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Genetic Testing Challenges in Oncology: Patient With BRCA1 VUS Has Prophylactic Surgery

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, 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 [email protected].

What happened?

A woman in her 40s visited a general surgeon for non-cancer related reasons and was assessed for her hereditary risk for cancer. The patient did not have a personal history of cancer, but her mother, who is in her 60s, had recently been diagnosed with breast cancer and had reportedly had ovarian cancer in her late 40s. According to the patient, her mother had just had the ovarian cancer surgically removed and received no other treatment. The mother was now undergoing treatment for breast cancer but had never received genetic testing.

The surgeon ordered an 84-gene next-generation sequencing panel to assess the patient's inherited risk for various cancers. The test detected four variants of unknown significance (VUS): one in BRCA1 and in three other cancer-linked genes. Pathogenic variants in BRCA1 are associated with increased risk of breast, ovarian, and pancreatic cancer. The names of the other genes are being withheld for patient anonymity, but generally, they are associated with colon cancer, colon polyposis, and neuroendocrine tumors, and the patient did not report any family history of these types of cancers or polyps.

Two weeks after receiving these results, the surgeon ordered a second NGS panel for this patient from a different lab. This time, the 81-gene test detected the same VUS in the four genes but also picked up additional findings in two other genes. This second lab identified a pathogenic variant in a gene for which there is currently limited evidence regarding its association with breast and ovarian cancer, and no National Comprehensive Cancer Network guidelines on how to manage patients with pathogenic variants. The lab also identified a single pathogenic variant in a gene associated with autosomal recessive conditions that do not typically significantly increase cancer risk.

The patient's gynecologist performed surgery to remove her ovaries and fallopian tubes, and documented in the medical records that the decision to perform the surgery was due to her being a BRCA1 carrier, having a family history of ovarian cancer, and having ovarian cysts. The gynecologist consulted with the general surgeon who ordered her genetic test during the surgery because the patient had a history of unrelated gynecological issues and there were difficulties due to adhesions from a prior hysterectomy. This surgeon's notes also documented that the prophylactic bilateral salpingo-oophorectomy was being performed because the patient had a "positive gene finding."

Subsequently, the patient was referred to an oncologist to discuss having a prophylactic bilateral mastectomy, but this doctor was uncomfortable interpreting the genetic test results and referred her to a genetic counselor.

How was this case resolved?

The patient met with a genetic counselor, who looked up the published literature on the BRCA1 VUS and referenced the public variant database ClinVar. She noted that in ClinVar at least 10 labs classified this variant as a VUS and an expert panel classified it as likely benign. The genetic counselor explained to the patient that she had a BRCA1 VUS, and that current guidelines recommend against making management decisions based on variants of unknown significance. The patient was conflicted about the information she received. But she seemed relieved to know that neither her family history, nor her genetic testing results, indicated a significantly increased risk of breast cancer, and that she would not need additional surgery.

The counselor used the session to educate the patient about the pathogenic variant with limited evidence. Ultimately, the patient did not seem to regret having her ovaries removed and said it allowed her to avoid gynecologic cancer, unlike her mother.

However, the patient was worried about her 20-year-old unaffected daughter, who had visited during her oophorectomy. The general surgeon had insisted that her daughter get tested for the six genetic variants (four of which were classified as VUS), and despite her expressed reluctance to be tested, sent her to the lab to have her blood drawn for evaluation. The daughters' test results were not available at the time of the genetic consultation.

Why is this case concerning?

The case is concerning because a physician performed surgery to remove the ovaries of an otherwise healthy woman based largely on a BRCA1 VUS and somewhat unclear family history of ovarian cancer. Based on the documentation of the surgeon involved in this case, it appears there was confusion about the clinical significance of the BRCA1 VUS, or lack of awareness that expert groups recommend against managing patients based on VUS and suggest physicians rely instead on their personal or family history of cancer.

