Cancer genetics: Angelina Jolie’s decision

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Cancer genetics: Angelina Jolie's decision

A life-saving surgery raises profile of cancer genes

Film poster of Lara Croft: Tomb Raider.

Angelina Jolie as Lara Croft: Tomb Raider. The movie was a smash-hit adaptation from a video game.

On May 14, cinema super-star Angelina Jolie announced that she’d had a double mastectomy to prevent the family scourge of breast cancer. With a courageous and medically explicit discussion of her odds and her “medical choice” to remove both breasts, Jolie splashed the issues of cancer prevention and genetic testing for cancer across the front pages.

Jolie explained her decision in the New York Times:

“I am writing about it now because I hope that other women can benefit from my experience. Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”

About 10 percent of breast cancers have a genetic component, and two mutations, called BRCA1 and BRCA2, greatly increase the lifetime risk of breast, uterine and other cancers.

The BRCA genes normally suppress tumors by repairing broken DNA; when the gene is mutated, both suppression and repair may fail. By itself, the BRCA1 mutation raises the lifetime odds of breast cancer to about 65 percent, about five times the U.S. average. The odds are higher if, as in Jolie’s case, many relatives have the cancer.

No longer behind the curtain

Man holds a guitar close to see the strings with a drum set in background.

Jim Janetski holds his bass guitar close to see the strings. Blinded by an accident long ago, he can see faintly. Janetski, who has struggled with colon cancer for much of his life, says, “I love music, it’s helped me through my cancer a lot more than I ever thought.” Colon cancer, and early-onset tumors, are often hereditary.

Just as First Lady Betty Ford’s open discussion of her mastectomy in 1974 brought sunshine to the issue of breast cancer, Jolie’s announcement has fueled discussion of genetic testing and preventative surgery. “Our calls have quadrupled in the last week,” says Suzanne Mahon, a professor of hematology and oncology at the hereditary cancer program at Saint Louis University. “Angelina Jolie … is high profile, and has definitely raised awareness among patients and the community: ‘Is genetic testing something I should consider?’ It begins the conversation about what it means to be a carrier for a gene for cancer predisposition.”

Mahon appeared on radio and television May 14, and had scheduled 67 patients by May 29, about four times the usual rate. Much of the interest has been among women, but the focus goes beyond BRCA. Mahon says many callers knew they had a risk (she had previously tested their relatives), but still had not phoned for an appointment. “Jolie’s announcement gave them the bump to make the call,” Mahon says. “That’s all good.”

In many cases, Mahon says, people who are worried about breast cancer “should actually be worried about another hereditary cancer syndrome. When they give us their history, it may be that colon or another cancer is most relevant.”

Unusual actress, unusual patient

Just as Jolie has played unusual women in her movies, it’s critical to remember that her medical situation is not usual. Carrying the BRCA1 mutation, and having multiple relatives with breast cancer, she said she had 87 percent lifetime odds of breast cancer. Because BRCA1 can affect other organs, she also had a 50 percent chance of ovarian cancer, which she plans to prevent by ovary-removal surgery.

Counselor talks to visitor with genetic testing results in hand.

Photo: NIDCC
A researcher at the National Institute on Deafness and Other Communication Disorders provides a genetic counseling session.

The discussion of genetics and preventive surgery reflects medical progress and changing social norms, says Victoria Raymond, a certified genetic counselor at the University of Michigan Cancer Genetics Clinic. Preventive surgery “is becoming more mainstream because we are more open about discussing the options. Saying ‘breast’ 20 years ago was taboo. It’s more a conversation to have today.”

How would a genetic counselor deal with a patient who, like Jolie, faced scary odds of getting cancer? “When we counsel women,” Raymond says, “we try to get a feel for what they need to do to feel more comfortable, to take control of the risk. Some women cannot fathom doing the surgery. They say, ‘Let’s stick with surveillance.’ Some say, ‘I cannot sleep at night, cancer is all I can think about.'”

“I don’t think a double mastectomy in this case is radical, but it’s not for everyone,” Raymond says.

Jolie had other options, including early detection through intensified screening with MRI and mammograms, or perhaps drugs that could abate the risk of breast cancer (but not as well as mastectomy). Although cost is no object for a rich movie star, we don’t know whether insurance plans would cover prophylactic removal of the breasts, followed by reconstructive surgery.

Who should get tested

As we’ve seen, seeking genetic counseling can be frightful, but it can have benefits even without testing, says Jessica Joines, a certified genetic counselor who specializes in breast and ovarian cancer at the University of Maryland school of medicine. “One of the biggest misconceptions is that meeting a genetic counselor means you are necessarily going to go down the road of testing. We are here to help discuss the pros and cons, and help the patient make the decision on whether genetic testing is right.”

ENLARGE

Graph shows both laboratories offering genetic testing and diseases susceptible to testing increased in last two decades.

As the number of diseases susceptible to genetic testing continues to explode, the count of U.S. and international labs offering in-house testing for inherited disorders began to stabilize in 2003.

The meeting can be valuable in either case, says Joines. “We do a very thorough risk assessment, based on the personal and family history, and the risk factors for the cancer in question. Sometimes women with a family history may overestimate the likelihood that they carry a mutation.”

Even before genetic testing begins, Raymond encourages women to think about how they would use the results. “That’s how we want to use genetics: How is it going to change how we take care of someone?”

Getting testing

With Jolie in the headlines, some people may wonder about saving money by ordering genetic tests over the Internet, but that’s not a smart way to test for a serious disease, Mahon says. “Unfortunately the wrong tests get ordered. It’s an emotionally laden situation, and people really should have counseling with a trained, credentialed genetic counselor.”

