HAND-ME-DOWN GENES
Women at risk for ovarian and breast cancers are helping physicians refine the scientific tools used to detect, and possibly prevent, the inherited mutations.
Someday, the grandmother knows, she will hand down the family legacy to her granddaughter. Perhaps it is a delicate set of china, a prized sapphire necklace, or some other priceless reminder of generations past.
Yet, the young granddaughter may already have inherited an unfortunate family gift that grandma would never have wanted to give: the susceptibility to cancer.
They are ovarian and breast cancers. And yes, the genetic basis for two of women’s most feared diseases can be passed from either parent to child. But instead of dreading the seemingly inevitable, women today have the tools to confront their cancer risk head on.
That is the idea behind the Lynne Cohen Preventive Care Clinic for Women’s Cancers at the USC/Norris Comprehensive Cancer Center.
With the help of a five-year, $500,000 grant from the Lynne Cohen Foundation for Ovarian Cancer Research, USC/Norris opened the Lynne Cohen Clinic, which unites research, screening and clinical care for women at increased risk for ovarian and breast cancers.
The thrust: to better detect cancer—finding it early, when treatment is most successful—and possibly prevent its onset.
Housed within the Harold E. and Henrietta C. Lee Breast Center, the Cohen Clinic welcomes patients once a week for morning screenings. James Waisman, M.D., associate professor of medical oncology and breast cancer specialist, has partnered with Lynda Roman, M.D., associate professor of obstetrics and gynecology and chief of gynecologic oncology at USC/Norris, to direct the clinic. Both point out that the clinic’s power lies in the dozen-plus physicians, researchers and other health professionals from a spectrum of disciplines at USC/Norris who are part of the project.
So how do doctors know which women are at increased risk for breast and ovarian cancers? It starts with genes.
Every woman (and man) has genes that deter cancer. Some genes hold a recipe for proteins that keep cells reproducing in an orderly fashion, policing against out-of-control growth. Some give orders to fix damaged DNA. Others cause faulty cells to commit a sort of cellular suicide.
But sometimes genes mutate and do not work as they should—contributing to the cancer process.
Any number of cancer-causing chemicals, environmental stresses and random errors in cell reproduction might induce genetic mutations and set the cancer process in motion. Physicians usually cannot pinpoint the cause of these cancers from patient to patient, but they believe some risk factors make them more likely. For example, a women’s risk for breast cancer will increase with early age at first menstruation, never having children, having late menopause and the like.
Some cancer cases, though—about 5 to 10 percent—can be traced to inherited genetic mutations, vulnerabilities for cancer that pass from generation to generation.
The Lynne Cohen Clinic focuses on women with these genetic risks.
Genetic Mistakes
At first, it was grandma, then an aunt. Then a sister. All diagnosed with cancer. How can a woman help wondering if she will be next?
That is when a genetic counselor steps in.
A genetic counselor is the first person a woman speaks with before visiting the clinic. Monica Alvarado, M.S., C.G.C., says that in her role as genetic counselor, she takes a woman’s family history of cancer and asks about her ethnic background. She then uses the information to calculate cancer risk.
“A lot of women tend to overestimate their risk for cancer,” Alvarado says. “I’ll often look at a woman’s family history, and be able to say, ‘Your family doesn’t look like it has a hereditary cancer risk.’ Then a woman can have a more realistic idea of what she faces.”
But for some women, results point to a need for more extensive genetic testing. Blood tests can show if they carry mutations in BRCA1 and BRCA2 genes. Doctors link these genetic alterations to an increased risk for both breast and ovarian cancers, possibly because intact BRCA1 and BRCA2 genes produce substances that suppress tumors in breast ducts and the ovarian lining.
Women with BRCA1 or BRCA2 mutations have as much as an 85 percent chance of developing breast or ovarian cancers in their lifetimes, Alvarado notes. Yet, tests in women with significant family cancer backgrounds may show no such mutation. “In these cases, they may have a mutation that has not yet been identified,” she says.
Those with an extensive family history of breast and ovarian cancers, as well as those with known genetic mutations, can then make an appointment at the Cohen Clinic. Services also focus on women who have already had either breast or ovarian cancer, those who have a close relative diagnosed with breast or ovarian cancer under age 40, and on women who have had a breast biopsy showing atypical cells or lobular carcinoma in situ.
Clinic patients consult doctors and undergo screenings in one morning, followed by a session on lifestyle changes that may help to reduce cancer risk, such as diet and exercise. Counseling for emotional and social issues is also available. Roman says the emphasis is on individualized care for each patient.
For many women, coming face to face with their personal cancer risk is daunting. Some would rather not know. But knowledge has its advantages.
“There is some security involved in this,” Roman says. “These women are taking charge of their health rather than waiting.”
Adds Alvarado, “One analogy I use when I speak to patients is, ‘If you choose not to learn about your risk of cancer, it’s like playing a game of cards and not knowing the hand you were dealt. Wouldn’t you have a better chance of winning if you know your cards and could plan your strategy accordingly?’”
Promising Tests
Amid frequent bad news about cancer, a bit of good news stood out over the past decade: the breast cancer mortality rate has declined steadily since 1989.
Experts believe better treatments have contributed; but improved screening methods, as well, mean women today detect their cancer at stages earlier than ever before. With early detection comes a greater chance for cure.
At the Cohen Clinic, imaging for breast cancer will include proven early detection methods: mammography and ultrasound.
Still, radiologists look to improve imaging—especially for younger patients, whose dense breast tissue can obscure cancer. So, researchers will investigate magnetic resonance imaging (MRI), near-infrared tomography and positron emission tomography (PET) scans through clinical trials to see if they help, Waisman says.
