Monday, February 6, 2017

Hot topics in genomics and immunotherapy

By Suzie Siegel

Sitting outside a sarcoma conference hall, she could have been anyone. She was down-to-earth and answered questions with the patience of a teacher.

Elaine Mardis, PhD
But she turned out to be Elaine Mardis, PhD, a renowned scientist and board member of the American Association for Cancer Research. It was 2015, and she had helped organize the AACR’s “Basic Science of Sarcomas,” its first conference on the subject. Last year, she became co-director of the Institute for Genomics Medicine at Nationwide Children’s Hospital in Columbus, Ohio.

The human genome is a genetic blueprint – a complete set of DNA – to tell our bodies how to develop. Physicians and scientists study the genome in hopes of finding the genetic changes that cause cancer or allow it to grow out of control. The goal is precision medicine (also called targeted therapy), in which treatments are matched to specific gene mutations. This differs from traditional chemotherapy with cytotoxic drugs that kill some healthy cells along with the cancer.

A famous example of precision medicine is the use of imatinib (Gleevec) for gastrointestinal stromal tumors (GISTs) that express the protein KIT.

A decade ago, I wrote about the hype surrounding precision medicine. It had not – and still has not – paid off as much or as soon as many predicted. Nevertheless, I still have great hope for it, and I was surprised recently to encounter doctors who thought it had little future.

“I don't think there are many people saying there is little future for precision medicine, really, who have any position of expertise/experience in the field,” Dr. Mardis said. “Fact is, we now are seeing reports emerge in the peer-reviewed literature that are indicating strong clinical benefit for these [genetic] tests in cancer patients. These large-number trials are establishing strong evidence that testing patients to predict their best drug/treatment options is worthwhile and should be pursued.”

For example, Nationwide Children’s is planning a trial using exome-sequencing to find targetable gene mutations in pediatric patients with treatment-refractory sarcoma, she said. This testing looks at the DNA that encodes proteins.

“The aim is to identify kids that might benefit from a targeted therapy or to detect those who might benefit from checkpoint-blockade therapy.” Checkpoint blockade is one tool of immunotherapy.

For those who say immunotherapy isn’t worth it, Dr. Mardis responds: “Ask someone who was at death's door and now is living a normal life. There are plenty [of immunotherapy drugs] to choose from already, and it's early days.

“I think the challenge in immunotherapy is that we need to better be able to define which patients will respond to it, and to be able to clinically monitor those likely to have adverse responses so they can be properly cared for during the difficult clinical period, thereby experiencing the long-term benefit of these therapies.

“The other open question in checkpoint blockade is the specifics around dosing, because it is quite clear we have patients who receive only one or a few rounds of therapy and have a durable response.”

Another hotly debated issue in precision medicine is the use of randomized controlled trials. In a recent panel discussion, one oncologist “indicated the trials for targeted therapies are not appropriately designed because patients with mutations in druggable target genes weren't being randomized to a placebo or standard-of-care arm.”

This may be appropriate for a phase IIa trial involving only a few patients, Dr. Mardis said. Once a targeted therapy has shown promise, however, patients don’t want to sign up for a phase IIb trial in which they may get a placebo or the older standard of care, she said.

“The ethics of putting a patient onto SOC [standard-of-care treatment] when they are likely to respond based on phase IIa results is questionable, in my mind. Some trials have solved this by using a ‘cross-over’ potential for patients who clearly are having no response, so they can get the drug being trialed.

“Medicine is an evidence-based practice, and all doctors do the best they can for their patients, but since this is such a new area, there are likely to be disagreements. The fundamental differences in targeted versus cytotoxic chemotherapies also evoke new ideas about clinical-trial design that are controversial.”

I often hear people complain that the FDA approves expensive new drugs that give cancer patients only a few more months of life than the older drugs do. These complaints are misleading, Dr. Mardis said, because those few months are an average of everyone’s response on the clinical trial. Some people may live for years while others get no benefit.

“Furthermore, there are myriad examples of patients who achieved a short benefit that bought them sufficient time for a better therapy to come along,” she said. “I was just speaking to the mother of one such patient with low-grade glioma. When we identified her daughter's driver BRAF mutation (a three nucleotide insertion that added an amino acid after position 600) in 2011, nobody had ever enrolled on a BRAF inhibitor trial (that we could identify) with that type of insertion and so her likelihood of response was unknown.

“As an alternative, she got a MEK inhibitor but didn't have a response after six months, which was long enough for someone to have seen a similar BRAF mutation who did respond to RAF inhibition. She then switched to a second-generation RAF inhibitor and has been responding now for over a year.”

“From Basic Science to Clinical Translation” will be the AACR’s next conference on sarcoma May 16-19 in Philadelphia. Its general meeting will be April 1-5 in Washington, D.C. I'm grateful for winning a scholarship to attend, as part of its Scientist↔Survivor Program. Sarcoma Alliance board member Dave Murphy participated in this program in 2004 and 2005. He returned in 2014 as an advocate mentor.

Thursday, November 3, 2016

Boston Strong athlete honors her brother

By Suzie Siegel

Shawna Kleftis rode her bike across America in 2014, ran the Boston Marathon in April and paddled across the rivers and lakes of the Adirondacks in September. She has raised as much as $25,000 for cancer patients.

“I’ve had the immeasurable support of family, friends and total strangers. It was never just me,” the 24-year-old said. “I feel like my job is easy. I just have to talk and write about what inspires me – my brother – and people respond. It never ceases to amaze me.”

On October 11, 2009, my older brother, Cullen, passed away from osteosarcoma at the age of 19,” she wrote on her fundraising page for the Adirondack Canoe Classic.

