HEREDITARY Mutations Cause 1 in Every 8 Cancers — Should All Patients Be Tested?

Approximately 1 in every 8 patients with cancer has inherited mutations that may have contributed to the development of their cancer, but almost half of these mutations may have been missed using current clinical guidelines.

Note: Mutation, in its simplest definition, means a genetic change. There are essentially 2 types of mutation: inherited and sporadic. Inherited mutations are transmitted from parents through DNA in sperm and egg cells, while sporadic mutations arise during life spontaneously, with aging, or because of environmental factors. In general, sporadic mutations are more common than inherited mutations. In medical terminology, inherited mutations are called germline mutations.

The findings that inherited mutations may have contributed to 1 in every 8 cancers come from the largest study of its kind to date, covering breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and uterine cancers among approximately 3000 patients with a wide range of cancer stages and types.

Lead author Dr. Niloy Jewell Samadder, director of the high-risk cancer clinic at Mayo Clinic in Arizona, commented, "This study tells us that current clinical guidelines are not very sensitive in identifying who does or does not have an inherited mutation predisposing them to cancer."

Finding an inherited mutation can change the approach to treating that cancer

Knowing that a cancer is inherited can indeed open up new treatment options for these patients. Recently, new-generation drugs such as PARP inhibitors have begun to be used primarily in patients with inherited cancer mutations.

The results were published online on October 30 in JAMA Oncology and presented simultaneously at the Society of Human Genetics.

Dr. Peter Beitsch, a surgical oncologist at Dallas Surgical Group who was not involved in the study, said, "I think the debate is over for cancer patients. We should test all patients with cancer for inherited mutations."

Mayo Clinic is changing everyday practice at all four of its cancer centers and will recommend testing all cancer patients for inherited cancer mutations. The changes will begin at the Arizona campus in the first quarter of 2021.

Every cancer patient coming to Mayo Clinic will be offered a genomic evaluation that includes genetic testing to determine whether they have an underlying inherited mutation predisposing them to cancer and how to incorporate this information into designing the best surgical and treatment options for that patient.

What are inherited cancer genes and mutations?

Some well-known inherited cancer genes include:

• BRCA1 and BRCA2: Hereditary breast and ovarian cancer syndrome
• MLH1, MSH2, MSH6, PMS2, EPCAM: Lynch syndrome (hereditary nonpolyposis colorectal cancer)
• TP53: Li-Fraumeni syndrome
• STK11: Peutz-Jeghers syndrome
• PTEN: PTEN hamartoma tumor syndrome
• CDH1: Hereditary diffuse gastric cancer syndrome
• PALB2: PALB2-associated cancer risk
• CHEK2: CHEK2-associated cancer risk
• ATM: ATM-associated cancer risk
• BRIP1: BRIP1-associated cancer risk  
• RAD51C and RAD51D: RAD51C- and RAD51D-associated cancer risk
• BARD1: BARD1-associated cancer risk
• NBN: NBN-associated cancer risk

Study details

The study included 2984 patients receiving treatment for various solid tumors at Mayo Clinic cancer centers in Arizona, Florida, and Minnesota and at a community cancer center in Wisconsin.

Next-generation sequencing was used to test patients with a multigene panel (84 genes).

• Among participants, 13.3% (n = 397) tested positive for pathogenic (cancer risk-increasing) mutations.
• Approximately 70% of these patients (282 of 397) carried moderate- and high-penetrance genes that increase cancer risk.
• For approximately 28.2% (n = 42) of patients with high-penetrance mutations, genetic testing led to changes in treatment. These included changes in surgery, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they might otherwise have been ineligible.

The researchers also compared these multigene-panel testing approaches with targeted testing recommended by the National Comprehensive Cancer Network (NCCN), the National Society of Genetic Counselors (NSGC), and the American College of Medical Genetics (ACMG).

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 (192 of 2984 patients) and 48.4% of patients testing positive for pathogenic mutations (397 of 2984 patients).

Testing inherited cancer genes is underused in cancer care for patients and their families because of outdated guidelines that often limit testing to a narrow high-risk group. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health.

Journal of Oncology published a similar study in breast cancer patients last year, whose lead author was Dr. Beitsch. He is among the doctors strongly advocating genetic testing for all cancer patients. The paper attracted considerable attention when the authors concluded that all breast cancer patients should have expanded-panel genetic testing(for example, Heredigene).

• Related topic: Are multigene tests for breast cancer risk replacing BRCA tests? 

A long-running debate

The new findings and opinions contribute to a long-standing debate about the role of genetic testing and screening for pathogenic mutations in oncology.

Dr. Beitsch says part of the debate about genetic testing comes down to the question of cost. When genetic testing first became available, it was performed manually at exorbitant prices. Since then, testing has become automated using next-generation sequencing, and costs have fallen significantly.

"The cash price of the Invitae test recommended by Mayo Clinic for a panel of more than 80 genes is 250 dollars. That is the cost of a manicure-pedicure in Dallas. I am not dismissing that this is a lot of money for many people. Yes, it is expensive, but far cheaper than before." Beitsch said.

Another issue is that doctors are not entirely sure how to manage findings of "genetic variants of uncertain clinical significance". In the Mayo Clinic study, approximately half of participants (47.4%; n = 1415) had this kind of genetic change of unknown clinical significance. The authors note that these results are consistent with previous studies.

Beitsch says genetic changes of unknown clinical significance are an educational issue. To date, only approximately 2% of these changes have been linked to cancer. The remaining approximately 98% do not affect treatment in patients already diagnosed with cancer.

"We all have these kinds of genetic changes of unknown clinical significance. They are just small changes in genes. The vast majority have no consequences and do not change gene function. I tell everyone to ignore them [when seen in patients with cancer]. Do not act on them. We need to educate everyone not to become stressed about this." he said.

However, genetic variants of uncertain clinical significance are more important when found in people without cancer but with a strong family history of cancer. Beitsch emphasized that clinicians should be more aware in such cases.

He added that an important advantage of genetic testing is enabling cascade testing of family members. Identifying pathogenic mutations in family members can lead them to screening for early cancers and potentially life-saving preventive measures.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for pathogenic mutations. Testing was free for up to 90 days after the participant tested positive. Family members were also shown an educational video.

However, only 17.6% (n = 70) of patients with pathogenic mutations had family members tested. Among these relatives, 45% (79 of 176) were found to carry pathogenic mutations.

Samadder said, "This really tells us that, for families understanding and undergoing preventive testing, the financial barrier is not the only barrier. There are probably a number of other socioeconomic or emotional barriers we need to address."

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• Related topic: What Is Lynch Syndrome — Hereditary Nonpolyposis Colorectal Cancer? 

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FURTHER READING

What does it mean for cancer to be genetic?

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