Kate Drabinski was hardly a stranger to breast cancer. Two of her aunts and her mother had all gone through it. Still, “nobody ever suggested genetic testing,” said the 46-year-old gender and women’s studies teacher from Baltimore, Maryland.
Her primary care doctor did suggest regular mammograms, though, so she began getting them at age 37. Five years later, when she was diagnosed with breast cancer, a surgeon finally ordered genetic testing. But instead of waiting for results, he performed her scheduled lumpectomy. Weeks later, she learned her cancer was the result of a genetic mutation.
“I got my test results while walking around a Costco,” she said. “The nurse told me I was negative for BRCA — the only mutation I’d heard of — but was positive for CHEK2. I asked her what I was supposed to do with the information and she said, ‘It might affect your surgery decision. You may want to consider mastectomy.’”
Their names can often sound like gobbledygook — CHEK2, BAP1, TP53, ATM, CDH1, PALB2 — but they’re the makings of what you might call the world’s worst bingo game, at least if you happen to be holding the letters and numbers of a harmful germline (or inherited) genetic variant associated with cancer.
Many people know that certain variants (or mutations) in the DNA-repair genes BRCA1 and BRCA2 can drive breast and ovarian cancers. But these two genes — which we all have — can contribute to other tumor types, as well. Genes have jobs, and some of them have incredibly important jobs, like suppressing tumors. When they become mutated and can’t do that job as well, cancers arise.
“There are a number of mutations we’re aware of — BRCA1 and 2, PALB2, ATM, CHEK2 — all of which can cause a host of cancers,” said Dr. Natasha Hunter, an oncologist and clinical researcher at Fred Hutchinson Cancer Research Center. “They aren’t just associated with breast and ovarian cancer. BRCA2 predisposes people to pancreatic cancer, to melanoma, to prostate cancer, so obviously men are affected. Men can carry a gene variant, the same way women do.”
Germline genetic testing has become cheaper and much more accessible in the years since University of Washington geneticist Dr. Mary-Claire King discovered cancer could be inherited through harmful BRCA1 gene variants. But accessibility doesn’t ensure understanding, especially with people now tapping direct-to-consumer labs for genetic analysis, which can come with automated reports, little interpretation and no counseling.
Misunderstandings still abound — in the general public, in patients, in surgeons and clinicians and even in the labs where this data is analyzed. And not all patients with cancer have their tumor’s genomic data analyzed so they may not be benefitting from more precise, targeted therapies.
Where are we when it comes to genetic testing and cancer?
“We’re still in the beginning stages,” Hunter said. “The technology and the computer power have expanded exponentially, but we have so much more to learn.”
Inherited genetic mutations play a major role in about 5% to 10% of all cancers, according to the National Cancer Institute, and there are more than 100 hereditary cancer syndromes. These include the BRCA-variant-driven hereditary breast and ovarian syndrome, a misnomer some would like to see renamed King syndrome since it drives numerous other cancers; Lynch syndrome which can drive colon, endometrial (or uterine) and other cancers; hereditary diffuse gastric cancer syndrome which covers CDH1-mutation-driven stomach and lobular breast cancers; a cluster of cancers that result from mutations in the tumor suppressor gene TP53 known as Li-Fraumeni syndrome and many more.
Some genes that can carry potentially harmful variants still aren’t well-known to the general public, like Drabinski’s CHEK2 mutation. Genetic counseling helped her fully understand the risk and hash out options for monitoring her health over time, commonly referred to as surveillance.
“The counselor said there are two baskets of things you can do,” she said. “There’s a basket of surgery, where you get a double mastectomy, which decreases the risk greatly but doesn’t end it. Or you can take anti-hormone therapy and have extra screenings. I chose to do that.”
Although diagnosed at stage 1, Drabinski’s cancer was aggressive, so after her lumpectomy, she went through both chemotherapy and radiation. Now, she takes a daily anti-estrogen pill, tamoxifen, and gets regular screenings.
“I feel like I live my life in six-month increments,” she said. “I have an MRI once a year and mammogram every six months. I also have my thyroid scanned and I’ve had a colonoscopy. I’m really compliant and researched all the things CHEK2 might increase my risk for.”