“Every time I sign up for another so-called crazy physical challenge – be it a bike ride across the country, a marathon, or this [canoe] race – I think about my brother and the level of mental and physical strength he exuded throughout his four years of being sick. I think about cancer’s inability to take away his drive, even as it ate away at his body. I carry his spirit with me whenever I think I cannot bike another mile, run another step, or paddle another stroke. It is with him in my mind and heart that I seek to raise funds for the Sarcoma Alliance.”

Shawna, who works in law enforcement in Boston, participated in the Adirondack race as part of Ocean of Hope, the Alliance’s largest fundraiser. She raised $2,877 and is still accepting donations at: She entered the race before she knew that Cullen had received a grant from the Alliance's Sarcoma Hand in Hand: The Suzanne RenĂ©e Leider Memorial Assistance Fund to help with his trip to Houston to get a critically important second opinion.

The Adirondack race, known as the 90-Miler, was a Kleftis family affair. With her mother and younger brother as pit crew, Shawna and her father shared the canoe for their first race together. Not that they were new to water.

“I had grown up sailing and doing all variants of water sports on Lake Ontario,” she said, and she was on the sailing team of her college her freshman year. She and her father started slow but made good time the second day. She’s proud they paddled 69 miles and survived some hardships despite the last day of the 3-day event being cancelled due to high winds.

“Much to my Dad’s dismay, I insisted on camping out each night between the legs of the race, like Native Americans and early settlers would have done on their travels through the same series of lakes and rivers.”

During one portage – when they had to carry the canoe between bodies of water – she disturbed a hornet’s nest while looking for a place to empty her bladder. She was stung about 20 times.

Shawna is an all-around athlete. “In high school, I played varsity soccer and volleyball and ran cross-country. I knew how to play hockey from growing up with my brothers and watching their games, and playing pickup hockey in our driveway. So I decided when I got to Wellesley College that I wanted to play hockey instead, and I sported a #11 jersey in memory of Cullen, whose jersey/lucky number was always #11.”

On her 18th birthday, she went skydiving with her father and Ridge Thorbahn, who had osteosarcoma and two other cancers. He had known Cullen. “When my family learned he wanted to skydive, we paid for his dive. Cullen got to jump before he died; we made sure Ridge also got that chance.”

In 2014, Shawna earned her bachelor’s degree in International Relations-Political Science and Middle Eastern Studies. She had spent a year abroad studying Arabic, and we talked about how cancer is not discussed as openly in many countries as it is in America. “It was quite interesting to learn and witness firsthand how cancer was perceived while living in Jordan,” she said. “I would say in general, it's kept hush-hush. There's almost a sense of shame surrounding disease, as well as a sense of resignation (things happen at God's/Allah's will).

“Beyond that, I think cancer is in some ways ‘new’ to the region because it's still very much developing, and cancer rates tend to increase as countries develop. The prevalence of certain behavioral and environmental factors unique to the culture and region also dictate which types of cancers people are being diagnosed with. As you can imagine, the popularity of smoking manifests as lung cancer, as being in the desert and unyielding sun manifests as skin cancers.”

Only hours after college graduation, Shawna flew to Baltimore to ride 4,000 miles to San Diego in the Ulman Cancer Fund for Young Adult’s 4K for Cancer. (The founder survived chondrosarcoma.)

“It was very appropriate,” she said. “Cullen received treatment in Baltimore at Johns Hopkins, and it was also his birthday weekend. He would have been 24 the day before I started biking.” Cyclists stopped along the way to talk to young people about cancer and visit them in hospitals. Shawna also helped with logistics and publicity. She had hoped to raise $11,111.11, but she surpassed those lucky 11s to raise $14,560.

In April, she ran the Boston Marathon. “I had been dreaming of running it since my first year at Wellesley, which serves as the famous halfway point of the race. It was always such a celebratory day on campus, as it is for Boston and the surrounding areas. And I have always loved running – running has been my outlet all these years. After the bombings in 2013, my desire to run in the marathon increased tenfold. I finally got that chance this spring, and it was wonderful!”

 She and her family have organized other fundraising events and done various volunteer work. “I'm now trying to determine how I can get involved in volunteering on weekends at any of the local Boston hospitals,” she said.

“I know my Dad and I will be doing the 90-Miler again, and I'm also looking at some other paddle-kayaking events. The hardest part is being in Boston – the weather and seasons are not conducive to year-round training – which is unfortunate because I'm always training for my next adventure/physical challenge, regardless of weather!”

Monday, January 25, 2016

'Basic Science of Sarcomas' fascinates

By Suzie Siegel

As a patient who last took biology 40 years ago, much of what was presented at the American Association for Cancer Research’s “Basic Science of Sarcomas” conference flew over my head. But even if you and I don’t know what a TLR4 agonist GLA-SE is, I hope you can get a sense of the ways doctors and scientists are working on better treatments for sarcoma.

Michael Dyer, PhD
At the first AACR conference on sarcoma this fall, the first presentation was by Michael Dyer, PhD, of St. Jude Children’s Research Hospital in Memphis. In 2013, he helped launch the Childhood Solid Tumor Network, which “offers the world's largest and most comprehensive collection of scientific resources for researchers studying pediatric solid tumors and related biology,” according to its website. It shares resources with other researchers without asking for credit, and shares its data with drug companies.

Dr. Dyer used mice with a piece of human Ewing sarcoma grafted onto them (“xenografts”). He gave them a PARP inhibitor with the drugs irinotecan and temozolamide. Increasing the dose of irinotecan made the combination much more effective.

“Irinotecan has been around for a million years,” Kurt Weiss, MD, of the University of Pittsburgh Medical Center, said later. “Combination therapy is going to be huge. If we had not one more drug developed, we’d be fine. We need to use drugs smarter.”

Testing drug combinations takes time, money and the cooperation of the companies that own the different drugs. As researchers learn more about the biology of different cancers, they are making better guesses of what combinations will work.

