = 118) and withdrawal (n = 7). Reasons for ineligibility included insufficient tumor material, ineligible pathology type, diagnosis made outside of the qualifying study period, and diagnosis made outside of Ohio.
Tumor screening and germline testing were performed in 3,310 patients, representing 12.4% of CRC diagnosed in Ohio during the study.
Baseline characteristics indicated that the mean age at diagnosis was 60 years (range, 17-89), and the majority of patients were male (52%). Self-reported race was reflective of that of the state of Ohio: 89% White, 8% Black, 2% other, and 1% not known. A total of 15% of patients had an additional malignancy. The most common cancers reported in first-degree relatives were colon (18.2%), breast (16.3%), and lung (14.8%).
Additional results demonstrated that 2 patients (.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (n = 76/86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene pathogenic germline variants (7.3% of total pathogenic germline variants identified).
If universal tumor testing had been the only method used to screen for hereditary cancer syndromes, 38.6% of patients (n = 91/236) would have been missed, including 6.3% (n = 9/144) of those with Lynch syndrome. A total of 5.3% of patients (n = 175/3310) had pathogenic germline variants in genes with therapeutic targets.
Regarding cascade testing, of the 144 Lynch syndrome probands from 142 families, 92 (64.7%) had at least 1 relative participate in cascade testing. In total, 596 relatives underwent genetic counseling and testing, and 223 had Lynch syndrome in: 105 of 242 (43.4%) first-degree relatives, 46 of 120 (38.3%) second-degree relatives, and 72 of 234 (30.7%) third-degree relatives and beyond.
Of the 144 patients with Lynch syndrome, 142 (98.6%) did not know that they had Lynch syndrome before they received a diagnosis of cancer. However, 19 (13.3%) of these patients had a family member with a known diagnosis of Lynch syndrome before they received a diagnosis of cancer.