And with good reason. Her identical twin sister was diagnosed with breast cancer shortly after Drabinski finished treatment.
“With CHEK2, if you have cancer in your family, it makes the mutation risk much higher,” she said. “It’s much more subtle than you either have a cancer gene or you don’t.”
— Dr. Natasha Hunter, Fred Hutch / Seattle Cancer Care Alliance physician-scientist
Case in point, in addition to a CHEK2 variant, both sisters also had a variant of uncertain significance, or VUS, in BRCA2, that was subsequently found to be “likely benign.”
Variants are commonly reported back as “pathogenic” (or harmful); “likely pathogenic”; “uncertain significance”; “likely benign” or “benign” as a way to inform people of their risk. There can be numerous variations along the long string of DNA “letters” that make up a gene and scientists have information on many but not all variants. With variants of uncertain significance, there’s not currently enough information to classify them as pathogenic or benign.
But there are instances where VUS results reported to patients and clinicians have been misinterpreted — and even used to justify surgery.
“I’ve had multiple patients freak out about these,” said Hunter. “They’ll say, ‘I have a VUS and maybe that caused my tumor,’ when it’s probably just crummy luck. I’m of the opinion that variants of uncertain significance should not get reported out. They cause an enormous amount of anxiety and something like north of 90% turn out not to be significant.”
Dr. Colin Pritchard, a molecular pathologist at Seattle Cancer Care Alliance and co-director of the Genetics and Solid Tumors Laboratory at the University of Washington Medical Center, agrees. Listen to three Fred Hutch/UW/SCCA physician-scientists discuss genetic testing in this UroToday video.
“A study in 2017 looked at BRCA1 and BRCA2 variants of uncertain significance and how that information was used in clinical practice and the results were horrifying,” he said. “In academic settings, the variants of uncertain significance were more often correctly interpreted but were still misinterpreted as positive findings much of the time. And in the community practice setting, it was worse. Half the time a woman was being advised to have a discussion about risk-reduction surgery.”
The study authors wrote that it was essential for patients — and surgeons — to understand the meaning of the results and that bilateral mastectomies should not be recommended for women with negative or VUS results. “Up to half of surgeons did not recognize this distinction,” they wrote, “reporting no difference in their management of patients with BRCA1 or BRCA2 variants of uncertain significance versus pathogenic mutations.”
Part of the problem, Pritchard said, is that many labs continue to categorize likely benign variants as VUS, which can lead to confusion in both doctors and patients regarding actual risk. He and colleagues, including UW geneticist King, even published a paper on these misclassifications last year, hoping to prompt reform within the agencies that create variant interpretation guidelines.
“Two-thirds of the genes for BRCA1 and BRCA2 are dispensable,” said Pritchard, who along with the Hutch’s Drs. Peter Nelson, Heather Cheng and others published research clarifying the link between BRCA variants and prostate cancer in 2016. “They don’t matter. The variants that matter for BRCA1 and BRCA2 are at the ends. Experts know this, but many commercial labs are still calling missense variants in the dispensable areas of the genes ‘VUS,’ when we know better.”
And this can have serious consequences, he said, potentially resulting in a prophylactic, or preventive, surgery which is “not reversible and unquestionably harmful.”
— Dr. Colin Pritchard, co-director of the Genetics and Solid Tumors Laboratory at UW Medical Center
While the classifications haven’t changed yet, the National Institutes of Health recently launched a $185 million effort to improve understanding of how variations in DNA influence our health with 30 research sites, including one at the University of Washington. Scientists within UW Medicine’s Center for Actionable Variant Analysis, which will conduct some of this research, hope to improve the accuracy of genetic testing by eliminating VUS as a test result.
In other instances, variants are unmistakably harmful and surgical interventions are not only warranted, but potentially lifesaving.
Such was the case with a germline mutation found in the DNA of a 47-year-old former bench researcher from Seattle who advocates under the name “PALB2Previvor” on social media (preferring digital anonymity).
