This article was written in 2007 and updated in 2013.
By Suzie Siegel
Get it out of me.
Like many cancer patients, that was my attitude toward my first tumor. I assumed it would be thrown away. Only later did I learn that my malignant tissue might hold the key to better care or even a cure.
Tissue is a hot commodity.
In the magazine Heal, lawyer Diane Balma details her desire to preserve her tumor samples, which she has in her closet. She was vice president of public policy for Susan G. Komen for the Cure, a breast-cancer foundation whose mission includes “uniform national standards for tissue handling, preservation and access.”
Sharon Anderson, MSW, a former social worker, kept tissue in paraffin blocks under her bed to ensure she would have access to them later. As executive director of Leiomyosarcoma Direct Research (LMSdr), she recommends people ask their doctor how tissue samples will be stored and what access they will have to the samples. In the flurry of paperwork before surgery, some patients sign away rights to any tissue that is removed.
Anderson, who lives near San Francisco, is coordinating a drive to collect tissue for an LMS repository at Stanford University in California and has encountered hospitals that won’t give up the samples, despite patients giving their consent. Patients may want tissue available in case, they:
- Become eligible for a clinical trial on a vaccine.
- Want tissue analyzed by a private laboratory. Some labs do genetic testing or test for sensitivity to chemotherapy drugs, for example.
- Want to send samples to another hospital. Patients may switch hospitals when they move, change doctors, or enter a clinical trial elsewhere. Generally, the old hospital will send tissue to the new hospital, as mine did when I moved from Texas to Tampa. A problem is more likely to occur when a survivor wants tissue sent to a researcher at another institution, as in the LMS project.
The Dana-Farber Cancer Institute in Boston offers answers to frequently asked questions about tissue banking.
The American Society of Clinical Oncology calls access to tissue critical. The problem is more complicated with rare cancers, such as sarcomas. How do doctors and scientists amass enough tissue to do meaningful research?
National sarcoma tissue bank
In 2004, the National Cancer Institute’s Sarcoma Progress Review Group called for “establishing a centralized sarcoma tumor and tissue repository (possibly in coordination with the National Biospecimen Network).”
“In theory, this could work well, if devoid of politics, and there is ready access to tissue samples and clinical outcomes, etc.,” said Matthew Anderson, MD, PhD, a gynecologic oncologist at Baylor College of Medicine in Houston. But, he added, “Who decides who is doing good science?”
For the tissue bank of the Sarcoma Alliance for Research Through Collaboration, SARC’s scientific leadership decides who receives tissue and serum samples, said SARC President Denise Reinke from her office in Ann Arbor, Mich. Those leaders are divided into three committees: developmental therapeutics, concept review and clinical research. Robert Maki, MD, PhD, medical director of the sarcoma program at Mount Sinai Medical Center in New York, is the director of translational research.
“He moves among the committees; he’s the glue that holds them together,” said Reinke, a nurse practitioner who also has an MBA.
SARC brings together physicians and scientists from different institutions to collaborate on clinical trials in the U.S. It celebrated its 10-year anniversary in November at the annual meeting of the international Connective Tissue Oncology Society in New York.
“We have been able to work together to make a difference for sarcoma patients.”
SARC created the tissue bank three years ago, Reinke said, and researchers can contact SARC if they have a specific study in mind. The national nonprofit has run more than 20 clinical trials across the country and has collected thousands of biospecimens.
“We’ve even got samples from the first trial.”
Tissue is saved frozen, in paraffin blocks and in unstained slides. Serum samples from blood draws are also frozen. Samples may come from different locations in the patient’s body and at different times. For example, in a trial of the drug Gleevec and dermatofibrosarcoma protuberans, surgeons took flash-frozen tissue before the patient got chemotherapy and afterward to gauge the drug’s effect.
“We have 20 paired samples, and we’re now looking for money to analyze them,” Reinke said.
Samples are stored at the biorepository at Nationwide Children’s Hospital in Columbus, Ohio, where SARC has bought space. Cooperative groups for other cancers save samples there, too, including the Children’s Oncology Group and the Gynecologic Oncology Group. COG runs some sarcoma clinical trials, as does GOG to a lesser extent.
