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Genetic Testing Challenges in Oncology: Broad Panel Assessment Reveals Unexpected RET Finding

genetic testing

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 gynecologist ordered genetic testing for a 51-year-old female concerned about her inherited risk for cancer because her mother was reportedly diagnosed with ovarian cancer at age 30. The patient received testing on a multi-gene panel that included genes associated with well-understood and rare hereditary cancer syndromes.

After seeing the gynecologist, however, the patient realized she had misunderstood, and her mother, who was still alive, actually had cervical cancer when she was 30, not ovarian cancer. But the test had already been ordered and revealed a pathogenic variant in the RET gene, associated with an inherited syndrome called multiple endocrine neoplasia type 2A. This rare syndrome is known to increase the risk for medullary thyroid cancer and noncancerous tumors in the adrenal and parathyroid glands.

How was this case resolved?

About a quarter of medullary thyroid cancer patients have a germline pathogenic RET variant, but pathogenic variants don't confer the same level of cancer risk. A patient with a high-penetrance RET variant has almost a 100 percent chance of developing medullary thyroid cancer in their lifetime, but there is often less evidence on the cancer risk conferred by low-penetrance variants, which makes patient management more challenging.

Due to the aggressive nature of medullary thyroid cancer, the American Thyroid Association recommends that doctors consider prophylactic thyroidectomy in carriers of germline pathogenic RET variants after age 5 since screening modalities may fail to diagnose the cancer at an early stage. The ATA recommendations don't distinguish between low- and high-penetrance pathogenic variants.

The gynecologist referred this patient to a genetic counselor, who noted that the patient had a low-penetrance pathogenic RET variant and had never had cancer. The patient recounted to the genetic counselor her family's experience with cancer, which included her mother's cervical cancer at an early age, a second-degree maternal relative who had brain and blood cancers, and two paternal relatives with lung cancer. The patient's parents had multiple siblings who all lived to be older than 50 years old and none had been diagnosed with the types of cancers that one would expect with a high-penetrance pathogenic RET variant in the family.

Since to this patient's knowledge she was the first in her family to have genetic cancer risk testing and found to harbor this RET variant, the genetic counselor told her that other relatives could have inherited the same variant and may benefit from genetic testing. The patient said she is debating whether to share this information with her children. The genetic counselor referred the patient to an endocrinologist with whom she can discuss imaging and biochemical screening for medullary thyroid cancer as well as prophylactic thyroidectomy as recommended by guidelines.

Why is this case concerning?

This case is concerning because a healthy woman received extensive genetic testing to assess her risk for cancer based on an inaccurate understanding of her family's cancer history. The genetic counselor worried that as a result of the broad genetic testing she received, this patient is now on a clinical path that may "lead to over-screening, stress, and possibly unnecessary prophylactic surgery."

The patient wanted to know about her inherited cancer risk because she thought her mother had ovarian cancer at age 30. However, if the patient herself is 51, then it is reasonable to estimate her mother to be in her 70s. This should have been a red flag for the gynecologist, said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel, since ovarian cancer patients tend to have poor survival because they are typically diagnosed with advanced stage III or IV disease.

It turned out that the mother actually had cervical cancer, which is associated with far better outcomes than ovarian cancer. "A genetics expert would have known what questions to ask to flush out the diagnosis of ovarian cancer at age 30," Matloff said. "The fact that this diagnosis was decades ago and the mother is still alive is unusual — but did she have surgery? Chemotherapy? What were her symptoms, her treatment, and prognosis? [From these details] we often learn that these cancers are uterine or cervical, and not ovarian."

Moreover, if a patient is requesting genetic testing based on a living relative's cancer history, then that relative should be tested first. If testing revealed clinically meaningful genetic variants in the patient's mother, then the patient could have received more focused testing to see if she had inherited those variants instead of being subjected to a broad gene panel.

Key takeaways_unexpected RET findingWhat could have been done differently?

The first thing that could have been done differently, according to Matloff, is the gynecologist should have questioned the mother's ovarian cancer diagnosis and established the correct family history. Second, the gynecologist should have tested the mother for cancer-risk variants before testing her unaffected daughter. If the gynecologist had referred the patient to a genetics expert before ordering a test, then in Matloff's view, it would have been far more likely that the right family history would have been taken and the appropriate cascade testing could have occurred.

However, cases like this are likely to increase as more healthy individuals seek out genetic testing to learn about their risks for diseases like cancer, and at the same time, commercial labs market broader test panels that gauge genes associated with less common tumors, such as medullary thyroid cancer, pheochromocytoma, and kidney cancer. Some labs, like the one that tested this patient, are also not allowing doctors to order customized gene panels that align with patients' personal and familial cancer histories. 

"It's always been assumed that more genes are better, and what we're finding is that in some cases maybe more genes are not better," said Matloff, who in Forbes last year wrote about the experience of a fellow genetic counselor who, just like the patient in this case, found out she had a pathogenic RET variant that didn't align with her family's experience with cancer. Through an extensive literature search and after talking with experts, the genetic counselor confirmed that this was a low-penetrance variant, and it would be appropriate to undergo screening from medullary thyroid cancer instead of a thyroidectomy. However, she discovered that while her insurer would cover the more invasive prophylactic surgery, the out-of-pocket costs for the RET-specific annual screenings would amount to $1,700 a year.

It's not clear the course of follow-up the endocrinologist recommended for the patient in this case, but increased screening and thyroidectomy are guidelines-backed options. Matloff pointed out, however, that there's often limited evidence on low-penetrance variants like the one this patient has, and it's unclear whether screening and surgery recommendations in guidelines, which are often written based on more substantial data gathered from high-risk families, should apply to an incidental finding like this. "It is one of the great unknowns in population testing, and one that is often overlooked by those pushing the field to adopt whole-exome or whole-genome sequencing in areas of medicine like newborn screening, which can reveal more low-penetrance variants."

Before casting a wide net and testing patients on these large gene panels, physicians should also consider the impact that unexpected or secondary findings may have on the patient, Matloff cautioned. If this patient's children decide to get tested, for example, then they'll also be expected to get screened and consider thyroidectomy. "Think of what it will mean in terms of insurability for the patient and think of the waterfall here in terms of her family members," Matloff said. "Are we doing these people a favor by finding this or are we doing them a disservice?"

At the same time, Matloff recognized that there are risks and benefits to labs marketing large panels and some restricting customization, given providers don't always know which genes to test patients for and often don't refer patients for genetic counseling. In this case, the gynecologist ordered genetic testing for a patient based on her mother's alleged ovarian cancer diagnosis, failing to recognize that diagnosis as highly unlikely. "Now, imagine that ovarian cancer was the right diagnosis, and the same gynecologist asked the lab to analyze only BRCA1 and BRCA2, not realizing that the Lynch syndrome genes would also need to be tested in a patient with a family history of ovarian cancer," Matloff said. "There are definite pros and cons to using large panels versus customization."

This story has been updated with additional comments from Ellen Matloff on how a genetics expert could have determined that this patient's mother did not have ovarian cancer.