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Genetic Testing Challenges in Oncology: Woman Without High Breast Cancer Risk Recommended 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, 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 [email protected].

What happened?

A woman in her mid-40s without a personal history of cancer came to see a breast surgeon due to her family history of breast cancer and a sister who was "BRCA positive." The surgeon ordered a large pan-cancer multigene panel, which revealed she had two variants of uncertain significance (VUS), one in BRCA2 and one in APC. The breast surgeon recommended risk-reducing mastectomy and salpingo-oophorectomy and scheduled her to consult with a plastic surgeon at the same institution.

Before going ahead with the recommended surgeries, the patient wanted a second opinion with a breast surgeon at a different institution. She also told this surgeon that she was "BRCA positive." Similar to the first, this second surgeon said that if she had indeed inherited a pathogenic variant in BRCA1 or BRCA2, genes associated with increased risk for breast, ovarian and other cancers, then according to guidelines, risk-reducing surgeries to remove her breasts or high-risk breast screening, as well as risk-reducing surgery to remove her ovaries and fallopian tubes would be appropriate. Except, unlike the first surgeon, this second surgeon did not want to act without reviewing the patient's genetic test results from the outside lab. The surgeon requested the results and referred the patient to a genetic counselor.

In addition to the patient's genetic test result, the genetic counselor also wanted to review the patient’s sister's test results, who was the closest relative with breast cancer and also "BRCA positive." The genetic counselor reviewed the patient’s personal and family history of cancer, as well as the tests results for her and her sister, summarized below.

Upon reviewing the patient's test report, the genetic counselor observed that the first surgeon, who had ordered testing, had written next to where the BRCA2 VUS was mentioned, "breast, ovarian, and pancreas cancer." Next to where the APC VUS was mentioned, the surgeon had written "colon and pancreas cancer." Based on the surgeon’s counseling and recommendation of surgeries, the patient believed she was at high risk for breast, ovarian, pancreas, and colon cancers.

Based on the family's cancer history and the sister's test result, the genetic counselor explained to the patient that she doesn't have the pathogenic BRCA1 variant that her sister has and was reported in another distant paternal cousin. As for the BRCA2 VUS and APC VUS, the genetic counselor informed the patient that according to expert guidelines, variants with yet unclear links to disease should not be the basis for medical decisions, such as risk-reducing surgeries.

The patient was relieved but wanted to share this information with the first surgeon and the plastic surgeon and gauge their thoughts. However, despite this additional information, the first surgeon doubled down on the original recommendation, and said that the surgeries should still be done based on the BRCA2 VUS result and the family's cancer history. This confused the patient and caused her significant anxiety.

How was this case resolved?

At this point, the patient was so distressed that the genetic counselor had to go over all the information with her late on a Friday night. Based on the patient's recounting of her interaction with the surgeon, it appeared that the surgeon did not take the time to review the additional information, especially the sister's test result. In an effort to reassure the patient, the genetic counselor suggested she undergo a formal breast cancer risk assessment at a high-risk breast clinic, which would factor in genetics, and personal and family history of cancer.

Meanwhile, the patient saw the plastic surgeon at the same institution as the first surgeon and shared her sister's genetic test results and the genetic counselors' notes. The plastic surgeon took the time to review the information and agreed with the genetic counselor, advising against risk-reducing mastectomy and salpingo-oophorectomy.

At the high-risk breast clinic, after a formal assessment, the patient further learned that her lifetime risk of breast cancer was close to the general population risk. Up to 72 percent of women with a pathogenic BRCA1 variant and up to 69 percent of those with a pathogenic BRCA2 variant develop breast cancer in their lifetimes. Comparatively, 13 percent of women in the general population will develop breast cancer during their lives. The experts at the high-risk breast clinic told the patient that because her lifetime breast cancer risk is similar to the average woman's, she would not even qualify for increased breast screening, much less risk-reducing mastectomy.

