More than a Game: Super Bowl Initiative Helps Scientists Study the "Normal" Breast
A physician removes tissue from a breast tissue donor. (Image courtesy of Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center)Connie Rufenbarger has always believed that healthy women would willingly donate breast tissue for research if they were convinced the samples could be used to help find a cure for cancer. Now, she has proof: More than 1,800 women have given breast tissue to the Susan G. Komen for the Cure Tissue Bank at the IU (Indiana University) Simon Cancer Center.
Rufenbarger, an advocate for breast cancer research, was instrumental in developing the bank. Its donors have no signs of cancer or breast disease when they provide specimens, making the repository a unique resource for learning about the "normal" breast and how it changes over women's lifetimes.
This weekend, the number of samples in the bank will grow tremendously. Seven hundred women have registered to donate tissue as part of next month's Super Bowl festivities in Indianapolis. As part of an event billed as Indy's Super Cure, some 600 volunteers will collect tissue, blood, and detailed health histories from the donors.
"The Super Bowl is an incredible opportunity," said Rufenbarger, who has survived breast cancer twice. When the Super Bowl host committee first approached the Komen Tissue Bank about a tissue drive, Rufenbarger envisioned a 1-day event involving 100 donors. But in keeping with the spirit of the Super Bowl, she developed a more ambitious plan.
The Need for Normal Tissue
Experts in the breast cancer field have been discussing the need for normal breast tissue for more than a decade. In 1997, NCI convened an expert panel to identify barriers to progress in preventing and treating breast cancer. The first barrier the panel identified was a "limited understanding of the biology and developmental genetics of the normal mammary gland."
In its report, the panel said that a more complete understanding of the normal breast throughout development—from infancy through adulthood—would be critical to advance the field. Now that the Komen Tissue Bank will have more than 2,000 donors, the staff wants to get the word out to researchers. (Investigators can submit proposals to obtain specimens to study.)
Studying normal breast tissues could reveal early changes that precede breast cancer and could be useful in predicting future risk for the disease. Normal tissue also could be particularly useful for researchers studying cancer prevention, according to Dr. Worta McCaskill-Stevens of NCI's Division of Cancer Prevention.
Prevention researchers have largely relied on breast tissue obtained from patients who were biopsied for clinical reasons or who underwent breast-reduction procedures. Although these tissues may appear benign, they may not be truly normal; the optimal "control" tissue would come from women without breast cancer or other breast lesions, Dr. McCaskill-Stevens noted.
"The ultimate question is: How does normal tissue become malignant?" she added.
Building the Bank
Bank builders: (left to right) Dr. Anna Maria Storniolo, Connie Rufenbarger, Dr. Susan Clare. (Image courtesy of Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center)When the idea of a normal breast tissue bank was presented at a 2004 scientific meeting in Indianapolis, some people doubted it could ever happen. Healthy women, they said, would never volunteer to have an invasive procedure that did not offer them a clear benefit, would cause discomfort, and might carry some risk. The regulatory bodies that approve research studies would have to review the plans, they noted, and obtaining approval could be difficult.
Rufenbarger, who attended the meeting, never doubted that women would participate. She and Dr. Anna Maria Storniolo, professor of clinical medicine at the IU School of Medicine, worked closely with ethics experts to develop protocols that allowed women to make an informed decision about donating specimens—initially blood and later blood and breast tissue—for unspecified future research.
Once the IU School of Medicine had carefully reviewed and approved the protocols, women began to donate blood at Komen Race for the Cure events in Indiana and Dallas, and then breast and blood samples at the tissue drives.
Some women have volunteered to donate again, even before walking away from the needle used to collect tissue, noted Dr. Storniolo, who co-directs the tissue bank. "These are women who have ice packs on their breasts as bruises are just beginning to form," she added.
"Critics doubted that women would flock off the street to donate tissue, but they have—at least in Indiana," said co-director Dr. Susan Clare, associate professor of surgery at the IU School of Medicine. She credited advocates like Rufenbarger for making the bank possible.
"Connie just would not let this idea go away," Dr. Clare said. "Breast cancer advocates want this disease to be over. And they want researchers to use this repository and find creative ways to study normal tissue."
Confirming "Normal"
Some people have argued that the Komen Tissue Bank may not actually have normal tissue. They have suggested that most donors would be relatives of women who had been diagnosed with breast cancer, and that these donors might themselves be at a higher risk of the disease.
A recent study provided evidence to the contrary. Dr. Amy Degnim of the Mayo Clinic and her colleagues compared three sources of breast tissue that might be considered normal: samples from the Komen Tissue Bank, from women with benign breast disease, and from women who had breast-reduction procedures.
