By Monica J. Smith

ORLANDO, Fla.—When genetic testing guidelines were established in the 1990s, genetic tests were expensive and came with concerns about genetic discrimination, psychological harm and uncertainty about risk-reducing strategies and cancer risk outside the context of a strong family history.

“The [historical] view is that genetic tests have the potential to cause harm to patients, that we need to protect people from that risk by establishing guidelines that tell us who we can test and who we shouldn’t test,” said David Euhus, MD, a professor of surgery at Johns Hopkins School of Medicine, in Baltimore.

But in the more than 30 years since those guidelines were published, the cost of genetic testing has fallen dramatically. Concerns about genetic discrimination didn’t bear out; psychological harm never really materialized; and knowledge of risk-reducing strategies has greatly expanded.

“I think we can get rid of those concerns and focus on the uncertainty of cancer risk apart from a strong family history, which is what drives the guideline writers at this point,” Dr. Euhus noted, speaking at the 2024 annual meeting of the American College of Breast Surgeons.

There are concerns that expanding genetic counseling to all patients will result in overtreatment, observed Puneet Singh, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, in Houston.
“In the United States, the rates of contralateral risk-reducing mastectomy are high, especially compared to other countries. Based on more recent data, many of the genes in breast cancer panels do not have a substantially increased risk of contralateral breast cancer, though patients may overestimate this risk,” she stated in an email to General Surgery News.

Dr. Euhus, too, acknowledged potential harms that well-intentioned people, both patients and providers, may create through unnecessary tests and procedures. “That’s a real concern. But we have to ask if the benefits of genetic testing outweigh the risks, and can the risks be mitigated?”

Guidelines and the Risks of Exclusion
Although guidelines were established to protect patients, following them may exclude people from reaping the benefits of genetic testing. For breast cancer, those benefits include personalized treatment: choices of breast-conserving surgery, contralateral mastectomy, avoidance of radiation and addition of a poly (ADP-ribose) polymerase (PARP) inhibitor. For advanced and metastatic cancer, genetic testing can identify the patients most likely to benefit from platinum-based chemotherapy or PARP inhibition.

Using a bar graph to illustrate data from six studies that compared genetically tested people who did or did not meet guideline criteria of the National Comprehensive Cancer Network, Dr. Euhus noted that many BRCA1/2 gene carriers will be missed by following guideline criteria. “Look at it another way: Criteria testing enriches for identification of high-penetrance genes and is agnostic for low/moderate penetrance genes. But a lot of people with high penetrance variants don’t meet testing criteria.”

Relatively recent research suggests that the findings of genetic tests influence decision-making regardless of whether patients meet criteria for genetic testing or not. In one study, the identification of germline genetic variants affected management (e.g., MRI screening, chemotherapy decisions, surgical strategies) for 84% of patients who met guideline criteria and 68% who did not.

“So yes, it sounds like we are making decisions based on pathogenic variants; reassuringly, in this study, variants of unknown significance did not affect management,” Dr. Euhus said (JAMA Netw Open 2022;5[9]:e2232787).

So, is there justification for excluding anyone? “This gets back to the uncertainty of cancer risk apart from a strong family history, and the concern that well-intentioned but incompletely educated providers spurred on by fearful patients do things to people that should not be done,” Dr. Euhus said.

The first study to look at population-based screening and the risk for breast and ovarian cancer in BRCA1/2 carriers identified regardless of personal or family history tested 1,895 Ashkenazi Jewish men, finding 175 with pathogenic variants. The researchers then enrolled female family members of those individuals (Proc Natl Acad Sci U S A 2014;111[39]:14205-14210).

“Based on that, they found 211 female carriers. Looking at the cumulative cancer incidence by age 80 for those female carriers, it was 60% in BRCA1 carriers and 40% in BRCA2 carriers-the same numbers we associate with variants identified based on strong family histories,” Dr. Euhus said.

“You might say, well, those were Ashkenazi Jews, a different biological context, but we also have two large population studies where a lot of people were tested, completely agnostic to their family history: the Breast Cancer Association Consortium (N Engl J Med 2021;384:428-439) and the CARRIERS consortium (N Engl J Med 2021;384[5]:440-451).

Both population studies showed that testing outside guidelines “provides very actionable information that can be used to adjust risk assessment. I’m going to cross off uncertainty about cancer risk apart from a strong family history.”

To conclude, Dr. Euhus gave two examples of population-based testing becoming part of health management. 

First, the Healthy Nevada project, which has tested nearly 27,000 people so far, focused on BRCA, Lynch syndrome and familial hypercholesterolemia. “Most of their patients did not meet testing criteria, so that’s a pretty good health initiative. They did find the cancer risk higher in those who met guideline criteria than those who didn’t, but again, you’re going to adjust your estimates of risk.”

Second, the Geisinger MyCode project has tested more than 320,000 people as of last January, by which point the researchers identified 4,652 pathogenic variants. By 2018, they had identified 55 BRCA1/2 carriers (now more than 800), of whom only seven were aware they carried a mutation (Genet Med 2018;20[5]:554-558). “Most of those women had no idea; 11 had already developed a BRCA-associated cancer, 26 initiated risk management strategies and three were diagnosed with early-stage BRCA-associated cancer within the first year. Good health management strategy; why wouldn’t you do that?”

So, should testing be offered to anyone? “My bias is yes,” Dr. Euhus said, “but providers need to commit to accurate individualized cancer risk assessment and communication, and choose not to present information in the most dramatic way possible.”

Dr. Singh noted that there are challenges in population-based genetic screening, such as a shortage of genetic counselors and other providers with expertise in managing genetic mutations, but she believed Dr. Euhus’s argument for ditching genetic testing guidelines in breast cancer patients was accurate.

“[The argument is valid] especially considering the guidelines are constantly changing and the criteria expanding,” Dr. Singh said. “As with any test, ordering genetic testing for patients who have a higher pre-test probability-i.e., meet guideline criteria-will identify more potential patients with a genetic mutation, so the guidelines still play an important role. However, if a patient desires genetic testing in the setting of a breast cancer diagnosis, then I believe counseling with the option of testing should be offered.”

Dr. Euhus reported no relevant financial disclosures. Dr. Singh reported a speakers’ honorarium from Physicians’ Education Resource.