Science —

If genetic screening helps those at risk, why not screen everyone?

Testing helps fight ovarian, breast cancers—but not everyone agrees on how to do it.

Trish Carlos and her husband Declan.
Enlarge / Trish Carlos and her husband Declan.
The Carlos family
Trish Carlos walks through the door and recognizes familiar faces, all watchful and wondering. She gives them an inquisitive look. Why are they in a maternity hospital? Must be expecting.

That wasn’t why Carlos was here. A few months earlier, the dark-haired school teacher from the hilly seaside town of Cobh in Ireland was standing on the same corridor holding a baby boy. Today's return visit had nothing to do with that happy event—the excitement she felt then had now been replaced by anxiety. She sits down next to the tall, broad figure of her husband Declan as they wait for their appointment. The genetic service comes down from Dublin to the southern city of Cork once a month and rents a room in the hospital. Trish had been waiting for eight months to start a process that begins with today’s blood test.

The Carlos family walks into the rented room. It's like any other in the hospital, with a simple desk and examination bed. The geneticist explains that Trish is being tested for a mutation in a gene called BRCA1, an entity linked to breast cancer. The geneticist goes through some of the symptoms and says that a mutation can not only give you a higher risk of breast cancer but ovarian cancer as well.

Eventually, Trish and Declan leave the room, walk down the corridor without talking, and go straight to the car. Trish looks at her husband. Before she gets a chance to speak, he goes first.

“You don’t have to say it… I know what you’re going to say. You have all of them.”

Trish knows he is talking about the symptoms, the little markers the geneticist mentioned. These clues include early periods, abnormal growth of cells... Trish also had a benign tumor removed at age 13. She's simultaneously angry and not yet ready to deal with this. Declan offers what he can.

“Look, it mightn’t be. It might be just coincidental.”

To test or not to test

Trish is just one of about 1,500 patients at risk of hereditary cancer that are seen each year in Ireland. Most of these cases are related to breast cancer, says Prof. Andrew Green, director of Ireland’s National Centre for Medical Genetics. “The way people are identified is either because they themselves have had cancer at a young age or they have relatives at young age with breast or ovarian cancer.”

The BRCA genes are among the highest profile pieces of DNA that have been linked with cancer. Specific mutations in the genes BRCA1 and BRCA2 result in an increased risk of breast and ovarian cancer. These mutations are autosomal dominant, which means that you only need one copy of the faulty gene to have a higher cancer risk. These genes encode proteins that help repair damaged DNA. So if they’re not working properly, cells are more likely to develop genetic alterations that can lead to cancer.

Currently, genetic tests are recommended in most countries when there is a family history indicating harmful mutations might be present. Josephine, Trish’s aunt, was diagnosed with ovarian cancer almost a decade ago. This aunt’s sister had died of breast cancer as well, so the doctor who treated the cancer suggested BRCA testing. They discovered a BRCA1 mutation and recommended genetic testing to other members of the family. Eventually, this led Trish and her siblings to the maternity hospital.

Women who carry these faulty genes can take preventative measures—things like regular breast screening, risk-reducing surgery, and the use of cancer-preventing drugs. Perhaps most famously, actor Angelina Jolie, who has a BRCA1 mutation, highlighted risk-reducing surgery when she revealed that she had a preventative double mastectomy and more recently had her ovaries and fallopian tubes removed.

But genetic tests are currently reserved for those whose family history suggests they’re at risk. Is that level of testing sufficient? Trish was tested because her aunt’s breast cancer was caused by BRCA1. If she had no family history, the school teacher’s mutation would not have been picked up unless she was diagnosed with cancer herself.

Prof. Mary-Claire King was instrumental in finding the first breast cancer gene, BRCA1, in 1990. Today, she says “to identify a woman as a carrier only after she develops cancer is a failure of cancer prevention." Last September, King, Prof. Ephrat Levy-Lahad, and Prof. Amnon Lahad used the Journal of the American Medical Association to argue that current practice isn’t good enough. “Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care.”

Prof. Levy-Lahad, director of the Medical Genetics Institute at Shaare Zedek Hospital in Jerusalem, says that this recommendation wasn't something that popped into their minds or seemed especially controversial. “It was based on data.” This data came from research on Ashkenazi Jews. Three BRCA mutations are common in this population, with a frequency of 1 in 40. Among the general population (excluding Ashkenazi Jews), the likelihood of having any BRCA mutation is about 1 in 400. Since we know a family history of cancer plus a BRCA mutation is associated with a high risk of getting cancer, Levy-Lahad wondered if those with no family history had the same high risk.

