Veronica Hackethal, MD
November 11, 2020
About 1 in 8 patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.
These findings come from the largest study of its kind so far, conducted in nearly 3000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.
"This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn't have a genetic mutation that is predisposing them to cancer," commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Arizona, Phoenix, Arizona.
Finding a genetic mutation can alter clinical management of the cancer.
"This really does open up treatment and management options that might not have been accessible to these patients," Samadder emphasized.
The results were published online on October 30 in JAMA Oncology and were presented simultaneously at the Society of Human Genetics. Samadder discusses details of the study in a video posted on YouTube.
A clinician not involved in the study said the new results should lead to changes in practice.
"For cancer patients, I think the debate is over. We should test everybody," Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, told Medscape Medical News.
The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.
"Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family," Samadder said.
The study included 2984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.
Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.
Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.
Researchers also compared their universal testing approach to targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.
They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2984 patients)."Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families' health," coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.
Some clinicians have been pushing for genetic testing of all patients with cancer, including Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.
This new Mayo Clinic study extends the findings in breast cancer to "all cancer patients, not just breast cancer patients," Beitsch told Medscape Medical News.
The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.
Part of the debate about genetic testing has hinged on the question of costs, says Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.
"The Invitae cash price for an 80-plus gene panel is $250. That's [the cost of] a mani-pedi in Dallas. I don't discount that it's a lot of money for a lot of people. Yes, it's expensive, but it's a lot less expensive than it used to be," Beitsch said.
Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors note that these results are consistent with past studies.
Beitsch says VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.
"We all have VUSs. They're just minor variations in a gene. The vast majority of them have no consequence and don't alter the function of the gene," he said. "I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don't get stressed about it."
These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.
However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Beitsch emphasized.
"Patients who have a VUS and don't have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history," Beitsch said.
He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.
In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.
Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.
"This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing," Samadder said. "There are probably a number of other barriers -- socioecomic or emotional -- that we have to deal with."
Genetic testing was provided by the Invitae Corporation. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic's Center for Individualized Medicine. Two coauthors are employees of Invitae. Beitsch reports participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.