Profiles in Cancer Research
Dr. Carol Fabian
Director, Breast Cancer Prevention Center
University of Kansas Medical Center
At the University of Kansas Medical Center in Kansas City, less than a 15-minute drive from her childhood home, Dr. Carol Fabian leads a team of researchers who are trying to understand how to prevent breast cancer. What is most notable about their work is that they are focusing on markers in tissue and genes as guideposts—a strategy now used to develop many targeted cancer treatments.
At the start of her career in the mid-1970s, Dr. Fabian began working with Dr. Barth Hoogstraten, who was head of oncology at the University of Kansas Medical School and chair of the Southwest Oncology Group (SWOG); there she shared in the excitement over tamoxifen, an investigational drug originally developed as a fertility agent. By the mid-1980s, tamoxifen was proving to be so effective in treating breast cancer, she recalled, that “many of us began to ask whether we could predict who was at highest short-term risk for breast cancer, so we could pick an optimal time to apply prevention therapy.”
Breast cancer treatment in the 1970s entailed surgery and radiation for local disease, but cancer recurred in about 40 percent of women. The discovery that women who responded to antihormonal therapies had tumors that were predominately estrogen receptor-positive ushered in the era of targeted therapy for breast cancer. “Before the discovery of estrogen receptors, we knew that estrogen increased breast cancer growth,” Dr. Fabian said, “but we did not widely appreciate exactly how.”
Birth of a Translational Researcher
With the early success of combination chemotherapy for Hodgkin disease, non-Hodgkin lymphoma, testicular cancer, and breast cancer, Dr. Fabian remembers how she and her colleagues “thought we could cure almost anything by applying the right drugs at the right time.”
She was drawn to Dr. Marc Lippman’s idea that, if women with hormone receptor-positive disease had tumors that depended on estrogen to grow, then providing them with estrogen for a short period of time might induce a growth spurt that would make the cancer cells more susceptible to chemotherapy. She realized that this approach would require knowing how much estrogen would trigger the cells to begin to divide and then how long one would have to wait before administering chemotherapy.
After first testing various doses of estrogen, she got her first R01 grant and performed serial biopsies—with fine needle aspirations of tumors—to determine if and when the cells began to divide more rapidly. “I really got hooked on translational medicine with that grant,” Dr. Fabian said.
By the mid-1980s, Dr. Fabian had been treating women with breast cancer for nearly a decade. “Survival rates were increasing and recurrence was less frequent, but too many women were still dying from breast cancer,” she recalled. She and other researchers were beginning to realize that, no matter how early they detected a woman’s cancer or how aggressive the treatment, some women were going to see their cancer recur. “We really needed to take stock and ask if there might be a better way,” she said.
“The idea of cancer prevention is to prevent the disease altogether or block it before it grows beyond the precancerous stage,” Dr. Fabian continued. By the late 1980s, tamoxifen had become the most widely used drug in breast oncology, and oncologists understood that the drug interfered with estrogen receptor signaling. Most side effects were moderate and women were able to take it over long periods of time. But, when it became apparent that women taking adjuvant therapy were getting fewer cancers in the opposite breast, the idea of primary prevention therapy for high risk women had arrived. Soon after came the landmark P-1 clinical trial, launched in 1992 by the National Surgical Adjuvant Breast and Bowel Project, to test long-term use of tamoxifen as a preventive agent.
Necessity is the Driving Force
“Despite the fact that tamoxifen reduces the risk of breast cancer by 50 percent, less than 5 percent of risk-eligible women agree to take it,” Dr. Fabian said. “While there were some rare but more serious side effects, commonly the patients I was seeing were concerned about the hot flashes and mood changes that threatened their quality of life.” The lesson for prevention researchers, she continued, is that “we need to pay attention to the personal beliefs and perceptions that can affect uptake and adherence, not just whether a drug gives us better results.” Adherence, as well as efficacy, drives prevention.
“I knew that for chemoprevention to have a chance, we would have to be able to predict with greater accuracy which women were likely to get breast cancer over the next 5 to 10 years,” Dr. Fabian recalled. She tackled this problem by following women classified broadly as high risk (for example, young women with a family history of close relatives with breast cancer) and looked for atypical cells and molecular markers in their breast tissue. “If we could predict which women were more likely to get cancer in the next 5 years, they would be most likely to have the best benefit-to-side-effect ratio with preventive therapy,” she said.
The practical problem, however, was getting women to submit to an invasive breast biopsy without any assurance that it would find an early cancer or reveal their future risk. The solution was to minimize their discomfort and, with funding from local philanthropic organizations and institutional support, Dr. Fabian developed and refined a technique called random periareolar fine needle aspiration (RPFNA). (Watch the “In Their Own Words” video slide show above.)
“The women we enrolled were fully aware that I didn’t have any idea what any of this meant and that we were going to follow them for 5 to 10 years to see who developed cancer,” said Dr. Fabian. “Most breast tissue was known to be stroma or fat, and when we first started the prospective cohort project in 1989, pathologists strongly believed you should put a needle into a breast only when you can aim at a specific lesion. So, at the time, they saw this as a really ridiculous exercise.”
However, after following the first 480 women for an average of 4 years, it was clear that women who exhibited cells with atypical characteristics were at very high short-term risk of developing either ductal carcinoma in situ or invasive breast cancer. What began in her clinic in Kansas City has become widely used to test new interventions in phase I and II prevention trials and to help locate biomarkers in benign breast tissue that correlate with cancer risk. “RPFNA as a tool has facilitated risk stratification and prevention therapy research,” she explained.
Reflecting on her career, Dr. Fabian recommends that young translational and clinical researchers “get a broad-based multidisciplinary education, focus early on an area that can be your lifetime passion, and get hands-on training in the techniques necessary to successfully complete your research.”