In this case, the mother's history of breast and ovarian cancer is instructive for how her daughter is managed, but there are details that are unusual. For example, the mother reportedly received only surgery and no other treatment, such as chemotherapy, for a diagnosis of ovarian cancer in her 40s.

This wouldn't be the typical course for a young ovarian cancer patient, "and it makes you wonder if this wasn't something benign or another type of gynecological cancer," said Meagan Farmer, a genetic counselor and business manager at My Gene Counsel. "Because we can't say for sure, it's understandable that the surgeon thought genetic testing was appropriate, but the unaffected patient wasn't the best person to test, when you had her mother in her 60s, with breast cancer, who supposedly previously had ovarian cancer." If a pathogenic variant had been found in the mother, then the daughter and other family members could have received more focused testing for that variant. The results could have also influenced the mother's breast cancer treatment.

Moreover, the general surgeon tested the unaffected patient twice on different multi-gene test panels from different labs. It is unclear why this was done, but it was a waste of healthcare dollars. "It could have also gotten confusing," Farmer noted, "if the two labs classified the detected variants differently."

The second test, interestingly, did identify a pathogenic variant in another gene that the first test didn't include. Given the lack of evidence on this gene's links to breast and ovarian cancer, risk-reducing surgery wouldn’t be recommended to patients with a pathogenic variant, but the surgeon didn't apparently spend much time discussing this with the patient.

Finally, based on the patient's account, it is concerning that the surgeon insisted on testing her daughter for the VUS in BRCA1 and other genes. This shouldn't be done unless patients and their relatives are enrolled in studies investigating the classification of variants. Farmer noted that some labs trying to arrive at a more definitive classification for certain VUS do offer to test patients and family members but outside of that, patients shouldn't be tested for VUS because they aren't informative for care.

The genetic counselor also expressed concern about testing the daughter because the protections under the Genetic Information Nondiscrimination Act do not extend to life insurance, and this young woman did not have a life insurance policy yet.

According to Farmer, it may be acceptable to offer the daughter testing for the pathogenic variant in the limited evidence gene, counsel her based on her family and health history, and educate her on the need to check back with a counselor about this variant in case more evidence emerges over time. "It sounds like the daughter was not only told to have testing for the BRCA1 VUS, but she was kind of pressured to have it," Farmer said.

What could have been done differently?

In this case, the patient, and perhaps her mother, would have benefitted from the involvement of a genetic counselor sooner. However, it's not always possible to quickly refer patients to genetic counselors, and Farmer recognized that plenty of oncologists and surgeons take the time to understand test reports and guidelines, know the difference between a pathogenic variant and a VUS, and treat their patients appropriately. Doctors who are not comfortable reading lengthy genetic test reports with references to unfamiliar genes would certainly benefit from taking advantage of decision support tools and educational opportunities, she added.

It may be that the surgeon ordered two NGS panel tests due to confusion about the identified variants, but this really shouldn't be done. Even though the two tests were covered for this patient, many insurers have stringent coverage criteria and redundant testing could result in thousands of dollars in out-of-pocket costs for the patient.

Both of the ordered tests gauged around 80 genes, and these types of large panels often contain genes that aren't well understood in terms of their association to specific cancers. Although physicians are increasingly ordering large NGS panels, they should also be prepared to discuss the findings.

"This pathogenic variant in this limited evidence gene, I wouldn't include that in the panel I was ordering unless I was comfortable coming up with a tailored plan for the patient based on the research we do have," Farmer said. "But, it seems this surgeon didn't feel comfortable because he didn't even address it."

The genetic counselor, however, appropriately focused the counseling session on educating the patient about the pathogenic variant in the limited evidence gene. "It's still important to discuss what current research shows," said Farmer. The patient should know, she said, that "we may learn more over time and there may eventually be guidelines related to the management of a pathogenic variant in this gene. Having an avenue to get that information in the long term is important."