Precision Oncology News and My Gene Counsel have partnered to produce the “Genetic Testing Challenges in Oncology” series to highlight real-world issues that genetics experts and medical professionals are encountering as genetic tests are increasingly used in cancer care. Experts submit anonymized case reports to My Gene Counsel, and based on the details in these reports, Precision Oncology News writes a feature that describes the case history, the challenges encountered by professionals in dealing with the case, and strategies they used in response to challenges or errors. The features also include a discussion with My Gene Counsel genetic counseling experts on better approaches that could be considered if similar cases are encountered in the future. In publishing this series, our aim is to educate experts in the field and foster discussion. If you would like to submit a case report, please email info@mygenecounsel.com.


What happened?

A 20-year-old man came in to see a surgeon and get genetic testing based on a history of breast cancer and a pathogenic BRCA2 variant in the family. The man’s mother, who accompanied him to see the surgeon, had been diagnosed with breast cancer in her late 20s and had known for some time that she had a BRCA2 mutation. Several of the mother’s relatives also had breast cancer and reportedly carried the same pathogenic BRCA2 variant.

The surgeon ordered a multigene panel for the young man. According to the test results, he had inherited the familial BRCA2 mutation and he also had a RNF43 variant of unknown significance (VUS). Because this man had a BRCA2 mutation and a condition called gynecomastia, where an overabundance of estrogen results in swollen breast tissue, the surgeon recommended breast imaging and bilateral risk-reducing mastectomy.

Pathogenic variants in BRCA1 and BRCA2 genes are known to increase risks for breast, ovarian, pancreatic, prostate, and other cancers. The National Comprehensive Cancer Network recommends that men with pathogenic or likely pathogenic variants in these genes begin breast self-exams annually from age 35. For men with gynecomastia, the NCCN advises annual mammograms starting at age 50 or a decade before the age at which the youngest male relative was diagnosed with breast cancer. Men with BRCA2 mutations are also recommended to start prostate cancer screening at age 40.

Although the patient and his mother were unaware of these guidelines at the time, the surgeon’s recommendation for risk-reducing bilateral mastectomy made them anxious. They sought an appointment with a genetic counselor, who took a detailed family history. The genetic counselor reviewed the NCCN guidelines and pointed out that there is no recommendation for risk-reducing surgery. Additionally, the genetic counselor informed them that male BRCA2 mutation carriers have between a 5 percent and 10 percent lifetime risk of breast cancer. By comparison, women with a BRCA2 mutation have between 45 percent and 55 percent lifetime risk of breast cancer.

The genetic counselor also made sure to discuss the RNF43 VUS with the man and his mother, particularly because the surgeon had not mentioned it. Pathogenic variants in RNF43 are associated with increased risk of certain colorectal cancer conditions. The genetic counselor explained that medical management decisions aren’t made based on VUS, but that as evidence accumulates on this variant over time, the classification can change from “uncertain” to disease causing. Alternatively, the variant could be downgraded to likely benign.

The genetic counselor also advised the mother to consider multi-gene panel testing since she had previously only been tested for mutations in BRCA1/2 and there may be another familial genetic mutation causing the breast cancers seen on her maternal grandfather’s side.

How was this case resolved?

The patient and his family were relieved to learn that he would not have to have risk-reducing mastectomy as it is not recommended in NCCN guidelines, not even for men with gynecomastia who are BRCA2 mutation carriers. The genetic counselor still recommended that the man and his mother get a second opinion from another breast surgeon, who agreed that risk-reducing bilateral mastectomy was not indicated.

The patient’s mother, meanwhile, got additional testing to see if she harbored cancer risk mutations in any other genes that might explain the breast cancer history on her maternal grandfather’s side of the family. The test results are pending.

Why is this case concerning?

Had it not been for this family’s own efforts to seek out genetic counseling, this young man, without any personal or family history of male breast cancer, may have undergone an unnecessary, invasive surgical procedure based on a surgeon’s recommendation that did not align with current practice guidelines. “The family was really surprised because the surgeon had not only recommended that this man have a bilateral mastectomy but had also set him up to have plastic surgery afterwards,” said Meagan Farmer, a genetic counselor and genetic clinical operations director at My Gene Counsel. “The mother got really nervous at that point and sought out genetic counseling.”

What is particularly concerning and frustrating to Farmer about this case is that the surgeon recommended this patient have a mastectomy even though the NCCN provides clear guidance on how to manage men with BRCA1/2 mutations and gynecomastia, and never mentions mastectomy as an option to consider in this setting. “Mammograms aren’t even recommended in BRCA2-positive men unless gynecomastia is present, and even then, not until age 50,” she said. “Based on NCCN guidelines, this man having gynecomastia wouldn’t alone justify mastectomy.”

Moreover, a man with a BRCA1/2 mutation has between a 5 percent and 10 percent risk of breast cancer over his entire lifetime, but this man’s breast cancer risk at age 20 is far lower. “Most surgeons would look at this case and say, ‘You’re a 20-year-old man with gynecomastia. Nothing is recommended for you at this point.'” And, this is what the surgeon providing the second opinion said.

Farmer expressed further concern that the surgeon never fully reviewed this man’s family cancer history and didn’t discuss all the results from multi-gene panel testing, specifically the RNF43 VUS finding.

What could have been done differently?

Ultimately, the family was extremely relieved to learn that surgery wasn’t needed. “What 20-year-old man wants to go through a surgery like that?” noted Farmer. The patient and his mother did wonder why the surgeon would recommend something that wasn’t supported by guidelines. The surgeon’s reasons for recommending surgery in the absence of relevant family history and guidelines are unknown. However, these types of mishaps can be avoided in the future, Farmer said, with better familiarity with NCCN guidelines.

Furthermore, the breast surgeon could have thoroughly reviewed this family’s cancer history and developed a more comprehensive genetic testing plan for the mother. Although the family sought out genetic counseling in this instance, the breast surgeon could have referred the patient to a genetic counselor.

Although male breast cancer is relatively rare, the fact that this man knows he has inherited a BRCA2 mutation is important not only for understanding his own cancer risks, but also for family planning. During the genetic counseling session, the man learned that if he had children with a woman who also had a BRCA2 mutation, and their kids inherited two mutated copies of the gene, then they may have a severe childhood onset condition, called Fanconi anemia. “Especially if the woman also has a family history of breast, ovarian, or other BRCA1/2-related cancers, then they may more strongly consider pursuing genetic testing for her, including for family planning reasons,” Farmer said.

Finally, VUS findings should not be ignored in test reports, Farmer noted, since the classification of such variants may change and become clinically significant in the future. As such, it is important for patients to understand the meaning of VUS results in the context of their disease and family history. “When ordering multi-gene panel testing, patients should be counseled on all variants that are detected, even VUS,” said Farmer.

Written by Turna Ray. Genetic counseling discussion provided by Meagan Farmer, MS, CGC, MBA. Originally published on PrecisionOncologyNews.com.