The study showed that the vast majority of tissue sections from the Komen Tissue Bank that were reviewed were histologically normal. The same could not be said for the sections from breast-reduction procedures or benign breast disease. This implies that tissue from the breast-reduction procedures "is probably not a great source of normal tissue in research studies," Dr. Degnim said.
"I would argue that the samples in the bank are the 'real' normal and that these are some of the highest quality breast tissues available," said Dr. Clare. The staff use standardized procedures to obtain the tissue, and samples are frozen within 5 minutes of collection.
Although the majority of donors to the Komen Tissue Bank are Caucasian, the bank has been reaching out to minority populations to increase diversity and make the resource more useful for researchers. Dr. McCaskill-Stevens noted, for example, that members of the Minority-Based Community Clinical Oncology Program, in Cook County, IL, will be participating in the future.
The bank is unique in another way: Four of the donors have developed breast cancer, including one of the very first donors, Traci Runge. (A video about her is online.) "All four women were wise enough to contact us prior to starting treatments," said Dr. Clare. "They asked if we wanted samples of their cancers. These are incredibly precious specimens."
Profiling Normal Tissues
Donors sign consent forms allowing their specimens to be used for unspecified future research. (Image courtesy of Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center)Changing as it does during adolescence, menstrual cycles, nursing, and menopause, the breast may be the most dynamic organ in the human body. The physical definition or molecular profile of a normal breast in each of these stages is still largely unknown, however.
"The poetry here is that normal is not a point; it's a cloud," said Dr. Mark Sherman of NCI's Division of Cancer Epidemiology and Genetics (DCEG), whose team has studied specimens from the Komen Tissue Bank. He noted that testing someone's cholesterol involves comparing results to a range of numbers. "This is just not possible with breast cancer, because there are not any normative values for the molecular features of the normal breast," Dr. Sherman said.
Using specimens from the Komen Tissue Bank and other sources, his group is trying to identify physical characteristics of the breast that could improve risk models for breast cancer.
Some risk factors for developing breast cancer include age, race, prior breast cancer or breast carcinoma in situ, number of first-degree relatives with the disease, age at onset of menstruation, whether a woman has given birth and at what age, and a history of breast biopsies.
"These risk factors have been identified, but we really don't know how the risk factors might be causing changes in the breast," said Dr. Jonine Figueroa, also of DCEG. She is investigating whether physical features of the breast, such as the number and size of lobules, are associated with any of the known breast cancer risk factors.
Dr. Sherman cautions that it is still early days. "The value of defining the morphology and molecular characteristics of the normal breast is unclear," he said. Nonetheless, he is optimistic that understanding how breast cancer risk factors are related to the microscopic appearance and molecular characteristics of the breast could reveal clues to the disease, as well as potential markers of risk.
"We're called mammals because we breastfeed our young," said Dr. Sherman. "Information about the normal breast and how it changes should be part of our basic knowledge about the human body. This is fundamental."
New Partnerships between the Public and Scientists
"This work has to be bigger than breast cancer," said Rufenbarger, noting that everyone who has been involved in the project has been affected by cancer in some way. She believes the project can be a model for developing resources to study other normal tissues that become cancerous, such as the skin.
Dr. Sherman and his colleagues at NCI have already begun to repeat the model by studying other normal tissues, such as the endometrium (the inner lining of the uterus) and the ovary, although these studies use tissues that were removed as part of clinical care.
The Komen Tissue Bank suggests that new partnerships between the public and scientists can expedite the research process, noted Rufenbarger. "The lesson here is that the public is willing and capable of participating in research studies like this one if we can develop a system that allows scientists to tell the public what they need," she said.
—Edward R. Winstead
Involution and Breast Cancer Risk
Most breast cancers seem to originate in structures known as terminal duct lobular units. In recent years, researchers at the Mayo Clinic led by Drs. Daniel Visscher and Lynn Hartmann have found that lobular involution, a normal, age-related process that leads to the shrinking of the glands that produce milk, is associated with a reduced risk of breast cancer.The Mayo studies suggest that women over age 55 may be at a higher risk of breast cancer if lobular involution has not progressed appropriately. As a next step, the researchers are trying to understand the biology of involution. They have partnered with researchers at the Barbara Ann Karmanos Cancer Institute in Detroit, MI, to study involution in a population of African American women.
"We would like to know whether involution happens in the same way and at the same age in African American women and Caucasians," said Dr. Hartmann.
Meanwhile, a colleague, Dr. Derek Radisky of the Mayo Clinic in Jacksonville, FL, is investigating whether certain characteristics of breast tissue obtained at biopsy could improve the accuracy of risk prediction models for breast cancer. He plans to use samples from the Komen Tissue Bank to assess the prevalence of these characteristics in people with normal breasts.
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