In 2006, the Government Accountability Office found that “direct to consumer” genetic tests were misleading.

An informed approach to genetic testing must assess the risks and benefits, and explore insurance issues like preauthorization and coverage, and results are best presented in person, Mahon says. “If the result are positive, we schedule 90 minutes, even multiple appointments” to discuss the results.

Once a mutation is detected, relatives, depending on their relationship to the patient, may need to consider counseling and testing, Mahon says. “And there are questions about insurance discrimination. Do you need to up your life insurance? There is a whole host of issues.”

Federal law prohibits insurance and employment discrimination based on a genetic test.

Definitive? Not always…

Although Jolie’s case was pretty clear-cut, genetic testing does not always give definitive results. Many patterns of hereditary disease, for example, have not been tracked to specific genes. “One of the biggest challenges, when you are working with a family who you feel does have a hereditary component to cancer, is when you do all this testing, and the result comes back negative,” says Joines.

Plenty of gray areas exist, even with the well-known BRCA genes. Not every woman with a harmful BRCA1 or BRCA2 mutation will develop breast and/or ovarian cancer, and not every cancer in these families is linked to these mutations.

ENLARGE

Graph shows BRCA mutations carriers' risks of breast and ovarian cancers are much higher than general population.

The BRCA mutations sharply increase the risk of breast and ovarian cancers, and men are not immune.

Even a failure to find a genetic abnormality can be confusing. “It takes a lot of education, counseling, to convey that the negative result does not mean there is nothing to worry about, that there is not something genetic in the family,” Joines adds. “There are causes we don’t know. Probably one-third of hereditary breast cancers are due to rare or unknown genes.”

Even a field as number-rich as genetics can stumble when it comes time to say, “You have X percent lifetime chance of getting cancer Y.” Variations in individual lifestyle, environment and other genes can all play a role, and so it can be difficult “to give one absolute risk number,” Joines adds. “A lot of times, we give a range for the number; we feel that’s most accurate. Inherent in genetic testing is a certain amount of uncertainty. You have to make a decision on percentage chances, and you need to be comfortable with the decision.”

Genetic testing: treatment aid?

ENLARGE

Proteins colored red intertwine with cellular nuclei colored blue.

Photo: Anna Lasorella and Antonio Iavarone, Columbia University Medical Center
An abnormal protein made by a fused gene causes glioblastoma, a deadly brain cancer.

The BRCA1 mutation that caused Angelina Jolie to choose surgery resides in reproductive cells. Because it is copied into every tissue, people carrying the mutation are prone to cancer in several tissues. But in the vast majority of human tumors, the genetic abnormality is local — due, perhaps, to radiation, chemical assault or spontaneous mutation.

In glioblastoma, the most common and aggressive brain cancer, three percent of cases result from a genetic abnormality called gene fusion, says Antonio Iavarone, a professor of pathology and neurology at Columbia University.

Gene fusion means just what it says: Two genes splice together and start producing a deadly protein.

When Iavarone injected the fusion gene into mice, “100 percent of those mice get very aggressive brain tumors,” he says. “The fusion gene [working through the fusion protein] causes the cancer.”

Last year, Iavarone reported1 that drugs that interfere with the fusion protein dramatically slowed the growth of glioblastomas in mice.

“The possibility to treat patients who were selected for the presence of the fusion gene was there since the first moment,” Iavarone says. “After our work was published, I was hoping that a clinical trial would follow very rapidly. But these drugs would only work for patients who have the fusion gene; it does not makes sense to give the drugs to other patients, so the first step is to screen … for that three percent.”

ENLARGE

Slice of human brain with a tumor in one hemisphere.

Photo: Sbrandner
Brain slice shows pathology of glioblastoma multiforme, one of the most deadly human cancers.

A new view of clinical trials

A simple DNA test could identify the fused genes, he says. “We know how to block the activity of this protein with drugs that are already available [although not approved for marketing] from pharmaceutical companies.” Unfortunately, he says, drug companies want to forego screening and give the candidate drug to everybody in the trial, but that is a recipe for failure. “The vast majority of patient will not benefit.”

And so a clinical trial has not begun, Iavarone says.

ENLARGE

Graph shows cost of DNA sequencing decreased steadily from 2001 to 2013.

The plunging cost of sequencing has enabled the use of genetics in cancer prevention and treatment. In 2008, the price drop began to exceed Moore’s law, which describes the accelerating pace of computer processing. In 12 years, the cost has fallen by a factor of 100,000; one “megabase” is one million units of genetic code.

Because the same gene fusion occurs in other cancers, Iavarone says it no longer makes sense to automatically categorize cancers by their source organ. Ideally, “You don’t treat tumors because of where they originate, but based on their molecular content, the genetic alterations.”

Eventually, Iavarone says, “Breast tumors may be treated exactly like tumors from the brain, as long as they have the same genetic alterations. This is really the genomic revolution in cancer research: using new sequencing technology to understand which patient can benefit from a certain drug.”

Ever since 2003, when the first human genome was decoded, we’ve been waiting for the health benefits touted by supporters of the $3-billion genome project. Finally, Iavarone says, all the knowledge and equipment stimulated by that project are starting to pay practical benefits.

Jolie’s public decision, Iavarone says, “Underscores the possibility of preventing cancer by using genomic knowledge. In brain tumors, and unfortunately for the vast majority of cancers, we don’t have the opportunity, there is no germ-line mutation, we can’t say you are at risk. But we are starting to see treatments, and that is another opportunity raised by genomic knowledge.”

– David J. Tenenbaum

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Terry Devitt, editor; S.V. Medaris, designer/illustrator; David J. Tenenbaum, feature writer; Amy Toburen, content development executive