The patient felt thoroughly reassured and was grateful that she avoided unnecessary surgeries.

Why is this case concerning?

This case is concerning because a breast surgeon recommended unnecessary, invasive surgeries to a patient who is at average population risk for breast cancer, based on a VUS result. Meagan Farmer, a genetic counselor and genetic clinical operations director at My Gene Counsel, pointed out the breast surgeon made the recommendation without having reviewed the patient's sister’s test results, who had breast cancer at 35, a BRCA1 pathogenic variant, and the same BRCA2 VUS as the patient.

This information is critical for putting this patient’s genetic test results in the appropriate context of her family's cancer history. "Finding a BRCA1 pathogenic variant in the sister was really a game changer in this instance," said Farmer. "Because then this patient no longer had an unexplained strong family history of breast cancer that may justify risk-reducing mastectomy. There is a [genetic] explanation, and she did not inherit it."

Farmer further pointed out that there are several distant paternal relatives with breast and ovarian cancer, and one of the relatives on this side of the family also reportedly had a BRCA1 pathogenic variant, though the genetic counselor was unable to review that report. "You wonder if those other cases in the family were also due to the same BRCA1 pathogenic variant found in the sister," she said.

It's particularly concerning that even after the patient brought in her sister's genetic test results and the genetic counselors' notes, the surgeon did not take the opportunity to reassess the original recommendation and continued to tell the patient that she was at high risk for breast cancer and needed surgeries. "One of the hardest things a genetic counselor does is clearly and sensitively address the misinformation and fear that a patient walks in the room with," said Farmer. "Unraveling incorrect information and replacing it with correct information is really hard for the genetic counselor, but especially for the patient."

Ultimately, it took an opinion from another surgeon, a genetic counseling appointment, a plastic surgery appointment, a high-risk breast clinic appointment, and multiple calls with the genetic counselor to address the misinformation provided to this patient. "This was very stressful for the patient and wasteful," Farmer said.

What could have been done differently?

When the patient told the surgeon about her family's history with breast cancer, particularly her sister's experience with breast cancer and that she was "BRCA positive," the surgeon should have asked to review her sister's test result before ordering the multi-gene panel for the patient. Upon receiving the patents' results, the surgeon should have factored in all the genetic and family history information in deciding whether to recommend risk-reducing surgeries.

Fortunately for this patient, this is precisely what the second surgeon, the genetic counselor, the plastic surgeon, and high-risk breast clinic did, Farmer observed. If the surgeon did not have time or did not feel comfortable conducting a formal breast cancer risk evaluation for this patient, then the patient should have been referred to a genetic counselor or another breast specialist with genetics expertise, she added. 

This case also highlights the dangers of commonly used terms like "BRCA positive" or "the breast cancer gene," which have become shorthand for describing pathogenic, cancer-risk variants in BRCA1 and BRCA2 genes. But this terminology can lead to inaccurate or incomplete information ending up in physicians' notes and patients' medical records, and result in unnecessary or harmful medical actions.

The patient in this case described herself and her family members as "BRCA positive," and based on that information alone, it seemed plausible that risk-reducing surgeries may be needed. But an actual review of the patient and her sister's genetic test reports painted an entirely different picture. The patient had a non-actionable VUS in the BRCA2 gene and had not inherited the pathogenic BRCA1 variant that explained her sister's breast cancer.  

"One of the most commonly said sentences in all of genetic counseling is, 'Everyone has the BRCA1 and BRCA2 genes,'" said Farmer, noting that the frequent use of terms like "BRCA positive" and "breast cancer gene" can lead to confirmation bias, where even if a patient has a nonactionable VUS or a variant in an entirely different gene, it ends up being treated as if it's a pathogenic variant of BRCA1/2. "If people are looking for a genetic explanation and something comes up in a gene, the feeling is it must be the answer and has to be acted on," she said. "That's what seems to have happened here."