Karen Cichowski, PhD
Karen Cichowski, PhD, of Brigham and Women’s Hospital in Boston, discussed a phase 2 trial that found selumetinib alone was not effective against soft-tissue sarcoma, but did show activity against leiomyosarcoma when combined with temsirolimus. The dosage of temsirolimus was reduced to lessen the side effects.

She taught us that researchers may not grasp how harsh drugs will be on humans, just by trying them in mice first.

Dr. Cichowski is also working on adding an mTOR inhibitor to either HDAC or HSP90 inhibitors for malignant peripheral nerve sheath tumors.  

Elaine Mardis, PhD
For genomic testing, doctors cannot just collect DNA from a tumor, said Elaine Mardis, PhD, co-director of the Genome Institute at Washington University in St. Louis. They also need RNA as well as a sample of normal tissue for comparison. But such a comprehensive study cannot guarantee a doctor will find a way to treat the person’s cancer, she noted. A drug may not be available or sufficient by itself. Dr. Mardis, who is on the AACR board, works on The Cancer Genome Atlas (TCGA) sarcoma project. All the results are made public for others to use.

Cancer gobbles up more glucose than does normal tissue. The trick is to starve the tumor, but not other cells. “The brain needs glucose, too,” said Matthew Vander Heiden, MD, PhD, of the Massachusetts Institute of Technology in Cambridge. His lab looks at the metabolism of cancer cells, with the realization that the tumor environment and tumor cell of origin make a difference. The metabolism of leiomyosarcoma of the kidney, for example, will differ from a bone sarcoma, he said.

Brian Van Tine, MD, PhD
Synovial sarcoma cells are "unusually addicted to glucose" and die quickly when deprived of it, said Brian Van Tine, MD, PhD, of Washington University in St. Louis. He bought the anabolic steroid DHEA to alter glucose biology and tried it on xenografted mice. He hopes to open a clinical trial with pharmaceutical-grade DHEA.

Rama Khokha, PhD, of the Prince Margaret Cancer Centre in Toronto, said a study of RANKL signaling in osteosarcoma led to a phase 2 clinical trial for denosumab. She helped develop Lentihop, a technology that uses lentiviruses to inject normal cells with elements to turn them into cancer. The process can help identify cancer genes and pathways.  She is offering the tech to others.

Cigall Kadoch, PhD
Cigall Kadoch, PhD, of Dana-Farber Cancer Institute in Boston, discussed her work to develop treatment for cancers, such as synovial sarcoma, that are driven by BAF complex alteration.

Research on an LSD1 inhibitor for Ewing sarcoma led to the drug SP-2577, said Stephen Lessnick, MD, PhD, of Nationwide Children’s Hospital in Columbus, Ohio. “This is a very, very encouraging molecule in pre-clinical development.”  

Pancras Hogendoorn, MD, PhD, of Leiden University in the Netherlands, also studies Ewing. By using zebrafish, he can see a 3-D image of a tumor in a living animal.

The number of possible combinations of immune therapy drugs outnumber sarcoma patients, and collaboration will be needed to figure out what works, said Robert Maki, MD, PhD, of Mount Sinai Medical Center in New York. With 70+ subtypes of sarcoma, he wondered whether researchers will focus on the biology first or look at patients who have exceptional responses.

A promising sign is the recent announcement by some of the companies with immunotherapy drugs that they are working with one another on combinations. 

Karolina Palucka, MD, PhD
We might not need to determine all the mutations of a cancer if we could turn on the dendritic cells in and around it, said Karolina Palucka, MD, PhD, of the Jackson Laboratory for Genomic Medicine in Farmington, Conn. But, she warned, doctors need to be careful in injecting a vaccine into a tumor because it could affect cells throughout the body.

Seth Pollack, MD
Macrophage and checkpoint inhibitors combined may be important for leiomyosarcoma, said Seth Pollack, MD, of the Fred Hutchinson Cancer Research Institute in Seattle. His research also includes a phase 1 trial for TLR4 agonist GLA-SE and radiation therapy for metastatic sarcoma.

David Langenau, PhD, of Harvard, described how NOTCH/SNAI1 inhibition may help children whose embryonal rhabdomyosarcoma has returned.

The Pax3:Foxo1 fusion gene can cause chemotherapy to fail in some children with alveolar rhabdomyosarcoma, said Charles Keller, MD, of the Children’s Cancer Therapy Development Institute of Beaverton, Ore. His team is researching whether the addition of the HDAC inhibitor entinostat to chemo will make it more effective.  

Questions? Ask them in the comment section; I’ll answer them the best that I can.

Wednesday, January 20, 2016

Collaborating for a moonshot on cancer

By Suzie Siegel

What can patients do to help the new federal “moonshot” cure cancers? “Demand collaboration from the scientific community,” Vice President Joe Biden, in charge of the project, said last week.

I’m happy to report that collaboration was evident at international meetings on sarcoma last fall in Salt Lake City. What stood out to me was synergy, whether it was drug combinations or people working together to be more effective.

The Connective Tissue Oncology Society (CTOS) celebrated its 20th anniversary with 750 doctors, scientists, students, advocates and other health-care professionals from around the world – more than expected.

The Sarcoma Alliance for Research through Collaboration (SARC) held its biannual meeting in conjunction with CTOS, as usual. For the first time, the American Association for Cancer Research (AACR) put on a conference on the “Basic Science of Sarcomas,” and nurses from the Oslo University Hospital in Norway had a symposium for their colleagues.

Dr. Jonathan Fletcher
The AACR conference grew out of a group of about 35 doctors, mostly men, who began meeting privately before CTOS to discuss cutting-edge sarcoma science, said Jonathan Fletcher, MD, of Brigham and Women’s Hospital in Boston. As the years passed, they wanted to open the meeting to others, especially younger doctors. This fall’s conference attracted 228 people, more than expected.

