Although a fifth of young people diagnosed with colorectal cancer (CRC) have inherited genetic mutations associated with the disease, more than half of those do not have a family history that would trigger genetic testing, say US researchers, who call on insurance companies to provide the tests to all young CRC patients.
The new findings come from a study published online November 13 in Gastroenterology.
In an analysis of data on 430 CRC patients younger than 50 years, the team found that 20% had a range of pathologic genetic variants that have been associated with CRC. Knowing of these variants would be useful for guiding therapy or alerting clinicians to an increased risk for the disease in their relatives.
Only half (51%) of the patients with such variants had a family history of CRC in a first-degree relative, which is a criteria commonly used by insurance companies to decide whether to cover genetic testing.
The findings run counter to perceived wisdom ― it is typically assumed that if cancer is diagnosed in someone without a family history of the disease, “the likelihood of an inherited factor is small,” commented lead author Elena M. Stoffel, MD, assistant professor, Department of Internal Medicine, University of Michigan, Ann Arbor.
“But our study suggests that even in the absence of a family history of cancer, the prevalence of inherited factors is so high in young colorectal cancer patients that it makes sense to test everyone, as these heritable alterations can impact their care, as well as the care of their family members,” she said in a press statement.
Dr Stoffel said that algorithms currently used to decide who undergoes genetic testing are inadequate and that “the people we used to test in the past were probably the tip of the iceberg.”
She added that there are “many other people” who do not meet the current strict criteria for genetic testing but who are at high risk.
The major stumbling block in making genetic testing more widely available is the strict guidelines employed by insurance companies, which sometimes require several relatives across multiple generations to have been affected.
Dr Stoffel said that adhering to these rules in the case of young people with CRC “means that you’re going to miss people.” She points out that “missing inherited alterations in young people arguably has a larger impact because of the opportunity to prevent cancers in their at-risk relatives.”
Speaking to Medscape Medical News, she explained that although the National Comprehensive Cancer Network has recommended genetic testing for patients younger than 50 years, “some of our insurers will only authorize genetic testing for individuals who have tumors that have mismatch repair deficiency phenotypes or for people who have had more than 20 polyps.”
Dr Stoffel added that a “family history can be helpful but is not necessarily conclusive, in that many of these folks who did have pathogenic germline variants did not have a family history that would have led you to suspect that.”
She pointed out that the costs for genetic testing have fallen ― in some cases, tenfold ― with the advent of next-generation technologies.
“Previously, costs of genetic testing for, say, Lynch syndrome were over $4000 for just four Lynch syndrome genes. Now we know that there are commercial laboratories out there that will offer multigene panel tests for under $400,” she said.
Aside from the costs, Dr Stoffel believes that the some of the requirements that insurance companies have put in place for genetic testing have, in effect, disincentivized testing. One such requirement is that testing be ordered by a genetics counsellor or board of professionals.
She said: “Part of that has been the idea that genetic testing requires a little bit more in-depth explanation to patients and wanting to make sure that the testing is ordered properly and explained to patients properly.
“But I think one of the other challenges has been that requiring a separate specialized genetics visit is yet another barrier for families that are dealing with a recent cancer diagnosis, and that requiring that extra specialty consultation is often where people are lost in the process.”
Nevertheless, Dr Stoffel remains hopeful that genetic testing will become more widely available for young patients with CRC.
There are pathogenic germline variants that have implications for clinical care that would not have been picked up by our standard algorithms.
“The fact that we are demonstrating now in several studies that there are pathogenic germline variants that have implications for clinical care that would not have been picked up by our standard algorithms…is a really compelling argument that this should be part of the diagnostic evaluation,” she said.
Noting that more and more therapies are chosen on the basis of the genetics of the tumor, she added: “Evaluating the germline DNA for genetic predisposition syndromes is a logical next step that would not carry such a huge cost compared with what we are already doing to investigate tumors, and the decreasing costs of next-generation sequencing.”
Study Details
One in 10 CRC diagnoses are made in individuals younger than 50 years, and it is estimated that the incidence of CRC in this age group will double by 2030.
For their study, Dr Stoffel and colleagues conducted a retrospective analysis of 430 CRC cases in patients younger than 50.
The patients, whose average age at diagnosis was 40 years, underwent evaluation by a clinical genetics service at a single tertiary cancer center between 1998 and 2015.
The team gathered data on the patients’ histories and tumor phenotypes, as well as the results of germline DNA sequencing. If the results were uninformative, samples were resequenced with the latest multigene panel.
Fifty-nine percent of tumors were located in the distal colon. On somatic testing, ten percent of patients were found to have DNA mismatch repair–deficient phenotypes with high levels of microsatellite instability.
Polyposis phenotypes, defined as >20 polyps, were identified in 24 (5.6%) patients at the time of their cancer diagnosis. A family history of CRC in a first-degree relative was reported in only 111 (26%) patients.
Germline DNA sequencing had been performed in 315 (73%) individuals, including 22 (7%) who had undergone sequencing with multigene panel tests. Pathogenic germline mutations were detected in 79 patients; variants of unknown significance were identified in a further 21 individuals.
The most common mutations were those associated with Lynch syndrome (n = 56); APC mutations, which are linked to familial adenomatous polyposis (n = 10); and MUTYH mutations (n = 8). Other mutations associated with predisposition to cancer included SMAD4 (n = 2), BRCA1 (n = 1), TP53 (n = 1), and CHEK2 (n = 1).
Patients with germline mutations were more likely than those without to have tumors proximal to the splenic flexure (35% vs 23%) and to have a family history of CRC in a first-degree relative (53% vs 16%). They were less like to have advanced disease at diagnosis (22% vs 46%).
In the 117 patients whose clinical evaluations were uninformative, six were found to have actionable germline variants on multigene panel testing. These included one patient each with PMS2, MSH6, MUTYH, TP53, POLE, and APC mutations.
Overall, 85 patients (19.8%) had germline mutations linked to a hereditary cancer syndrome. However, only 43 of those patients (50.6%) reported a family history of CRC in a first-degree relative.
The team writes: “As CRC is one of the most preventable cancers, it is important to identify individuals at high risk for colorectal neoplasia who would benefit from specialized surveillance for CRC (and potentially other extracolonic cancers) beginning long before age 50.
“Given [the] rising incidence of young onset CRC and the availability of effective interventions, individuals with CRC age <50 should be referred for genetic evaluation, with strong consideration for use of multigene panels for germline sequencing,” they add.
The research was supported by the National Cancer Institute of the National Institutes of Health. The authors have disclosed no relevant financial relationships.
Gastroenterology. Published online November 13, 2017. Abstract
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