The promise and pitfalls of gene testing for cancer risk

Melissa Cook lay alone in the recovery room. It had taken about seven hours to surgically remove the growths that had been pressing on her bladder, and now her mouth felt parched. Still groggy and unable to open her eyes after anaesthesia, she felt a nurse swab her dry mouth with moistened gauze. Then she overheard someone saying: “We have a 39-year-old with a port.” Her stomach dropped.

The port, a small reservoir implanted in a vein in her arm, was one of many catheters and tubes that snaked in and out of her body, and is typically used to deliver chemotherapeutic drugs. The nurse’s comment was how Cook, a single mother, learnt that she had advanced ovarian cancer. “My doctor had told me that if it turned out to be stage three or higher cancer, they’d put a port in,” she recalls. “But nothing had prepared me for that moment.”

It was June 2016, and the beginning of Cook’s journey with the disease. For her daughter Ella Chmielewski, finding out that her mother had stage-three ovarian cancer was “the scariest thing I’ve ever heard”, says Chmielewski, who was 12 at the time. The diagnosis sank in as she left her mother in the hospital to go on a class trip to a local amusement park near Minneapolis, Minnesota, where they live. “I’d never had to worry about something that big,” she says. “I didn’t know what to do with myself. What is there to do?”

Cook’s cancer began early: most ovarian cancers arise after menopause, and half of all women in the United States with the disease are over the age of 63. In part because of her relative youth, Cook’s oncologist recommended she take a test to check for genetic mutations that might have spurred tumour growth. The test revealed she carried a disease-associated variant of the BRCA1 gene that increased her risk of ovarian, breast and other cancers. For women in the general population, the lifetime risk of ovarian cancer is less than 2%. But a BRCA1 mutation raises those odds to between 35% and 45%. And it was a risk factor that she might have passed on to her daughter.

Genetic tests to gauge that probability have become more accessible in many parts of the world over the past decade. Initial concerns from researchers about costs, the relevance of such tests to patient care, and families’ distress over genetic risks have not been borne out, says Allison Kurian, a medical oncologist at Stanford University in California. Instead, she says, clinicians’ increased awareness of the importance of genetics has led to better screening and preventive care, and to the development of drugs that target disease-linked mutations. The costs of genetic testing have also come down. “Over the past two decades, we’ve seen strong evidence of the success of these interventions at reducing cancer risk,” Kurian says. “It’s been a thrilling example of integrating basic science into patient care, and it’s really made a difference.”

Still, only about one-third of people with ovarian cancer undergo genetic testing, according to a study conducted in two US states. That’s despite national guidelines that recommend all people diagnosed with the disease undergo genetic risk assessment. The results can help women to make choices about preventive measures or treatments, including new drugs that target mutation-bearing cells. When an individual is found to carry a known genetic marker of risk, clinicians then recommend genetic tests for relatives who are likely to have inherited the same marker. Those who do, sometimes called previvors, then face a slew of complex health decisions.

Silent killer

Unlike many other kinds of cancer, ovarian tumours cause few symptoms and cannot easily be identified through imaging. The fatigue, bloating and stomach upsets that Cook experienced for nearly two years before her diagnosis were dismissed as signs of approaching menopause or increasing age. Like her, many people are diagnosed when the disease is in its advanced stages. Preventive action is therefore crucial.

People who are known to be at high risk because of their genetics face frequent screening tests. They must think about their use of routine medications that might affect their risk of cancer development, as well as whether to have preventive surgery and hormone therapy — both of which have their own risks and benefits. Navigating these decisions is complex. Genetic risk is not a certainty, and emotions about related past events or fear of future disease can be equally powerful motivators of individual choices. Although there’s no right answer, making informed decisions can help individuals to feel empowered.

“When you’re diagnosed with cancer, you feel like you have no options,” Cook says. “What I’ve learnt is you always have an option. We have an option on how we’re going to die, too, if that’s what it comes to.”

