Genetic testing helps patients
assess their cancer risk

The young woman in the chair was composed, yet almost resigned. Now in her early 30s, she had watched both her mother and grandmother die of early onset breast cancer, and she had always believed it was only a matter of time before she too would succumb to the disease.

But this was 1996, and science offered something more definitive than just the documentation of her family's medical history and the likelihood that she could face the same grim future. The woman now had the opportunity to take a DNA test that would look for two red flags -- mutations in BRCA-1 and/or BRCA-2, the so-called breast cancer genes. Mutations in these two genes are believed to account for 10% of all familial breast cancer cases. The National Cancer Institute estimates one in 800 people are carrying the genetic mutation, about half of them men.

A blood test revealed that the young woman had a genetic mutation in BRCA1.

"Actually, she was relieved," recalls Ellen Matloff, director of the Cancer Genetic Counseling Program at the Yale Cancer Center, who had to deliver the news. "She had always believed she would get breast cancer, and this result confirmed that she was right to be concerned. Her doctor had told her she should see a psychiatrist."

Once she knew that she was at great risk for breast cancer ­ 55% to 85% of women who test positive for the genetic mutations develop breast cancer and 15% to 60% develop ovarian cancer ­ the young woman decided to opt for a prophylactic mastectomy. Five years later she had her ovaries removed in a procedure known as an oopherectomy, because both BRCA1 and BRCA2 mutations increase the risk for both breast or ovarian cancer, even if only one cancer has been seen in the family so far.

According to Matloff, the number of people seeking genetic counseling has increased as more people become aware that the screening is available. When she first came to Yale, she counseled about three people each month. Today, she and her team see 14 families weekly, and there is a two month waiting period for an appointment.

"Our referral source has grown tremendously," Matloff said. "We are getting calls not just from primary care doctors, oncologists, and obstetricians and gynecologists, but from surgeons too. The surgeons say the results of the genetic testing will affect their surgical decision-making."

Testing is available at the Yale Cancer Genetic Counseling Program for at least 10 different types of cancer, including breast, ovarian, colon, melanoma, medullary thyroid and many rare forms of the disease.

Genetic counseling is recommended for anyone who believes they are at high risk of cancer that is hereditary. Those at risk include individuals who have already had one form of cancer or who have a family history where multiple relatives on the same side of the family have had the same cancer or related cancers -- such as breast, ovarian, uterine and colon cancer. Also at risk are people who have a personal or family history of cancer at unusually early ages, more than one diagnosis of cancer in the same individual, rare cancers (such as male breast cancer) and a family history of a known altered cancer-predisposing gene.

At the first appointment, the genetic counselor takes a detailed family history, or pedigree, of all family members with or without cancer. Patients are asked to supply medical records because self-reporting is often inaccurate.

At the second appointment, the counselor and patient discuss the likelihood that the cancers in a family are hereditary. Then the risks, benefits and limitations of genetic testing are explained. The patient is told about available DNA screening and risk-reduction options.

The results of the test are disclosed at the third appointment, along with an estimate of risks for other family members. Options and recommendations for future cancer detection and risk reduction are offered based on the results.

"We offer counseling and testing, with informed consent before the testing, and accurate result interpretation and long-term follow-up," Matloff says.

About 50% to 60% of those who seek genetic counseling have already had cancer, she notes, while others are worried because the disease is in their families.

"A test showing a genetic mutation is hardest for people who at the time are unaffected -- especially women and, in particular, young women -- because of the prospects. What I tell them is, 'This is information that can save your life,'" she says.

While some patients opt for prophylactic surgery, others decide to take medications, such as Tamoxifen for breast cancer and birth control pills for ovarian cancer, which are believed to lower their risk of the disease.

All those who are found to carry a problematic gene also are enrolled in an intensive surveillance program, which includes regular mammograms beginning at a much earlier age, ultrasounds, magnetic resonance imaging and breast examinations at least once a year by a breast surgeon.

"We space things around the calendar so there is some type of surveillance every four months," Matloff explains.