"We're thrilled to see this expansion," said Dr. Fletcher, one of the conference organizers. Everyone with whom I spoke raved about the conference.

Dr. Herman Suit
The CTOS meeting began by honoring Herman Suit, MD, its founding father. In the early 1950s, he said, each discipline was for itself and waged verbal combat. At England’s Oxford University, he was delighted to find it multidisciplinary and collaborative.

That is now the norm, except for a few people who have this “big Y chromosome problem,” said Dr. Suit, a professor emeritus of radiation oncology at Harvard Medical School in Cambridge, Mass.

In 1993, a patient funded a meeting of sarcoma oncologists. Afterward, Dr. Suit suggested the doctors meet regularly. They thought of merging with the Musculoskeletal Tumor Society, but its members had to be surgeons.  In 1995, they founded CTOS.

In my next post, I’ll highlight the AACR presentations.

Monday, January 4, 2016

Could changes in the use of tissue hurt research?

By Suzie Siegel

Proposed changes to the use of blood and tissue will greatly hurt sarcoma research, some pathologists say.

For four years, 16 federal agencies have worked on changes to the Common Rule on the ethics of research on human subjects. Comments have been sought along the way, but Wednesday's deadline is fast approaching. (This link details the changes and allows people to comment.)
In general, health-care workers remove blood and tissue from patients to treat them or to do research. If done for research, the project has to be explained and patients have to give written permission. This is called informed consent.

Dr. Jerad Gardner
Patients also give permission for procedures to diagnose and treat them. Leftover blood and tissue may be preserved and stored (a k a “archived” or “banked”) in case they need to be reviewed or tested later to help the patient, said Jerad M. Gardner, MD, assistant professor of pathology and dermatology at the University of Arkansas in Little Rock.

Although these biospecimens weren’t taken for research, current rules allow doctors and scientists to use them for research without patients’ consent if all identifiable information is removed. This is called deidentifying.

Under the proposed changes to the Common Rule, specimens now in storage could be used for research without patients’ permission if deidentified. In the future, however, patients would have to sign a form saying specimens could be used in whatever projects might arise. The health-care system would have three years to comply.

In an article Dec. 10 in the New England Journal of Medicine, the director and deputy director of the National Institutes of Health wrote that many patients want to decide if their blood and tissue can be used for research. “In the beginning, there will be additional costs and effort needed to make the consent process work and to track the consent status of stored biospecimens,” the article says. “Enormous benefits, however, will be realized as biospecimens become more available for secondary research.”

Dr. Brian Rubin
Some sarcoma pathologists disagree. “The proposed changes are unnecessary and overreaching,” said Brian Rubin, MD, PhD, director of Soft Tissue Pathology at the Cleveland Clinic. “While they are well-intentioned, they lack any knowledge of research practices in the USA. They will only inhibit research, not facilitate it, and they will not help patients in any way.”

“While we fully agree that privacy concerns need to be addressed, we think that the proposed changes go too far,” wrote Matthew van de Rijn, MD, PhD, a pathology professor at Stanford University in California, and Alex Lazar, MD, PhD, director of the Soft Tissue Pathology Fellowship Training Program at M.D. Anderson Cancer Center in Houston, in a letter to patient advocates in October.

They urged us to oppose the changes, citing the opinion of William Grizzle, MD, PhD, head of the Pathology Program for Translational Research in Neoplasia at the University of Alabama in Birmingham.  (I’ve written before on the importance of tissue banks.)

“Using these old tissues for research gives us a priceless opportunity to better understand rare diseases while causing essentially no real risk to any of these patients from whom the tissues were obtained,” Dr. Gardner said. “Institutional review boards (IRBs) and other research ethics authorities have long recognized this potential for large benefit but extremely low risk, which is why studies of this sort are often approved by the IRB without any need for additional consent.”

The Dec. 10 article cited a famous case in which cancer cells removed from a woman without her consent have been widely used in research.

“I loved Rebecca Skloot's book about Henrietta Lacks,” Dr. Gardner said. “It certainly made me think about who owns tissue. Her story is very different because extra tissue was taken from her during an operation solely for the purpose of research without her permission. It would be like intentionally taking blood from you just to do research but not telling you about it.

“Compare that to the archival pathology research we do now, which would be like if you had blood drawn to check your cholesterol level and then instead of throwing the leftover blood away, we used it for research. It may seem subtle, but it's different in my opinion. The intention of why the tissue/blood sample was removed is the key. If purely for research, you must get consent. If it was removed with permission for diagnosis or patient care, and then there is an extra sample that isn't needed, it seems reasonable to be able to use that for research.”

The Dec. 10 article noted that even if tissue is deidentified, molecular testing might still reveal the patient’s identity. A member of the Presidential Commission for the Study of Bioethical Issues wrote:

“Over the past 3 years, technology has advanced rapidly, such that it is now possible to identify the donors of biospecimens, even when samples are stripped of traditionally recognized identifiers. As a result, the deidentification process no longer sufficiently protects biospecimen donors from privacy and security risks.”

“But to put things in perspective,” Dr. Gardner said, “all of this tissue, when it is not being used for research, is stored in filing systems in laboratory storage rooms and can be looked up and accessed by any pathologist in the department at any time. The report with all patient identifiers can be pulled up and reviewed also. This, of course, is so we can access old cases to compare with new specimens on the same patient when needed (I have to do this often in my practice). But it means that I could go and search for any rare tumor, pull it out, look at it and see all patient identifiers, and as long as I was doing that for quality control or my own education, it would be totally OK. Even the new proposed regulations would not prevent this.

“But as soon as I want to take that tissue and compare it to other similar cases and learn something from it to write up and publish and share with the medical community, then it becomes ‘research’ and is subject to all sorts of rules. I understand why all of these rules exist, but sometimes they strike me as not only unnecessary but even as a bit ridiculous when it comes to the type of research we usually do in pathology.