Complicated connections

When Cook discovered that she had the BRCA1 variant, shortly after she completed chemotherapy, her care team recommended her family be tested. Cook’s mother was found not to carry the risk factor, suggesting it had probably been inherited from her father.

Tracing a gene’s trajectory through a family in this way can help to catch certain cancers early and inform people’s medical decisions. But genetic tests are inextricably linked with personal histories, says consultant clinical psychologist Sue Gessler in London. Gessler knows of genetic counsellors with clients who, on discovering their genetic risk of cancer, unearthed past familial trauma and long-hidden love affairs or doubts about paternity and heritage.

Cook’s father had been absent for most of her life. When she sent him the information from her care team on how genetic risks get passed through families, “he just told me I should take better care of myself”, she recalls. Her search for the source of her risk led her to try to trace her extended family online, where she found a first cousin on her father’s side. The woman’s profile picture was framed by a pink breast-cancer ribbon, hinting at some experience with the disease. But she didn’t respond to Cook’s message, and Cook still wonders whether cancer has touched unknown relatives’ lives.

People with risk variants of BRCA1 might need to contend with the possibility of prophylactic surgery to remove organs before tumours can form. Clinicians typically recommend that people with an increased genetic risk of ovarian cancer have their ovaries and fallopian tubes removed in their 40s or 50s, depending on the specific risk variant.

But this increased genetic risk does not mean that the disease is a certainty. Although clinicians make recommendations on the basis of biology and medical history, individuals’ choices depend on their own personal history of disease or risk tolerance. In one 2020 study¹, genetics researcher Michael Murray at Yale University in New Haven, Connecticut, and his colleagues set out to learn what people did when they found they carried a disease-linked BRCA1 or BRCA2 variant. The team examined the electronic health records of more than 50,000 biobank participants and identified 59 women who had been informed that they carried BRCA1 or BRCA2 variants but who had no history of cancer¹. Around half of these people met a genetic counsellor within a year of receiving the news; 45% had a mammogram and 32% had a magnetic resonance imaging scan. Around 3% had a mastectomy, and almost 12% chose to have their ovaries removed.

Anecdotally, Murray thinks that people who have seen family members with advanced ovarian cancer are more likely to accept the idea of surgical prevention than someone who learns out of the blue that they carry a pathogenic BRCA1 variant. But he adds: “Our duty as health-care workers is to let people know their options. There’s no right answer to these choices.”

Difficult decisions

Although some people might welcome the results of a genetic test as a way to inform their decisions, others can find them a source of anxiety. Similarly, people’s perceptions of preventive surgery on the basis of this information vary, too. For example, even among post-menopausal women, the emotional burden of having their ovaries and fallopian tubes removed can be greater among those who never had children than among those who have, Gessler says.

In her practice, Gessler has met people who are comfortable with finding out their genetic risk but cannot bear the thought of preventive surgery, and others who are willing to undergo surgery but are traumatized at the thought of a tainted genetic inheritance. “The meanings of these tests are very different across individuals — it’s not one-size-fits-all,” she says.

One concern for many at risk of cancer is the surgical menopause that follows the procedure, because it can occur a decade before the natural ebb of hormones. To counter the symptoms, people who have their ovaries removed are often given a cocktail of drugs called hormone replacement therapy (HRT). In the early 2000s, initial results from a large US study of HRT known as the Women’s Health Initiative led some women to stop taking the therapy because of safety concerns, including that it led to a small increased risk of breast cancer. However, subsequent data analyses have shown that women using oestrogen-only HRT actually had a reduced risk of breast-cancer incidence and death. Those on combined HRT (oestrogen and progestogen) did have a slight increased risk of breast cancer, but importantly, this did not increase the risk of death².

Kurian points out, however, that those data reflected risks in the general female population using HRT after natural menopause, not in a person who might be taking hormones at a younger age following an early menopause owing to risk-reduction surgery. Although randomized trials of this patient group have not been conducted for HRT, Kurian says that individuals with BRCA1 mutations should talk to their clinicians to weigh up their options, taking into account both their individual genetic risk and the potential risk of taking HRT after prophylactic surgery.