Before the DNA testing, it was thought to be radical for women to seek prophylactic surgery based strictly on family history. Matloff finds it ironic that some women are willing to withstand the risks of breast implants for cosmetic reasons, but would never consider a mastectomy, even if it was certain it would greatly reduce their risks of developing breast cancer.

"At least now these people have a choice," Matloff says. "The question is whether they take the preventative measure, or do they leave it to fate."

Nina Horowitz, assistant clinical professor of surgery oncology at the School of Medicine, says the BRCA markers are very good predictors of a woman's risk of developing breast cancer.

"A positive test result means a 60% to 80% chance of getting breast cancer in one's lifetime," she says. "Yet, in the general population, only a fraction of the women who worry about breast cancer do get breast cancer."

Horowitz says the patients who she recommends for DNA testing are those under age 40 who have breast cancer. The test result, she says, is important for other family members in assessing their own risk. She also recommends testing for families where there have been multiple generations of breast cancer or ovarian cancer, and especially families with histories of both breast and ovarian cancer.

A third group for whom she recommends testing are the "cancer phobic," she says. "Their top worry in life
is that they are going to get breast cancer. They over-
estimate their breast cancer risk. Once or twice a year
I have a patient who wants both breasts removed because they are so worried about breast cancer. The genetic testing can be of enormous benefit to them."

If a woman's mother had breast cancer derived from a mutation in the BRCA genes and the woman herself tests negative, her risk of having breast cancer are then no higher than the general population, says Horowitz, noting a woman's risk of having the gene is only 50%.

Another group that Horowitz talks with about breast cancer risk are Ashkenazi Jews, those of Eastern European descent who are far more likely to carry the BRCA1 or BRCA2 mutations than the general population.

A woman deemed to be at high risk for developing breast cancer reduces her risk by 90% to 95% by having her breasts removed, Horowitz says. The risk reduction is even greater for women at risk of developing ovarian cancer who also have their ovaries removed.

Although Horowitz is a general surgeon, breast surgery has become an area of special interest to her because she believes that receiving a diagnosis of breast cancer is one of the most stressful times in a woman's life.

"It requires an incredibly delicate and sensitive relationship with her physician," she says. "Breast cancer is one of the few types of cancer where a patient is required to make some decisions about her own care. There are a wealth of options available, and that reflects the fact that there is no perfect answer yet, and it reflects the fact that breast cancer decisions involve body image and sexual issues. Treating these patients offers me an unusual opportunity to get to know more about them, their lives and their feelings."

For more information about the Cancer Genetic Counseling Program, call (203) 785-5938.

-- By Jacqueline Weaver

T H I SW E E K ' SS T O R I E S

Law School helps launch Legal Affairs magazine

Skull discovery boosts theory that all humans came from a single species

Investor confidence 'unshaken,' according to new indexes . . .

Yale Library honors aviator Lindbergh's 100th birthday

In Focus: Yale Cancer Center

Academy pays tribute to noted Yale composer

Physicist's honor recognizes his research on quantum dots

New Drama Dean hails theater's ability to change lives

Non-native but common reeds in Connecticut are changing the state's . . .


MEDICAL SCHOOL NEWS

• Grants to help bring smoking research to policymakers
  
  
• Obese youths at high risk for diabetes, says study
  
  
• Virus that 'vanishes' raises questions about roots of brain damage
  
  
• Pearson is honored by the American Pediatric Society
  

  
  

Robert C. Johnson, former dean of the Divinity School, dies

Students win travel fellowships for summer research abroad

Graduate student forum to explore 'the art of great teaching'

Health-care experts to discuss challenges and dilemmas of 'patient-driven care'

Hellenic studies program to host conference on modern Greece

Impact of new technologies on architecture to be explored

Conference will focus on the problem of illegal logging in tropical forests

Medical anthropologists to discuss their work

Notice from the New Haven Police Department

Yale Books in Brief

Campus Notes

---

Bulletin Home|Visiting on Campus|Calendar of Events|In the News|Bulletin Board

Yale Scoreboard|Classified Ads|Search Archives|Deadlines

Bulletin Staff|Public Affairs Home|News Releases| E-Mail Us|Yale Home Page

---