“As a pathologist, all of the tissue is at my fingertips and can be accessed and identified any day of the week, and yet privacy breach isn't a concern when I go to work every day because I am a physician and I respect and hold dear the rights of my patients. I would never voluntarily compromise their privacy. But if I pull 20 cases (oftentimes cases that I originally saw and diagnosed!) to look at for a research project, then I have to jump through hoops to protect privacy and meet other regulatory requirements.

“I do jump through the hoops since that is the rule and I want to stay out of trouble, but in pathology we get painted with the same brush that is used for other specialties even though it isn't really very pertinent or appropriate for the work and research that we usually do. I understand why this happens. We are a unique field that works behind the scenes. Most doctors don't fully understand the work we do. How could I expect lawmakers and IRBs and administrators to have a firm grasp on it?”

Dr. Andrew Rosenberg
If the changes are adopted, there has to be a push to obtain informed consent and have this information easily available to research through electronic medical records, said Andrew E. Rosenberg, M.D., director of Bone & Soft Tissue Pathology at the University of Miami. “Maybe this information can be organized in tumor registries that many hospitals have.”

Dr. Gardner was less hopeful. “It is yet another form for patients to read and sign and for administration people to track and file, so it adds complexity and burden to the already vastly overburdened system. How will the pathologist know if the patient had signed this form or not? So many electronic medical records are difficult to use and finding documents can be very challenging, especially in a patient with a complex disease (like sarcoma, for example!) requiring multiple hospital stays and visits with numerous associated forms each time.

“Just figuring out if the patient signed a form or not may take a lot of extra time and effort. This roadblock to research would either result in pathologists wasting valuable time finding paperwork or it would just push even more pathologists away from doing research at all because of all the regulatory headaches.

“Even with a 3-year phase-in, many hospitals and clinics, particularly smaller ones, may not implement this form (or not implement it routinely) meaning that none of their tissue could be used for research without first tracking down the patient to get permission. In my research studies of rare sarcomas and soft-tissue tumors, many of the cases originated from small laboratories or hospitals and were then sent in to us for expert consultation.

“Many research studies of rare tumors conducted by pathology experts will deal largely with consultation material like this. So even if the expert works at a major academic medical center that is very good about getting permission forms signed on its own patients, the vast majority of the cases will be from outside of the system where it will be hit or miss whether permission has been obtained or not.

“I have personally spent HUNDREDS of hours on the phone trying to track down patients with rare diseases to obtain follow up information for research studies; it is often impossible to locate patients years after treatment as they may have moved or transferred to another physician for care.

“It will become more complicated to use tissue for research that came after the new rule change. Thus I suspect many pathologists will just conduct research on older tissue since it will be grandfathered and avoid the complexity of the new regulations. We need research on new material and new types of disease, and this rule may limit that.”

Tuesday, October 27, 2015

After Yondelis, which drugs may get OK'ed next?

By Suzie Siegel

Many of us have waited years for the FDA to approve trabectedin (Yondelis) for soft-tissue sarcoma.

Dr. Gina D'Amato
“I was ready to march on Washington if it didn't get approved!” Dr. Gina D’Amato said Friday, after the FDA approved trabectedin for patients with liposarcoma and leiomyosarcoma who have already tried an anthracycline, such as doxorubicin, but have an inoperable tumor or one that has spread. Dr. D’Amato, a board member of the Sarcoma Alliance, treats patients at Georgia Cancer Specialists in Atlanta.

For metastatic leiomyosarcoma, Atara Weinstein had three surgeries and more than 35 rounds of chemotherapy with six different drugs before starting a clinical trial for trabectedin in February.

“I have been fortunate that with Yondelis I've had some stability these past few months. And it will be easier, all round, to get the drug without the hassles and red tape of a clinical trial protocol,” she said. “Spiritually, getting this approved is a big affirmation to never give up hope.

“Until a cure is discovered, chemo can be a good way to stay ahead of the rampage, and even though side effects are definitely a consideration, they can absolutely be managed for quality of life.”

Because sarcomas are rare, they get less money for research, companies have less interest in investing in them, and enrolling enough patients in clinical trials is difficult.

The FDA has approved only six other chemotherapy drugs for soft-tissue sarcoma: Dactinomycin in 1964 for rhabdomyosarcoma, doxorubicin (Adriamycin) in 1973, imatinib (Gleevec) for gastrointestinal stromal tumor (GIST) in 2001, sunitinib (Sutent) for GIST in 2006, pazopanib (Votrient) in 2012 and regorafenib (Stivarga) for GIST in 2013. Doxorubicin and pazopanib are the only ones commonly used in different types of sarcoma.

Some drugs approved for other cancers also help sarcoma patients. Because the FDA hasn’t approved them for sarcoma, however, doctors give them “off-label.” Examples are ifosfamide (Ifex), dacarbazine (DTIC), gemcitabine (Gemzar) and docetaxel (Taxotere).

Dr. Breelyn Wilky
Some doctors may try trabectedin off-label for sarcoma subtypes other than the two for which it got approval. One problem with this practice is that a person’s insurance may not pay for an off-label drug, noted Dr. Breelyn Wilky, assistant professor in the sarcoma program at the Sylvester Comprehensive Cancer Center in Miami.

Scientists and physicians have been working on trabectedin for more than 15 years, back when it was called ET-743. It was approved in Europe in 2007 and is widely used there. U.S. sarcoma doctors have grumbled over the length of time it has taken for FDA approval. This year, a phase III trial confirmed that the drug can keep leiomyosarcoma and liposarcoma from growing and spreading longer than can dacarbazine. The trial couldn’t prove patients live longer on trabectedin, perhaps because of the trial design.

