Precision Medicine Online and My Gene Counsel have partnered since 2019 on the "Genetic Testing Challenges" series to highlight real-world issues medical professionals are encountering as genetic tests are increasingly used in patient care. Healthcare providers and genetics experts share anonymized case reports with My Gene Counsel, and based on the submitted details, Precision Medicine Online writes features that describe the case history, difficulties encountered by professionals managing the cases, and how they responded to challenges or errors. The features also include a discussion with My Gene Counsel genetic counseling experts on better approaches for addressing similar challenges in the future. In publishing this series, our aim is to educate and foster discussion among professionals interested in improving precision medicine access. If you would like to submit a case report, please email [email protected].
What happened?
A gynecologist saw a young woman concerned about her own cancer risk based on the history of cancers in her family. This patient had never had cancer but had a paternal aunt and a grandmother who had been diagnosed with breast cancer in their 40s. The gynecologist ordered genetic testing to gauge her inherited risks for cancer from a well-known commercial lab.
More than a year after the gynecologist ordered this test, the patient, at age 31, was diagnosed with stage IV breast cancer. At this point, her oncologist referred the patient for genetic counseling. At the genetic counseling session, the patient recounted her family's cancer history and shared that her gynecologist had ordered genetic testing to assess her inherited risk for cancer and told her that testing did not uncover any pathogenic variants associated with heightened cancer risk.
How was this case solved?
The genetic counselor reviewed the patient's medical records and noticed that the gynecologist had ordered next-generation sequencing analysis of multiple cancer risk genes from the lab. Based on the type of testing ordered, it would have been this lab's procedure to report results from a core panel comprising two genes, BRCA1 and BRCA2, for billing purposes and then report findings from an expanded panel of other cancer risk genes on the same day. According to the patient's record, she was negative for pathogenic variants in BRCA1/2. However, the genetic counselor did not find any mention of the test results from the expanded gene panel in the patient's records.
The genetic counselor called the lab for the full set of results. With the patient's written permission, the lab released both test reports to the genetic counselor. The results showed that this patient was indeed negative for pathogenic variants in BRCA1/2, however, among the broader list of cancer risk genes, the patient had a germline pathogenic variant in TP53.
When the genetic counselor shared this with the patient, she said her gynecologist had never told her she had this TP53 pathogenic variant. In fact, neither the patient nor any of her relatives had ever heard of the TP53 gene or that people with pathogenic variants in this gene are diagnosed with Li-Fraumeni syndrome. People with this syndrome have around a 90 percent risk of developing cancer during their lifetimes, and women with the syndrome are highly likely to develop early-onset breast cancer, which is often diagnosed before age 30.
Why is this case concerning?
This case is concerning because the genetic testing lab had sent the report with the pathogenic TP53 variant result to the gynecologist more than a year before this patient was diagnosed with stage IV metastatic breast cancer at age 31. Only around 38 percent of women survive for five years if they're diagnosed with stage IV breast cancer when they are younger than 50 years old.
According to screening guidelines, adults with Li-Fraumeni syndrome should have a complete physical exam every six months and follow an aggressive cancer screening schedule. For example, guidelines for managing the risk of breast cancer associated with Li-Fraumeni syndrome state that at-risk women starting at age 20 should have clinical breast evaluations twice a year, an annual whole-body MRI, and consider bilateral risk-reducing mastectomy. "If the gynecologist had shared the TP53 result with the patient and managed her according to guidelines, she could have received the necessary surveillance, which potentially could have caught her breast cancer at an earlier, more survivable stage," said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel.
Moreover, labs have different processes for ordering genetic tests and reporting the results. In this case, the genetic counselor was familiar with the lab and the type of test ordered for this patient and knew that the lab would disseminate the BRCA1/2 results and the expanded panel on the same day in two separate reports. As such, when looking through the patient's records, the genetic counselor knew to look for two sets of test results and immediately flagged the missing report from the broader test panel.
While some doctors may be comfortable ordering genetic tests and capable of appropriately counseling their patients about the results, the gynecologist in this case appears to have mismanaged the test ordering and post-test counseling process. It is unclear if the gynecologist didn't know to expect a second set of results and missed them or saw them and misunderstood the findings. Regardless, it is highly problematic that, according to this patient, her gynecologist never told her she had a pathogenic TP53 variant or about its associated cancer risks for her and her relatives.
"Some providers are taking on this really important job of doing pre-test and post-test genetic counseling and this shows what can happen if they don't understand the process," Matloff said.
Once diagnosed with stage IV breast cancer, it would have been important for this patient's oncologist to know she had a pathogenic TP53 variant because it could have influenced her treatment plan. Patients who carry germline TP53 pathogenic variants are radiation-sensitive and have a greater risk of developing a new primary cancer in the field of radiation. Understanding a patient's germline TP53 status can be "critically important" to deciding the treatments that can and cannot be prescribed, Matloff said.
Earlier in her career, Matloff recalled a young woman with early-onset breast cancer who had undergone a lumpectomy and had radiation therapy. The patient's oncologist later learned that the patient carried a TP53 mutation. "That patient developed a primary bone cancer in the field of radiation and died of that cancer a few years later," Matloff said.
According to the genetic counselor involved in this case, the patient luckily did not receive radiation therapy.
What could have been done differently?
Given this patient's family cancer history, ideally, the gynecologist would have referred her to a genetic counselor or medical geneticist at the outset, so she could have learned of the TP53 pathogenic variant and started screening in time to diagnose her breast cancer at an earlier stage. However, Matloff acknowledged that it is not realistic to insist that every patient considering genetic testing be recommended for genetic counseling and that it often falls on doctors and other types of providers to educate patients about genetic testing and communicate the results afterward.
It isn't uncommon for Ob/Gyns to do this work. In a 2017 opinion, the American College of Obstetricians and Gynecologists' Committee on Genetics advised Ob/Gyns to discuss with patients what to expect from genetic testing before tests are ordered and to disclose results in a "timely manner." However, it was also the committee's opinion that if an Ob/Gyn doesn't have genetics expertise to do this pre- and post-test counseling themselves, that they refer patients to a genetic counselor, medical geneticist, or another genetic specialist.
"Anyone who is taking on this important task of genetic counseling patients and ordering testing for them should fully understand the tests they're ordering and the testing process and become responsible for making sure all the results are received and transmitted to the patient," Matloff agreed. "If you're going to take on this responsibility, this is what you're responsible for doing."
If the patient had received timely and appropriate genetic counseling about the TP53 pathogenic variant a year earlier and received the necessary screening, would that have helped diagnose her cancer earlier, while it was in a more treatable stage? Would this have made a difference for her health? "We don't know the answer to this, since no one can predict how quickly this patient's cancer was progressing," Matloff said. "But a year could have made a big difference."