“I wanted to do something where I could make a difference,” says Nicole Urban, Ph.D.
And making a difference is exactly what Urban has been doing for the past 25 years as a leading researcher at the Fred Hutchinson Cancer Research Center in Seattle. More specifically, she’s been concentrating on preventing women’s cancer deaths, especially from breast and ovarian cancer, by looking for biomarkers — proteins and other substances in blood and tissue that indicate that cancer may be invading the body. This has special urgency for ovarian cancer because there are usually no physical symptoms until the cancer has advanced.
She works in an expansive office with a panoramic view of Lake Union, decorated with a sprawling windowsill plant and photo collages of her children and her horses.
“I didn’t really know anything about cancer, except that I’d had it,” she says.
Urban attended Simmons College, a women’s school in Boston whose goal was to prepare women for professions rather than simply providing a liberal arts education, she says. “So, I enrolled in the College of Education, but I became disillusioned with the practice of teaching and the things I had to do. I was interested in the content (of English literature), but I didn’t want to learn how to make bulletin boards and lesson plans.”
She dropped out halfway through her sophomore year, went to business school and learned computer programming in the early days of the field.
Still working in computers she returned to Simmons, persuading them to let her work toward a B.A. in English Literature, if she promised to go to graduate school. During that time she took a summer school class in economics and statistics at Harvard. “I loved it,” she remembers “I like the concept of making order out of chaos.”
She was able to snag an interview with the head of Harvard’s School of Public Health, and “for no good reason,” he recommended that she enroll in the master’s program in biostatistics and provided her with a scholarship. “I had to catch up on math and calculus,” she says of those years. “I took full advantage of the Harvard education to get trained in both biostatistics and health economics. The people at Harvard were so nice to me.” She went on to earn a doctorate in the same subjects.
But a year into her graduate studies, Urban felt a lump — a cyst on her ovary about the size of a grapefruit. She went to a young doctor, one of the few then trained specifically in gynecological oncology. “I told him I intend to have children,” she said. “I made him promise not to take out my ovaries without consulting me.” Although the first pathologist told her surgeon that the cyst was malignant, he cleared out extensive endometriosis but kept his promise to leave the ovaries alone. It was not an open-and-shut case: Different radiologists thought the cyst might be benign or a “non-malignant pre-cancerous” growth.
“I went to Europe with a friend. It changed my priorities; I thought I might die,” Urban remembers. Instead of radical surgery, she agreed to a laparoscopy every year and was treated with birth control pills to induce a “pseudo-pregnancy” with no periods until she decided to get pregnant and had her two children, now 31 and 34. After that, she “had everything out.”
Married in 1974, Urban followed her husband to Seattle in 1976 and finished her doctoral dissertation here. She accepted a faculty position in the Health Services Department at the University of Washington and researched hospital costs and ways to reform health care. “I was excited and passionate about doing something about the health care system,” she says.
Her excitement turned to disillusionment. “I found that everything had been decided, and the right answers had been found, as far as research went, and it was all down to politics,” she says. Twenty-five years later, she says little has changed. She doesn’t follow the current health care debates.
Facing a divorce and unhappy with the direction of her career, she interviewed with the Hutch in 1984 and was hired to work on early detection of women’s cancer. For the first 10 years she studied mammography, including ways to promote it and analyze how well it works. She also studied how dietary changes affect cancer outcomes, including whether a low-fat diet helps prevent breast cancer, and she helped design and conduct cost analysis on the Women’s Health Initiative. (The 15-year study, run by the National Institutes of Health, was launched in 1991 to test the effects of postmenopausal hormone therapy, dietary modification, and calcium and vitamin D supplements on women’s heart disease, osteoporosis and breast and colorectal cancers.)
Studying dietary changes was not completely satisfying to Urban, she says, since they are difficult to measure and are self-reported. She also studied the link between smoking and cancer, but feels that this — like health care reform — is a political question because the relevant health research has already been done.
