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 now has in her closet. She is vice president of public policy for Susan G. Komen for the Cure, a breast-cancer foundation working on “uniform national standards for tissue handling, preservation and access.” http://ww5.komen.org/uploadedfiles/Content_Binaries/PathologyWhitePaperB2.pdf
Sharon Anderson, who lives near San Francisco, explained that people might want to:
- Save tissue to be tested later, as new treatments become available. For example, tissue from my 2005 surgery was tested for hormone receptivity.
- Test tissue at a private laboratory for experimental treatments.
- Send samples to another hospital. Patients may switch hospitals when they move, change doctors, or enter a clinical trial elsewhere. Some tissue samples from a 2002 surgery came with me when I moved from Texas to Tampa.
- Participate in a study at a different hospital. Many patients with leiomyosarcoma (LMS), the cancer that Sharon and I had, sent tissue samples to Stanford University, which is doing genetic analysis. Sharon helped organize this project.
- Save frozen tissue in case patients become eligible for a vaccine.
In the flurry of paperwork before surgery, some patients sign away rights to any tissue that is removed. Their hospitals won’t return tissue to them because researchers use these samples to develop new drugs and other treatments.
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 samples to do meaningful research?
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 Dr. Matthew Anderson, director of the gynecologic-oncology division at Baylor College of Medicine in Houston.
But, he added, “Who decides who is doing good science??”
Dr. John Brooks, chair of pathology at Penn Hospital, hopes to answer that question. He founded and directs the LMS Sarcoma Repository Tissue Bank. It will have a scientific advisory committee, created along National Institutes of Health guidelines.
“Sarcoma oncologists, surgeons and researchers will be on it … representing the country as a whole,” he said.
LMS patients worked to collect samples for Dr. Matt van de Rijn’s research at Stanford. As of August 2007, he had about 500 in paraffin and about 80 fresh-frozen.
“He is basically finished with the samples but may be doing more research with the genes he found,” Brooks said.
Patients have encouraged others to sign new consent forms so that the tissues can find a home in the LMS bank, funded by the National LMS Foundation. Once Brooks has all the correct forms, he will collect samples from Stanford and other hospitals that have them. The forms, plus more information, can be found at: http://www.lmsdr.org/tissue.php
The tissue bank will hold only paraffin samples; it isn’t equipped for fresh-frozen ones. As of August 2007, Brooks estimated Penn Hospital had about 50 of its own LMS samples, and he could add those after the others are collected.
Does he want other patients and institutions to send tissue samples in paraffin blocks?
“First I want to complete the task of getting the blocks for those patients who signed up – getting them from the original hospitals will take mailings, calls and time. After that point, we can evaluate where to go from there.”
The forms include basic medical histories, and patients were asked to send their original pathology reports. The bank gets updates only if a patient sends another tissue sample. But researchers have the option of following up on particular patients, Brooks 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.”
Brooks hoped to create the advisory committee in 2008 to seek research proposals and choose who gets tissue samples. Fall 2008 would be the earliest that anyone would receive tissue samples, he said.
Researchers will get a curl of paraffin, “anywhere from 5 to 50 microns thick,” he said. They are not required to make their results public, but he said they would want to do so. “All researchers with successful results do publish.”
In the past, only the largest cancer centers had enough samples to do statistically significant research, he said. “If they had too few of their own, they collaborated with another sarcoma institution.”
At this time, the Sarcoma Alliance for Research through Collaboration (SARC) “does not have the money or structure for its own centralized bank,” he said. “However, SARC researchers do collaborate and institutions do share …”
Dr. Matthew Anderson researches uterine leiomyosarcoma, and he said he has access to hundreds of ULMS samples at Baylor and the M.D. Anderson Cancer Center. These samples are mostly in paraffin, he said.
He welcomes recent NIH efforts to allow multiple principal investigators on grants.
“Foundation funding for specific projects where collaborative research is integral is another key,” he said. “In some ways, research is still a ‘cottage industry’ driven by individuals. So much of what is necessary to accomplish this goal comes down to finding ways for individual investigators to establish professional relationships that in turn facilitate their individual research goals.”
One problem with collaboration is: If a new drug is developed, who owns the rights?
“There are many stories where scientists or medical schools have sold the rights to potentially promising therapies that have then languished in the drawer of a drug company,” Anderson said.
To better explain how researchers collect tissue samples, let me detail a project at the H. Lee Moffitt Cancer Center & Research Institute in Tampa.
Buckle your seatbelts – this can get confusing. For example, Moffitt’s Web site reads: “Cancer tissue removed during surgery normally is discarded.” In an interview in 2007, Dr. Timothy J. Yeatman clarified that Moffitt stores some tissue in paraffin, usually for 10 years. In the mid-1990s, Moffitt also started freezing tissue samples.