“We tested 8,000 Ashkenazi men and 10 percent of them had a mother with breast cancer, which is what you would expect with breast cancer rates,” she said. But this random screen also turned up 175 BRCA carriers. These individuals wouldn’t have been found through family histories, but they showed the same frequency of cancer. “Cancer rates for carriers were just as high as they were in other families that are found in cancer genetics clinics."

This means that breast and ovarian cancer risks are high in women who carry mutations in BRCA1 or BRCA2 even if these women do not have a family history of cancer. It led Levy-Lahad to strongly feel that “every woman identified as the first in her family, only after she became infected, is a missed opportunity to prevent."

Today, however, not everyone agrees that BRCA testing should be rolled out to every woman. “Here in the [United States] we generally live in a 'more is better, information is knowledge' culture that is pro-screening and fails to discuss its limits and harms,” says Karuna Jaggar, executive director of Breast Cancer Action. Jaggar deeply respects King and agrees that more women need access to breast cancer testing. She points out that Breast Cancer Action “was the only breast cancer organization that took an active role as a plaintiff on the lawsuit challenging a patent on the BRCA gene.” Winning that case meant that the price of testing dropped dramatically overnight.

Rolling out population screening without sufficient genetic counseling is one of Jaggar’s top concerns. “I see people who feel they were not informed about the harms and limits of the test before they engaged in it. I see people who talk about the way that family relationships are disrupted and they did not anticipate that. I talk to people who will never know if they lost insurance or their insurance premium went up because they had done BRCA testing but they're concerned about it.” Jaggar feels it’s wrong to test people for mutations without full consultations about what the test does and doesn’t mean. “You cannot have informed consent without genetic counseling.”

Beyond counseling and risk, mere logistics may stand in the way of testing for all. The current requirements for genetic counseling along with the small number of qualified professionals means that waiting lists for BRCA tests are getting longer. Waiting times for people with a family history can be more than a year in many countries. Judy Garber, Harvard Medical School professor and director of the Cancer Risk and Prevention Clinic in the Dana-Farber Cancer Institute, points out that if everybody is tested, there currently aren’t enough genetic counselors to prepare patients in detail. “Most people will be negative and they probably don't need as much counseling. But we have a lot of data showing that women who do get genetic counseling and make informed decisions cope very well with the information, even when it's bad.”

Prof. Ian Jacobs is president and vice-chancellor of the University of New South Wales in Australia as well as leading researcher in the area of women’s health and cancer. He hopes that it would be possible to modify the counseling approach so it's much more streamlined and much less time intensive. “One could have a fairly light touch counseling, probably for most of the population, and a more intense counseling for people who have abnormal results.” Jacobs believes this would need to be properly evaluated in a trial before rolling out any testing. “You don't [want to] cause more psychological harm than benefit."

Like genetics itself, the ideal test strategy may be a bit of a puzzle.
Like genetics itself, the ideal test strategy may be a bit of a puzzle.

The effect

Six weeks after the initial appointment, Trish is back in the same room for her results. The geneticist opens the sealed brown envelope. “Unfortunately, you have it.” It being a mutation in the BRCA1 gene that leaves Trish at very high risk of both breast and ovarian cancer. The geneticist is surprised by Trish’s reaction—she isn’t very upset. “We had a feeling that I probably did," explains Trish.

The new diagnosis means that Trish is registered in the monitoring unit where she will have regular mammograms, ultrasounds, MRIs, and blood tests. Any abnormalities will be checked immediately in the hope that cancer will be picked up and dealt with as early as possible. Down the line, preventative surgeries to remove the breasts and ovaries are also an option. “Do you have any questions?” The new mother sat there trying to take the information in. Was she being told that she could lose her ovaries, in of all places, a maternity hospital?

Trish puts a brave face upon learning she has the mutation, but behind closed doors the psychological impact is very real. She is scared senseless when she thinks about early menopause or losing her breasts. Trish feels that her breasts and ovaries are her female identity, and forty seems like a very young age to be expected to give up all of that. This is one part of her body that she never had a problem with, but now she keeps having the same conversations with her husband, whom she has loved since they met at school 21 years ago.

“You’re not going to find me attractive.”

“You won’t want to have sex with me.”

“You're not going to love me.”

The constant ‘what ifs’ and the fear of losing him, it's a feeling Trish likes to ignore as much as she can. Declan keeps saying that she has nothing to worry about, they’ll deal with everything together. But it’s the unknown implications that frighten her, sometimes to tears. If she takes aggressive measures, she will have a lower risk of cancer, but how will it affect everything else?

Channel Ars Technica