Clinical trials are broken into three phases. The latest trabectedin trial may have succeeded because it focused on the two types of sarcoma that have gotten the most benefit. In the past, the FDA has hesitated to approve drugs that couldn’t be proven to significantly extend patients’ lives. In 2012, however, it didn’t require that proof for pazopanib. It approved the drug for keeping patients stable longer – just like trabectedin.

Dr. Jonathan Trent, co-director of the Musculoskeletal Center at the Sylvester cancer center, said he wants to stress how effective trabectedin is. “We have had metastatic patients in regression for more than two years.”

Trabectedin was synthesized from a sea squirt. The next sarcoma drug that may win approval also comes from the ocean. Eribulin (Halaven) was derived from sea sponges. This month, the FDA gave it Priority Review status, which means the FDA is expected to make a decision within six months. In a phase III clinical trial, eribulin helped patients with liposarcoma and leiomyosarcoma live longer, compared with dacarbazine. The FDA has already approved eribulin for breast cancer.

The FDA has granted Fast Track status to evofosfamide, formerly called TH-302. This designation speeds up the review process, but not as quickly as Priority Review does. Results from phase III studies are expected this year.

There is hope evofosfamide will be safer than its older cousin, ifosfamide. Dr. Trent said ifosfamide can be more dangerous than some drugs because patients have to be monitored more closely, and some oncologists weren’t trained in sarcoma centers that used it regularly. He said he uses higher doses of ifosfamide than some other doctors because he knows how to monitor it.

With some chemos, more is better, he said. For example, the higher the dose of doxorubicin and ifosfamide, the higher the percentage of patients who benefit.

Results of a phase IIb study of aldoxorubicin were published last month, saying it kept sarcoma stable longer than its cousin, doxorubicin. Because of the danger of damaging the heart, patients are limited on how much doxorubicin they can receive. So far, patients have been getting much more aldoxorubicin without hurting their hearts. A phase III clinical trial is underway.

Dr. Daniel Rushing
In the past, a common chemo combination was dacarbazine, doxorubicin and ifosfamide. Use of dacarbazine peaked in 1993, said Dr. Daniel Rushing, professor of clinical medicine at Indiana University in Indianapolis. It fell out of favor because of nausea and vomiting, he said, but it has made a comeback in recent years as new drugs have better controlled the side effects.

Regorafenib is in a phase II clinical trial for liposarcoma and bone sarcomas. But Dr. Trent said it’s unclear whether it will be approved – the FDA has issued a black-box warning for its potential to damage the liver.

A phase II study of masitinib found it superior to sunitinib for GIST. “I think masitinib could be the next super-Gleevec,” Dr. Wilky said. Another phase II study is looking at the addition of MORAb-004 to gemcitabine + docetaxel.

A phase Ib/II trial this year found olaratumab helped sarcoma patients (a third had leiomyosarcoma) live longer when the drug was added to doxorubicin, as opposed to doxorubicin only. The FDA gave it Breakthrough Therapy Designation.

In phase Ib/II trials, TRC105 + pazopanib got complete remission for two patients with angiosarcoma.

Dr. Jonathan Trent
It’s too early to tell whether AG-120, in a phase I clinical trial for chondrosarcoma, will prove effective, Dr. Trent said. But he describes a patient whose cancer was growing before the trial and now has been stable for nine months. “Is that success? I think so.”

The FDA has approved pembrolizumab (Keytruda) and nivolumab (Opdivo) for other cancers, and they are now in phase II trials for sarcoma. A clinical trial of avelumab may open in 2017. These drugs are anti-PD1 antibodies, a form of immunotherapy. Immunotherapy drugs help the body recognize and attack cancer cells. Immunotherapy has gotten great acclaim.

“Research is exploding,” Dr. Wilky said, adding that alveolar soft-part, synovial and clear cell sarcomas may respond well. In general, however, she sees sarcoma doctors becoming less enthusiastic.

“One issue is that the sarcoma may be growing quickly while the immunotherapy takes longer to work. Another issue is getting the drug into tumors that no longer have a big blood supply. Side effects also can be very dangerous.

“Single-agent anti-PD1 is not going to be enough to cure people.” Immunotherapy will probably need to be combined with other drugs, Dr. Wilky said. Next year, she hopes to open a trial with pembrolizumab + axitinib, which is similar to pazopanib.

PD1 is a checkpoint that keeps the immune system from eating cancers. Ipilimumab (Yervoy) targets another checkpoint, CTLA-4, while palbociclib (Ibrance) inhibits CDK4 and CDK6. The FDA has approved both for other cancers. A phase II trial of palbociclib in liposarcoma had promising results, Dr. Wilky said. She also is interested in the phase I/II clinical trial for ipilimumab + nivolumab.

She recalls how clinical trials were once the last resort for patients. That’s no longer the case, she said, because doctors can better predict which patients will benefit from an experimental drug. “You should consider going on a clinical trial early in your treatment.”

I got a chance to talk to Drs. Wilky and Trent at a patient education conference last month at the Sylvester cancer center, co-sponsored by the Sarcoma Foundation of America. Dr. Trent said it was the first conference for sarcoma patients in South Florida.

For more information, check out Dr. Wilky’s blog post on clinical trials: The Sarcoma Alliance has a page on clinical trials: The Sarcoma Alliance for Research through Collaboration lists its trials: And the Sarcoma Foundation of America can help you find a trial:

Tuesday, October 20, 2015

Annual meeting of world sarcoma society

By Suzie Siegel

New research on sarcoma will draw hundreds of doctors and scientists from around the world to a conference in Salt Lake City next month.

The international Connective Tissue Oncology Society (CTOS) will celebrate its 20th anniversary Nov. 4-7 at its annual meeting. Executive Director Barbara Rapp expects 600-700 people will attend.