A SPORE (Specialized Programs of Research Excellence) grant helps SARC pay some expenses. Nevertheless, it cannot afford to store all of its samples, Reinke said. “In our IGF1R trial, for example, we had 25,000 serum samples, and it costs money to keep them in a repository.” SARC’s scientific leadership decided they needed to keep only a third of the samples.
Samples are being collected with annotated information, which Reinke calls critical. The information includes the patient’s age, treatment, the response to treatment, survival, the location of the tumor, when the sample was taken, and whether the sample came from the original tumor or a metastasis. This information comes from medical records, not the patients themselves.
“Sometimes patients don’t know all the details of their cases,” she said.
What’s the difference between a centralized bank, as discussed in the 2004 PRG report, and the SARC tissue bank? The SARC bank contains samples only from its clinical trials, while a centralized (and larger) bank would also include tissue and serum from patients who did not participate in clinical trials. Like the SARC bank, a centralized bank would be run by a group who had no vested interest in one institution or another.
Tissue banks at hospitals
A centralized bank differs from a hospital that manages its tissue collection for the benefit of its own researchers, who may or may not choose to share the resources.
“Sometimes institutions don’t want to send them out because they don’t want to compromise their own institution’s ability to do research,” Reinke said.
The H. Lee Moffitt Cancer Center & Research Institute in Tampa created one model for collaboration. In 2006, it founded a for-profit subsidiary called M2Gen, which partners with drug and biotech companies to assist in discovery and development.
It “offers the world’s largest cancer-focused tissue biobank linked to longitudinal clinical and molecular data,” according to its website. There are 10,000+ frozen tissue samples and 80,000+ liquid samples, including blood, urine and bone marrow taken from patients as part of the Total Cancer Care consortium. Moffitt and 17 other hospitals participate.
The goal is to provide “personalized medicine” to patients based on the genetic profile of their cancer. TCC intends to track patients for life. Moffitt assigns a medical-records number to each patient and stores data by that number. Researchers can see all the data in a patient’s file, but not who the patient is.
In 2007, before the M2Gen facility was built, Timothy J. Yeatman, MD, said Moffitt usually stores tissue in paraffin for 10 years. In the mid-1990s, it also started freezing tissue samples.
“We spend a million a year just to maintain a tumor bank,” said Yeatman, who ran the TCC program before moving to Gibbs Cancer Center in South Carolina.
Moffitt claims ownership of those tissues. But he said they could be used for all the purposes mentioned above, including sending them to other research institutions.
“We share tissues quite regularly.”
Yeatman said Moffitt still has a tissue bank for diagnostic and therapeutic purposes. When people sign up for TCC, however, extra tissue is saved separately for research. Surgeons do not remove more tissue than they would normally, he said. But, he noted, only 25 mg. of tissue is needed to test for the 30,000 genes in the human genome.
Before surgery, he said, a patient’s physician can ask for tissue to be frozen for a vaccine if such a clinical trial is open. After patients donate tissue to TCC, however, they cannot ask for it back to be used for a vaccine because it will not have been stored in the proper conditions.
Frozen tissue is better than tissue saved in paraffin wax, sort of like frozen vs. canned food. But freezing tissue is more expensive.
Can patients who donate tissue request the results of genetic testing, just as we now get reports on MRIs, CT scans, etc.? No. Yeatman said someone trained in bioinformatics would need to translate the data obtained from such testing.
“Even I can’t look at it and say what it means.”
Sarcoma centers store tissue
Comprehensive sarcoma centers also save biospecimens, often tied to patient details, said Dafydd G. Thomas, PhD, MD, co-director of the University of Michigan’s Molecular Pathology Research Laboratory and its cancer center’s Tissue and Molecular Pathology Core in Ann Arbor.
“University hospitals like Stanford, Moffitt and UM are sitting on a gold mine of tissue. I have over a thousand sarcoma specimens sitting in my freezers, linked to clinical data. I take the viewpoint that I have joint ownership with the patient of the tissue and that I will not refuse a reasonable request for tissue samples. Unfortunately, I do not have grant money to do much with this resource.”
He’s more focused on breast-cancer research these days because he has grant money for it.