“I had never heard of the PALB2 gene when I got my news, but I knew that a four-nucleotide deletion could have more serious risks and consequences than other types of mutations,” she said. (Nucleotides are the “letters” of the DNA code.) “Not every mutation is going to be like this, but mine was pathogenically deleterious.”
After receiving results of a germline genetic test at the UW in 2018 (prompted by her biological mother’s breast cancer diagnosis at 41), PALB2Previvor opted for a double mastectomy and the removal of her Fallopian tubes and one ovary to significantly reduce her risk of a potential breast or ovarian cancer, both of which are driven by mutations in this gene.
“I wanted a ‘get out of jail free’ card in my back pocket,” she said. “Having a higher probability, there was no way I was not going to do whatever I could to prevent cancer.”
So far, no cancer has cropped up and the advocate, who now counsels others through the nonprofit FORCE (Facing Our Risk of Hereditary Cancer Empowered), has no regrets about her decision.
“I feel incredibly lucky with my timing and the medical system I had access to,” she said. “I’m personally okay with complete preparation for something bad and never having it happen. Especially when it comes to breast cancer and the potential financial and physical devastation of it. Plus, the possibility of metastasis [cancer spread] down the road. That’s what happened with my biological mother, who died of a metastatic recurrence at age 69.”
One thing many patients with hereditary cancers quickly learn is the importance of genetic counseling, especially if a germline test produces an unexpected finding.
“My body isn’t able to suppress tumors,” said Lisa Francis, a 34-year-old former contracts coordinator from Irvine, California, who was diagnosed with metastatic breast cancer at the age of 32, after repeatedly being refused screening, even though she had symptoms. Doctors told her she was “too young to be at risk.”
A cancer diagnosis at a young age, particularly an initial diagnosis of metastatic cancer (also called de novo stage 4) can be a red flag for inherited mutations, so Francis’ oncologist ordered genetic testing.
“That’s how I found out I had the TP53 mutation [also known as Li-Fraumeni syndrome, or LFS],” Francis said “My family got tested and nobody else had it. It was a spontaneous occurrence with me. The genetic oncologist said it’s like being struck by genetic lightning. Couldn’t I have just won the lottery instead?”
Francis currently takes drugs for her estrogen-receptor positive metastatic breast cancer; she also does twice-yearly PET scans.
“It’s a lot,” she said. “And it would be worse if I did everything I’m supposed to be doing for LFS, like yearly colonoscopies. I feel like I’m actually really old for someone with LFS. I see people with children under 10 and they’re on their fifth cancer. The risk is really high.”
Francis said she still feels fortunate because her oncologist was aware of the mutation. Not all clinicians are.
“They knew what to do and I was pushed towards a genetic oncologist,” she said. “But I had some doctors who were not familiar with this mutation. I’m now in an LFS Facebook group with people from all over the country. There are places where the doctors have never heard of LFS. I see that all the time.”
SCCA breast oncologist and Hutch researcher Hunter said genetic counseling can help patients navigate the many nuances and intricacies of probability and risk.
“There’s a lot of complexity that’s emerging,” she said. “Genetic counseling is very important and it’s becoming increasingly important.”
American Cancer Society's Family Cancer Syndromes
American Society of Clinical Oncology's Genetic Testing for Cancer Risk
FORCE (Facing Hereditary Cancer Empowered)
Seattle Cancer Care Alliance's Clinical Genetics and Genetic Counseling Service
Seattle Cancer Care Alliance's Inherited Cancers Information Page
University of Washington's BROCA Cancer Risk Panel
Washington State Department of Health Genetics Clinics in Washington
When it comes to choosing therapies, though, germline testing alone may not be enough.
Genomic sequencing of tumor tissue allows clinicians to see the somatic (or acquired) mutations accumulated since birth, changes wrought through lifestyle or environmental exposures or just plain bad luck. Paired testing — germline and somatic — can often provide a roadmap for the best targeted therapies to use.
“Germline mutations work with somatic variants, so you need to get genetic data from the tumor as well as the person in order to make therapeutic decisions,” Pritchard said.
Hutch translational researcher Dr. Kevin Cheung, who treats patients with breast cancer at SCCA, said he often does tumor testing when the cancer is resistant to therapy or his patients are diagnosed with metastatic disease.
