BRCA1/2 mutations and cancer risk

What the mutations mean

The identification of the BRCA1/2 gene mutations is one breakthrough of precision medicine. The mutations are well-known because they are associated with a high risk of breast cancer. Variations in the BRCA1 and BRCA2 genes are also associated with melanoma as well as ovarian, pancreatic and prostate cancer. It’s been more than 20 years since scientists nailed down the mutations in the BRCA1 and BRCA2 genes linked with breast cancer. Genetic testing can detect BRCA mutations.

The risks

According to the National Institutes of Health …

• A BRCA1 mutation is now believed to confer a 55 to 65 percent lifetime risk of breast cancer.

• A BRCA2 mutation carries a 45 percent lifetime risk.

• While mutations in the tumor-suppressing BRCA genes account for 20 to 25 percent of all hereditary breast cancer, most breast cancer is not hereditary; the BRCA mutations are behind 5 to 10 percent of all cancers.

The ‘Angelina Jolie effect’

After learning she carried a BRCA1 gene mutation, actress Angelina Jolie had a preventive double mastectomy and had her ovaries and fallopian tubes removed. She’s been open about the process, raising awareness of the issue. “She’s done a very good job in my opinion of discussing her situation and making people more aware,” St. Charles Bend oncologist Cora Calomeni said.

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Across the top of the page of breast cancer patient Marta Izo’s genetic test results is a big red stripe.

Positive, high risk for breast cancer.

Izo, 65, carries a variation in the ATM gene that’s associated with a high risk of breast cancer and an elevated risk of pancreatic cancer, according to testing company Myriad. Less than 1 percent of the population carries this variation of the ATM gene, which plays a central role in cell division and flagging damaged DNA.

The ATM gene was suspected as a cancer link because it’s the key player in an autosomal recessive disease, ataxia telangiectasia, or Louis-Bar syndrome, which occurs in extremely rare cases when someone inherits two copies of the mutated gene. Families in which Louis-Bar occurred also seemed to have higher instances of breast cancer.

Now research on people who carry a single copy of the ATM mutation indicates women have a 17 to 52 percent chance of developing breast cancer from age 50 to 80, compared with 10.2 percent of all women in that age range.

The risk of pancreatic cancer, which applies to women and men, isn’t quantified.

When Izo was diagnosed in 2014, her oncologist at Bend Memorial Clinic didn’t think she was a carrier of the BRCA1 or BRCA2 gene mutations, well-known because they mean a high risk of breast cancer, but based on her family history, some other genetic syndrome might play a role in her cancer, Izo said. Myriad was to begin offering a 25-gene panel test that summer, so she took it, even though she’d already undergone a lumpectomy and radiation.

“I think it’s kind of a blessing and a curse,” said Izo, a nurse at St. Charles Bend.

Because of her breast cancer risk, Myriad recommends clinical breast exams every six to 12 months and an annual MRI in addition to mammography.

“They will watch me differently and they will treat me differently, but it will always hang over your head a little bit that you have this gene mutation,” Izo said.

This type of genetic testing is the bread and butter of precision medicine, which aims to develop treatments tailored to individual patients. The National Institutes of Health this year made its first grants under a $200 million initiative, which seeks to build large-scale participation in research. The effort depends on people like Izo, who authorized her test results to be included in a national registry of people who’ve had this newer form of genetic testing, called multiplex gene panels.

With the panel tests, doctors no longer have to guess which gene to test, and they’re learning more about common genetic links across cancer types. Variations in the BRCA1 and BRCA2 genes are also associated with ovarian, pancreatic, melanoma and prostate cancer.

In another example, mutations in one of five genes can cause Lynch syndrome, which is behind 3 to 5 percent of colorectal cancers. People with this syndrome have cancer at a young age and may experience multiple types of cancer over their lifetime.

Critics say precision medicine isn’t living up to the hype that began with the Human Genome Project, which completed the sequencing and mapping of all human genes in 2003. They say breakthroughs, such as the identification of BRCA1/2 mutations, are the exception, and large reductions in cancer deaths stem from broad societal changes like fewer people smoking cigarettes.

“Yet the sort of meta-narrative continues,” said Dr. Michael Joyner, who studies blood pressure at the Mayo Clinic. “We’re going to get a whole bunch of people, genotype them, find out the mysteries of disease, rapidly turn that information into cures. It’ll all be sweetness and light.”

Researchers are trying to quantify the genetic risks of cardiac conditions and other chronic diseases, but Joyner said the effects are too small to explain a complex condition like hypertension. “You just don’t get much predictive power from these things.”

