J    ennifer McManigal felt a dreadful certainty, based on her family history, that the news would be bad. And when she turned out to be right—when she got a call telling her she had tested positive for a breast cancer gene mutation—she knew exactly what she was going to do. She had lost her own mother to breast cancer when she was only 21, so the 30-year-old mother of two young children took the boldest step possible to save herself: She had both breasts removed. “God help me if I pass away when I’m 40,” McManigal says. “My children will only be 13. And I know how hard it was to lose my mother when I was 21.” She had the genetic testing done through the Familial Ovarian/Breast Cancer Center at the University of Miami/Jackson Memorial Medical Center. McManigal and her sister were told by genetic counselor Talia Donenberg that if they tested positive for a mutation, they had an 85 percent chance of developing breast cancer at some point. In addition to their mother, their grandmother and both of the grandmother’s sisters had died of cancer. “Basically I want to live and see my children go to college and get married and have children of their own,” McManigal says. “Had my mom had this option, she might still be alive today.”

Saving lives by counseling families about their cancer risk is central to the mission of the Familial Ovarian/Breast Cancer Center. It began less than two years ago, a cutting-edge place to help women with a strong family history of breast and ovarian cancer figure out their risk of developing the disease—and then decide what to do about it. In its short history, the center has already expanded to encompass other cancers, counseling families with rare syndromes about reducing their risk of colon and endometrial cancer as well.

Information about the risks posed by various genetic mutations is growing by the day, and the School of Medicine is determined to use that information to help as many families as possible. “Doctors are getting more educated about the genetic aspects of cancer risk assessment,” says Ramin Mirhashemi, M.D., assistant professor of gynecologic oncology, who heads the center. Asking about family history becomes critically important because it could save other lives.

“It’s not just testing for a gene,” Mirhashemi says. “It’s a way to counsel people about what they can do to reduce their risk of cancer.” That can involve anything from modifying diet and increasing exercise, to starting screening at a young age, to prophylactic surgery to remove organs at risk.

For affected families, the stakes can be devastatingly high. A woman with a BRCA1 or a BRCA2 gene mutation has an 85 percent risk of developing breast cancer. Both mutations also carry a high risk of ovarian cancer.

Donenberg, the center’s genetic counselor, works with patients to create pedigrees, or family trees showing which members have been affected by cancer—and at what age. Early onset of the disease is a warning flag that a genetic mutation might be involved. People of Eastern European Jewish descent are at particularly high risk of carrying the breast cancer gene mutations.

One of those people is Karen Morton. Until she was diagnosed with breast cancer and came to the University of Miami for a second treatment opinion, Morton had no clue about her astronomical risk. Morton, who was only 33, had found her cancer early and knew of no strong family history. She had been advised to have a lumpectomy with radiation.

Manuel Castillo, M.D., a UM surgical oncologist, reached a starkly different conclusion. “He just asked me a couple of questions and he saw what looked to him like a clear case for genetics,” Morton says. “He didn’t even want to talk to me about surgery options until I had genetic testing.”

The red flag: Morton’s paternal grandmother had ovarian cancer in her early 50s. Though Donenberg never tells patients what course to take, she told Morton that a mastectomy could reduce her risk of developing a second case of breast cancer by as much as 90 percent.

“Now I see the picture clearly,” says Morton, who has three young daughters. “But at the time it was very confusing to have two surgeons giving me extremely different views.”

Morton had the blood test done that day. Then began an unnerving wait for the results, wondering if the cancer was spreading and agonizing over treatment options. “I remember being very emotional and getting very frustrated,” Morton says. But she eventually concluded that she would rather have her breasts removed than face the possibility of another lumpectomy and chemotherapy.

So when she learned she tested positive for a BRCA1 mutation, she proceeded with a bilateral mastectomy. Her breast reconstruction continues, and she will address her ovarian cancer risk by scheduling a hysterectomy with oophrectomy (ovary removal) sometime in the future.