“We have a large tissue bank here at Memorial,” said William Tap, MD, section chief for sarcoma oncology at Memorial Sloan-Kettering Cancer Center in New York.
MSKCC researchers collaborate with colleagues at other institutions, he said, but they don’t send tissue just because someone asks for it. Tissue is very valuable. “Once the tissue is sent out, it’s gone.”
The National Cancer Institute has given MSKCC a SPORE grant for sarcoma. MSKCC, SARC and NCI representatives have met to discuss ways to share information and material, Reinke said. “There are clearly initiatives focused on working together to effectively use samples.”
“It’s still critical to have a centralized bank, with the resources to properly manage it and establish quality control,” Dr. Tap said.
Nonprofits collect tissue
“In the future, we will look at patient-driven initiatives” for collecting sarcoma tissue, Reinke said.
In 2007, Dr. Brooks said the repository would have a scientific advisory committee, created along National Institutes of Health guidelines. This committee would seek research proposals and choose who got tissue samples.
“Sarcoma oncologists, surgeons and researchers will be on it … representing the country as a whole,” he said at the time.
Survivors encouraged others to sign new consent forms so that the tissues could find a home in the LMS bank, which was to be funded by the National LMS Foundation.
The bank would ask for the patients’ basic medical histories and original pathology reports. It would get updates only if a patient sent a sample from another tumor. But researchers would have the option of following up on particular patients, he said.
“If researchers discover something and then want to correlate with patient outcome … then that could be obtained on those cases which had the discovered gene or protein. It would require a huge effort to continually update information on all patients – that is typically done by hospital tumor registries at a huge cost per year. It is not simple and requires standard forms to be filled out periodically.”
“Foundation funding for specific projects where collaborative research is integral is key,” said Dr. Matthew Anderson, who researches uterine LMS. “In some ways, research is still a ‘cottage industry’ driven by individuals. So much of what is necessary comes down to finding ways for individual investigators to establish professional relationships that in turn facilitate their individual research goals.”
The LMS bank at Penn Hospital never got enough funding to sustain itself, and Dr. Brooks shipped the tissue samples back to Dr. van de Rijn. Dr. van de Rijn describes himself as the curator of the tissue, not its owner.
In 2013, Sharon Anderson began another drive to collect tissue for him. The project is called the LMS Paraffin Tissue Block Repository, and Anderson volunteers as the tissue coordinator. She interviews LMS survivors to get their medical history. After being rendered anonymous, the information is linked to the tissue samples.
“You can help researchers all over the world” by sending tissue, says the LMSdr website. “The advantage of having a tissue bank is that researchers can go to one place & access enough tissue to conduct research. … Bottom line, without a tissue bank, it is impossible for researchers to get enough samples to conduct any valuable research on LMS. No samples, no research, no cure!” The NLMSF uses similar wording. Both nonprofits also raise money for Dr. van de Rijn’s research.
He said his primary focus is his research, not managing a tissue bank for other researchers. But he added: “I’m all for collaboration. We need to collaborate.”
This work is crucial, he said. “I can’t emphasize that too much.”
He has worked with Dr. Thomas and many others in the U.S. and abroad, but he has had few requests for tissue. “There are very few people working on leiomyosarcoma, and not all of them can use paraffin-block samples.”
In an ongoing study, he and his colleagues determined that people with more macrophages in their tumors tended to do worse. “We had 147 patients where we knew the outcome, and we could correlate macrophages and how patients did. These findings have been confirmed three times.
“The macrophages encourage angiogenesis, which leads to a better blood supply for the tumors. Macrophages have another major function – they eat up bad things in your body. We’ve found that if you inhibit a protein, CD47, on the surface of LMS cells, that will change the macrophages so that they will eat the LMS cells.”
The cases were almost equally split between LMS that started in the uterus and LMS that began elsewhere. In some cases, the LMS spread, and the bank received tissue from the metastases.
It’s important to find something, such as macrophages, that can help the medical community make a prognosis in LMS cases, Dr. van de Rijn said. More important, however, is finding a better way to treat patients.
“I’ve never felt so close,” he said, to developing a new therapy, whether a small-molecule inhibitor or the use of antibodies.