And while the term “precision medicine” connotes something very specific and definitive, genetic testing sometimes leaves individual patients facing a lot of uncertainty. The test can identify risk of a disease, like pancreatic cancer, that’s hard to detect. In the case of early-onset familial Alzheimer’s, a rare form of the disease, there’s no cure.

The test result itself can be ambiguous.

Laboratories classify genetic variations as benign, deleterious or of “unknown significance,” based on the most recent available data, as well as the lab’s interpretation of that data. A “variant of unknown significance,” or VUS, means that one has a mutation, but no one knows whether it has an impact on health.

Even within the categories of harmful and benign, risk levels are not absolute. The risk of breast cancer associated with BRCA1 and BRCA2 has been downgraded several times since they were discovered 20 years ago. A BRCA1 mutation is now believed to confer a 55 to 65 percent lifetime risk of breast cancer, while the BRCA2 mutation carries a 45 percent lifetime risk, according to the National Institutes of Health.

“Variation in the human genome is mostly suggestive, not definitive,” Harvard University bioinformatics professor Arjun Manrai noted in a March viewpoint article in the Journal of American Medical Association.

Pancreatic cancer killed Izo’s mother at age 74.

The test seems to have put into black and white Izo’s own suspicions about her fate, even though it doesn’t explain everything about her health history. Before her breast cancer, Izo had three melanomas, one when she was 40 and two more in her 60s that required significant surgery. Melanoma isn’t associated with the ATM gene, but she said, “I’ve always in the back of my mind felt like heart disease was not going to be what killed me, that it probably was going to be cancer,” she said. “I think I’m right.”

The pancreas lies deep inside the body, which makes the cancer difficult to detect and quite deadly. Izo’s mother lived about three months after her diagnosis.

Myriad recommends people with the elevated risk of pancreatic cancer consider screening with MRI, ultrasound and scoping technology. Izo’s former BMC oncologist connected her with a pancreatic cancer screening research project aimed at high-risk patients being conducted by Oregon Health & Science University. Izo is on the short list for enrollment.

The risk of pancreatic cancer for the general population is 1 percent. Breast cancer, by comparison, has a general population risk of 12 percent, which means 1 in 8 women will get it. So even at an “elevated” level, Izo’s risk for pancreatic cancer could still be lower than her risk of breast cancer, as her husband often reminds her.

Yet the pancreatic cancer risk is the aspect of the genetic test result that nags her. “Normally it wouldn’t bother me so much, except that my mother had it,” Izo said.

Izo’s doctor recommended her adult children also be tested for the ATM mutation, but they aren’t ready to do so yet. Discrimination in employment and health insurance coverage because of genetic test results is illegal, but that does not extend to life insurance, or long-term disability and care insurance.

Izo said she doesn’t regret the test.

“It’s an exciting time to live in because they are discovering so much more about diseases and how they happen,” she said. “I think they’ll target in the future certain cancers differently based on gene information. So I kind of feel like I’m almost a pioneer.”

Life-changing answers

It’s been more than 20 years since scientists nailed down the mutations in the BRCA1 and BRCA2 genes associated with breast cancer.

Now women are routinely screened for personal and family histories that would indicate they should be tested. And, thanks in part to actress Angelina Jolie’s outspokenness on the matter, many women who test positive consider a bilateral mastectomy in order to reduce their risk.

St. Charles Bend oncologist Cora Calomeni is grateful for the so-called “Angelina Jolie effect.” “She’s done a very good job, in my opinion, of discussing her situation and making people more aware.”

Connie Rodda was 28 years old when she had breast cancer. It was the 1970s, and no one knew what to expect about her future, except that she probably shouldn’t have children. “They literally did the mastectomy and patted my hand,” said Rodda, who lives in Sisters.

Rodda did not have cancer again until she was in her late 50s, and that time it was ovarian. Rodda tested positive for the BRCA2 mutation. The information proved to be invaluable for a niece, who was in the midst of making decisions about her own breast cancer treatment, but it came too late for Rodda.

At 71, she’s undergoing a third round of treatment for ovarian cancer. If she’d had the test even a few years earlier, she would have had her ovaries removed. “So I would not be where I am,” she said.

While mutations in the tumor-suppressing BRCA genes account for 20 to 25 percent of all hereditary breast cancer, most breast cancer — indeed, most cancer — is not hereditary. So the BRCA mutations are behind 5 to 10 percent of all breast cancers.

Yet when Katy Yoder, a 54-year-old breast cancer patient from Sisters, first found a lump in her breast, she put off seeing a doctor. “I told myself, ‘My family’s never had breast cancer. I’m probably fine.’”

After she was diagnosed in 2013, she was tested for the BRCA mutations because there’s a history of cancers in her family, including a cousin who’d had ovarian cancer in her 30s.