Dr. Lor Randall
“Treatment has evolved from trying to control the spread of sarcoma through surgery and radiation to standard chemotherapy to targeting the biology of different types of sarcoma as well as helping the natural biology of the individual patient,” said Dr. R. Lor Randall, director of sarcoma services at the Huntsman Cancer Institute in Salt Lake City. He is a former CTOS president and its current program cochair.

“We are looking at which patients face the greatest risk of developing sarcomas and having the sarcoma spread. We are trying to detect this spread microscopically before tumors become visible via searching for tumor DNA in the blood,” he said. “We also will examine the specific challenges facing adolescents and young adults with sarcomas.”

CTOS has dubbed 2015 the Year of Angiosarcoma and Hemangioendothelioma, two related vascular sarcomas. Angiosarcoma survivor Corrie Painter, cofounder of Angiosarcoma Awareness, said: "I'm excited about the progress we're making in this aggressive cancer."

A scientist who has studied biochemistry and cancer immunology, Painter is associate director of operations at the Broad Institute in Cambridge, Mass. Each year, about 300 people are diagnosed with angiosarcoma, she said, and almost a third of them will die within five years.

For the first time, the American Association for Cancer Research (AACR) will hold a special conference on the “Basic Science of Sarcomas” Nov. 3-4, in conjunction with the CTOS. Participants will discuss recent advances in genomics using new sarcoma models, immunotherapy, metabolism and signaling pathways.

Once again, the Sarcoma Alliance has planned a dinner for patient advocates Nov. 4. "It's a great forum for advocates to talk to one another in person and discuss ways we can work together," said Executive Director Alison Olig, a rhabdomyosarcoma survivor.

The next day, the Sarcoma Alliance for Research through Collaboration (SARC) will discuss its tissue bank, portal for genomic data and progress in its clinical trials. Another first will be a symposium Nov. 6 to strengthen international cooperation among sarcoma nurses, arranged by a group from Oslo University Hospital in Norway.

On Twitter, you can follow the news by searching for the hashtags #CTOS2015 and #AACRsar15.

Thursday, September 17, 2015

Twitter Q&A on drug development next Thursday

By Suzie Siegel

Dr. Laurence Baker
While waiting for "the cure," many of us would settle for more effective drugs that have fewer side effects. Let's talk about this at 9 p.m. (EST) Thursday, Sept. 24, on Twitter.

Sarcoma medical oncologist Laurence H. Baker, DO, will answer your questions during the 45-minute chat. Use the hashtag #scmsm to tweet and find other people’s tweets.

Here are the basics on Twitter:
the-basics. Before the chat, you may want to learn about drug development here:

Dr. Baker, a professor of internal medicine and pharmacology at the University of Michigan Medical School in Ann Arbor, brings a wealth of knowledge to the subject. He has served as director for clinical research and hematology/oncology at UM’s Comprehensive Cancer Center; chairman of the Southwest Oncology Group, the largest clinical trials organization in the United States; executive director of the Sarcoma Alliance for Research through Collaboration, a national cooperative group that runs sarcoma clinical trials; and president of the Connective Tissue Oncology Society, an international group of sarcoma physicians and scientists.

Corrie Painter, PhD
He has treated sarcoma patients for more than 40 years, but instead of retiring, he helped establish UM’s sarcoma survivorship clinic last year.  He tweets @laurencebaker2. My Twitter co-hosts will be Bert E. Thomas IV, PhD, MBA, @SFA_Bert and Corrie Painter, PhD, @Corrie_Painter. Bert is CEO of the Sarcoma Foundation of America, the Alliance’s sister organization in Damascus, MD.  Corrie, an angiosarcoma survivor, is vice president of Angiosarcoma Awareness and associate director of operations and scientific outreach at the Broad Institute of MIT and Harvard in Boston.  I’m a leiomyosarcoma survivor who served on the Sarcoma Alliance board 2008-2013. I tweet @SuzieSiegel. The Alliance supports this chat.

I'll update this post as more people commit to the chat. 

This year has brought exciting news on trabectedin (Yondelis), eribulin (Halaven), aldoxorubicin and evofosfamide (TH-302). Some of you may be following the news on other experimental drugs, wondering why it takes so long for them to get FDA approval. Other possible questions include:
      -- How long does it take and how much does it cost to develop new drugs?
      -- Why does it take longer for some drugs to be approved in the U.S.? Yondelis, for example, is already approved in many countries. 
      -- What are the challenges of developing drugs for rare cancers like sarcoma?
      -- Are there initiatives to speed up the process without sacrificing safety? 
      -- In addition to raising money for research, how can people help speed up the process?

What would you like to ask?

Thursday, August 27, 2015

A Brother's Story: Jeff Darling


My sister Ali was diagnosed with either Stage 3 or 4 Alveolar Rhabdomyosarcoma when she was 13. She had been having pains for some time, but I don’t think we had a correct diagnosis for months. I think doctors assumed they were dealing with a benign cyst, and they performed a surgery to remove the “cyst” before performing a biopsy. The post-surgery biopsy came back with the cancer diagnosis - this is exactly the sort of “oops” surgery that Sarcoma Alliance tries to prevent through education.

I’d never heard of sarcoma before her diagnosis and cancer was one of those things that definitely happened to other families. It wasn’t until after word of her diagnosis spread through our school and friends that I started to hear from other people whose lives had been impacted by cancer.

I’m pretty sure we were all home when we got the official diagnosis. When you’re that young, you don’t have the understanding of what, “your sister has cancer,” really means. My reaction was along the lines of, “This isn’t a big deal, right? She’ll be fine, right?” 
Ali's diagnosis came just before my 16th birthday. Not having a birthday celebration was the first way that I really felt like the disease impacted me. Obviously, that was incredibly naive, and I never could have guessed how much cancer would impact our entire family.


At one point, I remember hearing that Ali had a 25% chance of survival. That was the first time it really sunk in that my sister could die. That I could actually lose my sister. I never heard this 25% number again, but that was the day it became real for me.