Whereas some mutations might warrant urgent and extreme preventive care, people with other, lower-risk variants might choose to delay preventive surgery. Certain mutations in the gene BRIP1, for instance, confer a moderate risk of developing ovarian cancer — higher than in the general population, but still much less than that carried by a BRCA1 mutation. “People with risk caused by a BRIP1 mutation would likely remove ovaries around the time of natural menopause rather than earlier,” Kurian says. “The actions we take are commensurate with the level of risk posed by a variant.”

In Cook’s case, for instance, having a BRCA1 variant also increases her chances of breast cancer — a probability that leads some women to choose a prophylactic mastectomy. She knows what recurrence looks like: her cancer reappeared after the first surgery and several rounds of chemotherapy. In 2018, she underwent a nine-hour surgery in which she was cut open from her breastbone to pubic bone so that surgeons could scrape out little metastatic tumours flecked throughout her abdomen, along with part of her colon. After the pain of major surgeries and chemotherapy, Cook prefers to live with the risk, at least for now. When she discovered her BRCA1 status, she’d just been through surgery and chemo, she says. “And now to think about having a double mastectomy, I don’t know if I can do that.”

But she continues to have frequent mammograms and screening tests, and since early 2019 she has taken a class of drugs known as PARP inhibitors. These block an enzyme that is important for repairing certain kinds of DNA damage created by cancer-linked BRCA1 mutations, so cells bearing the mutations are killed.

Informed choices

Although decision-making after receiving genetic results is complex, it doesn’t fully explain people’s choices around getting tested in the first place. Precisely why only about 30% of people opt for tests is unclear. In two studies^3,4, Kurian and her colleagues found that this trend persisted for individuals diagnosed with breast or ovarian cancer across California and Georgia between 2012 and 2019. Rates of genetic testing were lower in Black patients than in white patients, and in uninsured patients than in those with health insurance.

“It’s not sufficient to simply put out guidelines saying all individuals with ovarian cancer should get genetic testing — it has to be implemented,” says genetic counsellor Alanna Rahm at the Geisinger Health System in Danville, Pennsylvania. “The reasons not to get tested could stem from issues at many levels — the individual, provider, systemic concerns or simply more things to worry about than whether the cancer is hereditary.”

Moreover, some people who do get tested might find there’s little to be done with the results. For instance, individuals might learn their genes have ‘variants of unknown significance’ — meaning that although certain mutations in the gene are pathogenic, their particular versions of the sequence carry alternative mutations with unknown functions. For such carriers, clinicians offer no advice except to wait and watch, and keep track of what research unveils about their genes.

Younger previvors might also find themselves on the ‘wait and watch’ path because of their age. For one-third of her life, Chmielewski has known she could carry her mother’s BRCA1-conferred risk of ovarian cancer, but the family’s doctors recommended she wait until the age of 18 for a genetic test. Cook’s medical history suggested hormonal birth-control pills might have stopped her first tumours from growing, however, so Chmielewski is already taking the drugs. “We talked about her future and what we should do now to prevent it,” Cook says. “They suggested putting her on the pill right away, since it might help keep it at bay.”

Chmielewski’s experience with her mother’s illness has guided many of her choices. In secondary school, she began taking university courses in genetics, and she plans to have children early in life. But family members don’t have to decide their lives on the basis of whether a cancer ‘runs in the family’. Finding out that you don’t share the risk gene can be liberating, Kurian says. “That was always the promise of genetic testing.” But for some, the certainty of knowing that they do carry a variant is liberating in itself.

Chmielewski got tested shortly after her birthday this year, and learnt she has inherited her mother’s risk of cancer. “If I hadn’t seen what my mom went through, getting tested might have made me anxious,” Chmielewski says. “But watching my mom go through so much, I never have doubted whether or not I’m going to get tested. No matter how scary it might be, I would rather know.”