“I wanted to work on something where there is a right answer: This will work or will not work,” Urban says. She also wanted to focus on studies that are “translational” — they can translate from the “bench to the bed” with practical applications. She jumped at the chance to look for biomarkers, especially for ovarian cancer. “I felt I owed the world something,” she says. “I had a low-potential malignancy and it was caught early and I had a great doctor.”
An early question was whether it is cost-effective to screen all women for ovarian cancer, since it is relatively rare — seven times less common than breast cancer. She and her colleagues published a study in 1997 saying that it is cost-effective. The most effective blood test so far is one that measures CA (Cancer Antigen) 125, a protein in the blood that is higher if ovarian cancer is present in the body.
Urban is excited about a current study in Britain involving 200,000 women, half of whom are being screened for CA-125. “They are looking at the change in CA-125 levels, especially an exponential change — not just a number — because a woman’s average levels vary. If you just go by the level of CA-125, you may get too many false positives.” Women who do show a marked rise in their levels after two tests will get an ultrasound, which may lead to surgery to remove the ovaries.
Another study, in the United States, has shown that ultrasound alone does not work as well as screening for CA-125 in detecting early ovarian cancer. “It misses a lot and it results in lots of false positives. Sending 30 women to surgery (to remove the ovaries) for every one cancer we find is not acceptable,” Urban says. “In the UK study, they are sending three to five women to surgery for every woman found to have cancer.”
The CA-125 blood test alone still misses a lot of cancers, so Urban and her staff of 25 have begun looking for other biomarkers. The process is a painstaking one, involving the collection of samples from ovarian tumors and healthy ovaries that have been removed at Swedish Hospital, packing them in liquid nitrogen and keeping them in the Hutch’s freezer to be carefully analyzed for differences. It is, in layman’s terms, an exercise in looking for the proverbial needle in a haystack.
“We found quite a few genes that are overexposed in the cancerous ovaries,” she says. “I found HE4,” she says, her eyes shining. She and her colleagues developed a blood test for it. “It has turned out to be a good marker — as good as CA-125 in some areas, not as good in others,” Urban says. She and other scientists wrote about HE4 in the scientific journals five years ago, and screening for it has just been approved by the FDA for monitoring recurrence of ovarian cancer.
What about screening all women for both HE4 and CA-125?
Urban and her staff will begin a Phase 1 study this year of 1,200 local women, to see whether measuring HE4 is a safe and effective screening tool or whether it may lead to too many false positives. One group of 600 women will get a yearly screening for both CA-125 and HE4, and if either one is high, the participants will receive ultrasounds. Women in the second group will get CA-125 screenings only, but if those levels are rising, they will also get a HE4 blood test and an ultrasound.
“It’s unlikely that both HE4 and CA-125 will rise at the same time and the woman will not have cancer,” Urban summarizes.
For every hopeful avenue of further exploration, there are dozens of dead ends. Urban and her fellow researchers have had less success finding biomarkers for breast cancer, which is not always caught on mammograms, especially in younger women with denser breast tissue.
“We’ve looked and looked for a marker for breast cancer — we’ve looked more closely at more than 50 proteins — but we haven’t found one yet,” she says.
Recently, she has turned her attention to nurturing the efforts of a young scientist at the Hutch who is looking into microRNAs (ribonucleic acids, similar to DNA, but usually with a single strand). They are frequently “dysregulated” when there is cancer in the body. He is specializing in prostate cancer, but Urban wonders whether microRNAs could be markers for breast or ovarian cancer as well. Research is in the infant stages.
In fact, much of Urban’s work is collaborative and long-term, including ongoing efforts to measure whether early detection methods actually reduce mortality (requiring 15-year longitudinal studies), development of a vaccine for women who are in remission from ovarian cancer (still a few years away), or an ovarian cancer vaccine for all women (40 to 50 years away). She is also working with other local scientists on making cancer therapy more effective and developing better methods of immunotherapy (strengthening the body’s immune system to fight cancer).
At 63, Urban says she’d like to spend more time in her small house on the tip of Mercer Island and with her three grandchildren, niece and nephew, whose pictures are taped to the glass wall of her office. “I’d like to retire,” she says, “But there’s more I have to do.”
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