After Morton’s experience, her aunt—the daughter of the grandmother who had ovarian cancer—had genetic testing as well. “My family was just caught by surprise to know that we have this gene,” Morton says. “I came away wishing there was more awareness about it, especially among Jewish people.”

The need to increase awareness drives Mirhashemi’s team. “We have to come up with a way to bridge the gap between what patients know and what we know,” says J. Fernando Arena, M.D., Ph.D., the center’s director of translational research. “We want to educate the community regarding cancer genetics; there is so much new knowledge.”

A critical tool in educating the community is the center’s new Web site, at www.um-jmh.org/fobcc/splash.html. Visitors can find genetics information, staff profiles, and links to cancer sites, and they can create their own pedigrees and make appointments online.

“There’s so much stuff coming out that’s cutting-edge,” Mirhashemi says. “We just have to make sure we’re part of it at the University. Providing the newest technologies and the newest knowledge—that is what really distinguishes us.”

Much of that new knowledge comes, of course, from research, another important focus of the center. A highly anticipated result of the explosion of genetics knowledge will be customized medicine, or pharmacogenomics. The UM center is studying genetic differences in response to first-line chemotherapy for ovarian cancer. Small genetic variants have been related to differences in response to treatment, which will eventually enable physicians to customize amounts and types of chemotherapy, for example.

“This would be a great advantage to the patient,” Arena says. “It would save a great deal of suffering, time, and money.”

Tailoring genetic testing by understanding more about gene mutations specific to certain populations also will save time and money. In the case of Ashkenazi Jewish women, for example, three such “founder mutations” have been identified. Ninety percent of Jewish families with breast and ovarian cancer who carry BRCA1 or BRCA2 mutations have one of those three founder mutations, meaning they can be given a much cheaper, faster, targeted test.

Arena is looking for similar information about women of African descent. Few mutations have been identified in this population, which suffers more aggressive breast cancer. “We need to study this population more thoroughly,” Arena says. “We could offer a better service for this community.”

He is expanding research he conducted in the 1990s with women of African descent that traced a founder mutation to the Ivory Coast. Together with Lisa Baumbach, Ph.D., of the Department of Pediatrics, he will include Caribbean women in this study; an unusual number of Bahamian women get cancer very early. The goal is to develop a screening method that can be tested in families who come to the center and who are recruited in the community.

Athird line of research will study the connection between smoking and cervical cancer. Florida has a particularly high rate of the disease, Arena says, and there seems to be a relationship with smoking. The research will investigate differences in gene expression in normal cervical tissue, in precancerous cells, and in invasive cancer.

Mirhashemi and Arena are building a team-training model they hope will be replicated elsewhere. “We have a vision,” Arena says—a vision that has taken him to Argentina to meet with a group of doctors who came to Miami to see the center in hopes of creating one like it. Other Latin American and European countries could be targets as well.

The range of diseases such centers can help prevent is growing rapidly. The UM center now counsels patients with a syndrome known as hereditary nonpolyposis colorectal cancer, which is triggered by mutations in a few genes that put patients at risk for several types of cancer. Among the recommendations for such patients may be early screening for colon and endometrial cancers.

Mutations in what has been identified as the P53 gene cause a predisposition to tumors. This rare condition, known as Li-Fraumeni syndrome, can result in leukemia, breast cancer, and sarcomas at an early age. Patients with early onset or rare cancers should be referred for genetic counseling. “Then we talk about what it means to have an inherited gene mutation,” Donenberg says, “what other cancers it may predispose you to, who might be at risk in your family.”

For Jennifer McManigal, it all came down to family. She persevered through counseling and testing and traumatic surgery to save herself for her children, and to help them protect themselves when the time comes. Her younger sister will have surgery for the same reason, after giving herself time to bring another baby into the family.

Together they mourn their mother, the grandmother their children will never know. “That’s what breaks my heart the most,” Jennifer McManigal says. “She always used to say, ‘If nothing else, let me see my grandchildren.’

“To see what she went through for us, how she fought for us—she’s the one who gives us the strength to do all this.”

Christine Morris is executive director of media relations for the School of Medicine. Photography by Donna Victor and John Zillioux.
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