“The reason I did that was not so much for me, but it was for my daughter. I wanted to make sure she had that knowledge,” Yoder said.

The result was negative, which was a relief to Yoder’s daughter, who is 23. But it didn’t solve much for Yoder as a patient. Genetic testing of her tumor revealed she has an estrogen-fed cancer, which meant she had to make drastic lifestyle changes to lower her risk of recurrence. She lost 35 pounds, and she eats no refined sugar, which stimulates estrogen production.

“I had to take a real hard look at how I can change me so that I don’t have it again,” Yoder said. “Cancer is a very good motivator.”

Could knowing one’s genetic risk of cancer have the same effect? That’s still a matter of debate. Some scientists think learning of a hereditary risk of disease could motivate people to lose weight or stop smoking in order to mitigate that risk.

That’s what bioethicist Katherine Wasson at Loyola University in Chicago expected from a pilot study of people who took direct-to-consumer tests, which now have a more limited scope than the tests that can be ordered by a doctor.

Wasson was surprised to learn, however, that the few people who reported a change in habits at a 12-month follow-up interview did so because their results had been less worrisome than they expected. They said things like, “I got good results and I want it to stay that way,” Wasson said.

Many of Therese Tuohy’s clients in genetic counseling for oncology at Legacy Health in Portland have just witnessed a family member’s illness, and they’re hoping for some answers about their own future.

Even a positive result can be reassuring because usually there are protocols for detection or prevention that come with it, she said.

Most of the results are negative. A negative result means the odds that a diagnosis is inherited will be reduced, Tuohy said. In the context of a strong family history, however, a negative result might mean only that an inherited cause can’t be found with the current available testing. In other words, it’s a false negative.

The minority of results are variant of unknown significance, or VUS, which means a gene mutation was detected, but no one knows yet whether it has an impact on health. The mutation’s status can change, for better or worse, as more data becomes available. So clients are told to keep in touch.

Although Tuohy sees few VUS results, she said, “It’s the one that takes the most time. The most time to explain, the most time to keep track of. The one that causes the most anxiety.”

Tuohy thinks people put their hope in genetic testing because they want to feel in control. “It’s much easier and intellectually appealing to just go in and find a gene, and have a mammogram or colonoscopy every year … than to be told you need to drop 50 pounds or not smoke,” she said.

Promise vs. actuality

In practicing oncology for the past 30 years, Calomeni at St. Charles Bend has seen targeted therapies revolutionize survival rates.

Oncologists test tumors for the presence of oncogenes, which tell the cells to grow out of control. For some types of cancer, there are drugs that can target the proteins coded by those cancer genes, which are not hereditary, and shut them down.

Gleevec, developed by OHSU oncologist Brian Druker, improved the survival rate for patients with chronic myeloid leukemia from 50 to 90 percent. Herceptin is used for breast cancers that test positive for HER2, which makes too many copies of itself and causes the cancer to grow aggressively. The drug attaches itself to the HER2 receptors and blocks them from receiving growth signals.

The $1 billion cancer “moonshot” announced by the White House in early February calls for, among other things, establishing a national database for the genomic analysis of tumor cells.

Calomeni fully supports the idea because she wants more drugs like Gleevec, which goes after a single target, but to work against more complex cancers.

“I think that’s very important. That’s the only way we’ll learn about these pathways and what needs to be targeted.”

Calomeni compares cancer to a spacecraft. “NASA has to incorporate backup systems for backup systems for backup systems so you don’t get stranded in space and die. That’s how cancer cells work,” she said. “Their goal is to survive, so they have all of these backup systems, and we have to learn all of them so we know which ones are the most important to take out.”

Vinay Prasad, a lymphoma specialist at OHSU, criticized the cancer “moonshot” as too focused in genetics when other fields of research, such as basic biology, could also lead to discovering cures. “The vast majority of cancer patients, they don’t have a gene mutation that is targetable,” said Prasad.

Prasad has reviewed drug trials and found that apart from true breakthroughs such as Gleevec, most targeted drugs offer a questionable improvement in life expectancy. Meanwhile, he said, the drugs are certainly toxic to the patient. “We’re embracing costly technology one step ahead of having evidence that it works.”

Rodda has seen the interval between her cancers grow shorter and shorter. She was treated for ovarian cancer for the first time 13 years ago, and a decade passed before the cancer recurred. She underwent chemotherapy again, and about a year passed before the cancer came back.

Rodda is finishing her third course of chemotherapy, and she said it’s unusual for a patient to tolerate this much. Anticipating that the cancer will come back a fourth time, Rodda’s oncologist at BMC has recommended genetic testing on the tissue that was removed two years ago because the results could point doctors to a different course of treatment.

Rodda added, “This can continue as long as my body can tolerate it.” •