Physicians also plan to offer ductal lavage, an investigational technique to identify cancerous and pre-cancerous cells by examining cell samples obtained from the milk ducts of the breast.
For ovarian cancer, though, there is not yet a definitive early detection test such as a mammogram for breast cancer or a PSA test for prostate cancer. Ovarian cancer strikes about 26,000 women and kills about 14,000 women in the nation every year. With a lack of symptoms to alert a woman to internal trouble, finding ovarian cancer early is tough, which is why 75 percent of women diagnosed with ovarian cancer have late-stage disease—and only a 12 percent chance of surviving five years.
A recent study from the Food and Drug Administration and the National Cancer Institute hinted at the potential of a new blood test that seeks out patterns of proteins that reflect ovarian cancer's presence, even in the early stages. The test, still under development, combines artificial intelligence and cellular protein technologies. "This is an area that has cried out for more research," Roman says.
A transvaginal (or pelvic) ultrasound scan can find some tumors early, although as a screening tool for ovarian cancer the scan does not yet have a proven track record like mammograms do for breast cancer. And most suspicious areas on ultrasound turn out to be benign masses, not cancer. “With such a high false-positive rate, this can be very stressful for women,” Roman says.
Gynecologists favor ultrasound only for women at high risk for ovarian cancer. If an ultrasound seems suspicious, gynecologists check for levels of a tumor marker, called CA-125, in blood. Elevated CA-125 levels may prompt gynecologists to get a closer look through laparoscopic surgery.
On its own, CA-125 is unreliable for screening because the level may be elevated above normal due to other benign conditions; but doctors may soon have another blood test option. USC cancer specialists will offer Cohen Clinic patients the chance to participate in trials of screenings for lysophosphatidic acid, or LPA. Early research on the LPA tests, which look for levels of an antigen in women’s blood, shows promise. Later, the USC physicians plan to work with Irvine-based LPA developer Atairgin Technologies Inc. to investigate a similar test for breast cancer.
Halting cancer
Early detection lies at the heart of the Lynne Cohen Foundation for Ovarian Cancer Research. For Lynne Cohen’s daughters, it is a personal issue.
Shortly after Lynne Cohen’s five-year battle with ovarian cancer ended in 1998, her three daughters, Whitney, Erin and Amy, created the foundation in her memory. Their mission: to keep other women from enduring the same hardship and pain their mother did.
Through fundraisers and committed donors, the trio has created a fund that sponsors clinics for women at risk for cancer and research into early detection tests, new treatments and preventive techniques.
Before even funding the clinic, the foundation donated $50,000 to support clinical trials at USC/Norris of an anti-cancer drug known as IM862. Much of the first research on that drug was done by Parkash Gill, M.D., USC professor of medicine and pathology.
Medical oncologist Agustin Garcia, M.D., USC assistant professor of medicine, is studying the drug in women with resistant ovarian tumors. In a recent phase I/II trial, patients had already been treated with an average of five chemotherapy drugs before receiving IM862, yet the new drug succeeded in halting the growth of many tumors. The drug appears to stimulate the immune system and inhibit the process known as angiogenesis, the development of blood vessels needed by tumors to grow and spread.
“Based on the results of the study, IM862 will now be combined with standard chemotherapy in clinical trials,” says Garcia, who also is medical director of the Clinical Investigation Support Office at USC/Norris.
Access to research makes the Cohen Clinic an exciting place, says Waisman, ticking off a list of several studies that involve chemopreventive agents that might help prevent cancer.
“We’re already doing work with tamoxifen,” he says. “We’ll be looking at indole-3-carbinol, a substance found in broccoli, and we will be looking at soy in collaboration with Dr. Anna Wu, who has been researching dietary factors in breast cancer.”
Another trial uses a novel preventive agent developed by Darcy Spicer, M.D., associate professor of clinical medicine, and Malcolm C. Pike, Ph.D., professor of preventive medicine.
Other research projects hope to shed light on how women’s cancers start and progress, and patients at the Cohen Clinic may play a role in increasing this understanding.
When tests show women have suspicious breast lesions, women often undergo biopsies to analyze tissue. In a research setting, Waisman says, scientists can examine those tissue samples to look for how hormone levels affect cells and to look for levels of proteins expressed by genes, leading to greater knowledge about breast cells.
Similarly, women deemed at high risk for ovarian cancer sometimes choose to have their ovaries removed as a preventive measure (a procedure called a prophylactic oophorectomy). Louis Dubeau, M.D., Ph.D., USC professor of pathology, will analyze cells from those tissues to learn about the earliest cellular changes that may lead down the path to ovarian cancer.
Until now, breast and ovarian cancer specialists have gone their separate ways. After all, though some patients are at risk for both cancers, the cancers’ mechanisms differ.
“We had been working apart; our offices were apart,” Roman says. “But this clinic enables us to work together. We talk and share ideas. When you put people together, the research flower begins to blossom.”
Waisman agrees, and believes that researcher collaboration and patient participation in research at the Lynne Cohen Clinic and USC/Norris—tapping on advances in molecular genetics and mapping of the human genome—will lead to new discoveries in fighting women’s cancers.
“Women’s cancers have known, testable genetic mutations. It’s an area where we have great epidemiological and clinical strength, and we can put all these strengths under a common umbrella,” says Waisman.
He adds: “We hope that by participating in clinical trials and research, these women will not only help the generations who will come after them, but will directly lead to discoveries that will help in the treatment of their own cancer.”
For more information about the Lynne Cohen Preventive Care Clinic for Women’s Cancers at the USC/Norris Comprehensive Cancer Center, call 1-800-USC-CARE (800-872-2273).
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