“I’m always thinking about potential mutations you can identify through genetic testing of the tumor that will clue you into actionable mutations and more targeted therapies,” he said. “There are also scenarios where germline testing is important for surgery, such as deciding to pursue lumpectomy vs. mastectomy for risk reduction. These are complicated decisions so having this additional information can be helpful.”
Pritchard said paired testing can also offer “immediate actionability.”
“There’s something you can do with this information — other than better understand why you have your cancer and identify the risk for other family members so they can screen and save their lives,” he said.
Mismatch repair genes — the ones that malfunction in patients with Lynch syndrome cancers like colorectal — have been shown to be responsive to immunotherapy, specifically checkpoint blockade therapy (drugs like pembrolizumab, or Keytruda, for example). And cancer drugs called PARP inhibitors have been shown to be effective in cancers driven by mutations in BRCA1 and BRCA2.
“If a patient has a metastatic disease, there are a number of mutations that are targetable,” Hunter said.
But Cheung cautioned that there are many factors at play in cancer, and paired genetic testing isn’t quite a magic bullet.
“When we talk about mutations, that’s clearly one part of the story,” he said. “But there are many changes beyond DNA mutation and they might not be revealed by either of these tests. The tumor microenvironment is also very important and very relevant. There is a lot to learn still.”
— Dr. Marianne Dubard-Gault, medical director, Seattle Cancer Care Alliance's Clinical Cancer Genetics Service
Currently, germline testing for newly diagnosed cancer patients is not yet standard practice at SCCA, said Dr. Marianne Dubard-Gault, medical director of the organization’s Clinical Cancer Genetics Service.
“At SCCA and many other institutions, it depends on many things, such as the disease group,” she said. “It’s very different for a new breast cancer diagnosis vs. a new kidney cancer diagnosis.”
Family history is key, she said. SCCA also factors in referrals for genetic counseling from oncologists and surgeons, guidelines for genetic testing criteria from the National Comprehensive Cancer Network and insurance coverage.
And even when it is offered, some patients turn it down.
“Genetic testing is not mandatory, and some patients decline testing after a thorough genetic counseling visit for many reasons,” she said, adding that worry about risk and concern over discrimination are the two biggest reasons.
Several germline genetic panels are available through commercial outfits and academic centers including the UW’s BROCA panel, Invitae and Color. Dubard-Gault said the panel SCCA uses depends on different factors, including insurance coverage.
“We use what the patient’s insurance is most likely to cover with an out-of-pocket that patients can afford,” she said.
Insurance, Pritchard said, remains a “huge sticking point” when it comes to genetic testing.
“My personal opinion is that all cancer patients should get genetic testing for inherited cancer risk, period,” he said. “But we’re not there yet; we’re not even close. It’s really unfortunate that insurers haven’t supported genetic testing. It could save so many lives.”
Additionally, not all genetic tests should be considered medical tests, as Fred Hutch/SCCA physician-scientist Cheng noted in her recent Scientific American piece, “The Problem with Direct-to-Consumer Genetic Tests.” Advocate PALB2previvor said she worries people are relying on recreational genetic tests to understand their cancer risk.
“23andMe is not a test,” she said. “They can’t even be called a quiz. They’re inadequate for detecting hereditary cancer risk.”
Cheung believes liquid biopsies will soon provide another way to identify more than just DNA mutations and the potential targets to treat the cancers they’re driving. (A liquid biopsy refers to a blood test that can accurately detect the presence of cancer and the mutations driving it.)
“In theory, if we could surveil the tumor in a multidimensional way using liquid biopsy at every point of their treatment, we could learn a lot about how tumors evolve and, in response, develop better therapies to combat resistance [to treatment],” he said.
Most of all, he said, it’s important to keep it all in perspective.
“Having a mutation is not the end-all,” he said. “There’s more to every cancer patient’s story than just their mutations. And there’s a lot we have yet to learn.”
Diane Mapes is a staff writer at Fred Hutchinson Cancer Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at firstname.lastname@example.org. Just diagnosed and need information and resources?
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