“We spend a million a year just to maintain a tumor bank.”
Moffitt claims ownership of those tissues. But Yeatman said they can be used for all the purposes mentioned by Sharon Anderson, including sending them to other research institutions.
“We share tissues quite regularly.”
This means that patients depend on Moffitt doctors to decide how tissue will be used. Patients who disagree with this approach need to talk to their doctors before consenting to donate tissues.
Yeatman runs the Total Cancer Care research project, and he hopes to gather thousands of tissue samples. The goal is to provide “personalized medicine” to patients based on the genetic profile of their cancer.
The TCC consent form says patients can leave the research project but cannot get their tissue samples back. To me, it sounded like you donated all your tissue or none. Yeatman explained that Moffitt will still keep its tissue bank for diagnostic and therapeutic purposes. If people sign up for TCC, however, extra tissue will be saved separately for research.
Surgeons will not remove more tissue than they would normally, he said.
Tissue goes to a pathologist to make a diagnosis. Samples also are saved for future diagnostic or therapeutic reasons. Surplus tissue heads to TCC, but is “kept in escrow,” until pathologists determine they don’t need it, Yeatman said.
TCC will study both cancerous and normal tissues. He noted that researchers need only 25 mg. of tissue 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, sort of like frozen vs. canned food. But freezing tissue is more expensive.
TCC wants only frozen tissue from patients who signed the consent form before surgery. This means many of Moffitt’s patients can’t participate. Like me, some have had tumors removed and have no evidence of cancer now, but they are not considered cured because their cancer had already spread, or metastasized.
“We need to get people in the database who are metastatic so that, when a new clinical trial comes out, they can be matched,” Yeatman said.
If TCC tested tissue in paraffin, people like me could donate samples. Yeatman thinks TCC will test paraffin samples in the future. In less than five years, he said, Moffitt may have the technology to extract the same data from a paraffin sample as it can from a frozen one.
Some patients have inoperable tumors and get other treatment, such as chemotherapy or radiation. He hopes they will donate tissue from a biopsy.
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.”
But he sees no reason why Moffitt researchers could not work with other institutions on projects such as the LMS research being done at Stanford and Penn.
Total Cancer Care differs from those and other research projects because it will try to track patients for life. People who sign consent forms will be encouraged to keep in touch. This is crucial, according to a May 2006 issue of Science magazine, because most tissue banks do not record what happens to patients later or how they respond to any future treatments.
In addition to tissue, TCC will collect blood and urine samples when patients get follow-up care at Moffitt. Urine may show what proteins are being expressed, for example. Blood samples matter for those with a cancer of the blood, such as leukemia. But they can supply information for other patients as well. Yeatman gave an important example: DNA sequencing is different in the tumor than the blood. Some people don’t understand that, just because a tumor has mutated genes, it doesn’t mean that they were born with those mutations – or that they will pass those mutations to their children.
The TCC consent form tells patients: “You don’t have to guess at things you don’t understand. Ask questions.”
Patients are given the forms “days, if not weeks,” before surgery, Yeatman said. “We try to give patients plenty of time to think about this.”
He estimates that 95 percent of the patients given the form have signed it. Moffitt has added a Spanish version, and it can be explained in sign language. Moffitt also produced a short video.
The consent form is long, and “very few people read it carefully,” he said. But “everyone listens” to the video.
The consent form shouldn’t take more than 10 minutes to complete, he said, but Moffitt also has a questionnaire on a patient’s health history that takes 45 minutes. “A lot of patients didn’t want to take the time.” He hopes to put the questionnaire online so that patients who have Internet access at home can fill it out there.
Patients also may worry that the questionnaire is delaying their appointment; they may not realize that a 45-minute wait is not unusual in a cancer center.
People fill out the questionnaire on a display device, not a computer. Thus, no one can hack in and steal someone else’s information, Yeatman said.
Some of us have had many tests and procedures, sometimes at different hospitals. Moffitt assigns a medical-records number to each patient and stores data by that number. TCC researchers can see all the data in a patient’s files, but not who the patient is.
Dr. Matthew Anderson sees benefits to the TCC project, such as the testing of fresh-frozen tissue and the follow-up with patients, and he would welcome the sharing of data. But he doesn’t want patients to think a cure is imminent.
“I would caution that ‘personalized’ genetic profiles from tumors are likely to be many years from becoming useful for real people in the clinic.
Suzie Siegel was a longtime journalist who now serves on the Sarcoma Alliance board.