School definitely suffered. My dad was working in another city, and my mom and sister traveled far from home for treatment. There were long stretches of time where I was by myself. This was the first time in my life that I realized no one was watching. I didn’t have to go to school if I didn’t feel like it. My grades slipped for one semester and I probably missed 3-4 weeks of class while my parents were both out of town.
I mostly didn’t get support and didn’t know how to ask for what I needed, especially when Ali needed so much just to stay alive. I always tended to “go with the flow,” and at the time, I saw that as a positive trait, but I took that too far.
My friends definitely helped - they would come by the house when they hadn’t heard from me, and I had a holiday meal or two with their families. 


Problems with school were definitely the most glaring example. I’d always been a good student, but somewhat lazy about school. The lack of parental oversight (no matter how necessary) enabled me to take that laziness to its full extent. After high school, I went to college and simply stopped attending classes. Did skipping classes in high school set me up to do the same in college?
I later learned that it’s very common for siblings of cancer patients to have similar academic problems.


I would tell other siblings that they deserve attention too. Most kids just aren’t capable of asking for attention directly and it’s natural (necessary) to focus entirely on the child with the disease. It’s literally a matter of life and death to make sure the child with cancer gets the best treatment possible.
The other siblings will survive, and so they may fall through the gaps. I don’t know if there’s a good answer - I don’t think our family found one, we just did what was necessary. Maybe it would have been different had there been extended family in the area - I could see a large family being able to share the weight of childhood cancer.
Sarcoma is a terrible thing, of course, but have there been any hidden blessings?

Ali and I were always pretty close as siblings, but I think there will always be a deeper bond from our family overcoming this life-threatening disease.  After many years of living in different states, we moved to within a mile of each other.  I don’t think there could have been a better close to this story than meeting my nephew the day of his birth.
Oh, and I’m still a fairly obsessive hand-washer more than 15 years later, so perhaps I’ve been spared some flu and cold seasons!

If we came to your house for dinner, what would we have?
Depends on who is cooking! If it’s on me to cook, my repertoire extends to spaghetti, lasagna, and grilling. Grilling was definitely a hidden talent - it’s all about getting the timing right. Put the food on, close the lid for a certain number of minutes, flip once, and then lid down until it’s done. I’d definitely grill if you were coming to dinner.

Tuesday, July 28, 2015

NCCN revises guidelines on uterine sarcoma

By Suzie Siegel

Guidelines on the treatment of uterine sarcoma have been “extensively revised” this year, according to the National Comprehensive Cancer Network® (NCCN®).

The nonprofit NCCN, an alliance of 26 leading cancer centers in the U.S., publishes separate guidelines for uterine cancers and soft-tissue sarcomas. Two separate panels of experts write them. In the past, some recommendations for uterine leiomyosarcoma (uLMS) differed from recommendations for LMS elsewhere in the body.

Dr. Suzanne George
In 2005, I urged sarcoma specialists to address this discrepancy. The next year, I wrote about the problem here and here. I stopped checking the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) until recently when I saw that Dr. Suzanne George, a renowned medical oncologist in sarcoma at Dana-Farber Cancer Institute in Boston, had been added to the uterine cancer panel in February 2013 as a liaison. I was thrilled, as were other LMS advocates.

“The NCCN Guidelines Panels for Soft Tissue Sarcoma and Cervical/Uterine Cancers have worked together since that time,” according to a statement from Drs. George, Wui-Jin Koh and Benjamin E. Greer. The latter two co-chair the NCCN Guidelines® panel for Cervical Cancer and Uterine Neoplasms. Dr. Koh is a radiation oncologist and Dr. Greer is a gynecologic oncologist, both at the Fred Hutchinson Cancer Research Center in Seattle.

“Uterine sarcomas are uncommon cancers, and women who are diagnosed with these tumors can be cared for by multiple disciplines, including gynecologic oncology, sarcoma-focused medical oncology, surgical oncology, radiation oncology and pathology,” Dr. George said in a separate statement. “It is our responsibility to work together across disciplines to help develop the best guidance possible for the care of women with uterine sarcomas.

"NCCN provides a unique opportunity to bring disciplines together to establish multidisciplinary clinical treatment guidelines with the aim to optimize patient care. It is an extension of the NCCN Mission to create the GYN/SARCOMA liaison position, which allows for collaboration between the Sarcoma panel and the Cervical/Uterine panel in the management of uterine sarcomas.”

The NCCN Guidelines for Uterine Neoplasms (v. 2.2015) primarily focus on the three most common forms of uterine sarcoma: uterine leiomyosarcoma (uLMS), which is the most common; low-grade endometrial stromal sarcoma (ESS); and high-grade undifferentiated endometrial sarcoma. This last category is treated similarly to uLMS. The Guidelines note that these categories are changing as we learn more. For example, some low-grade uLMS is being downgraded to tumors of unknown malignant potential, which are not considered cancers.

The NCCN Guidelines now separate three pathways toward diagnosis and treatment: total or supracervical hysterectomy; biopsy or myomectomy; and "any modality." The Guidelines state that sarcomas should be removed whole, not cut up (morcellated). However, some tumors fall apart on their own or become fragmented. According to the Guidelines, if a tumor was removed in pieces, doctors can consider a second surgery to remove any tumor fragments that may have been left behind.

Ovaries can be left in select patients with early-stage uLMS, but removing lymph nodes is controversial, the Guidelines say. Pelvic radiation remains controversial and isn't recommended routinely for stage I uLMS, the Guidelines say, adding that tumor-directed radiation therapy may be appropriate for people with higher-stage disease, depending on individual circumstances.

It's still not proven that chemo helps women with stage I uLMS if their tumor has been removed completely, but the Guidelines say some doctors may want to consider it because of the risk of relapse. More doctors will consider it for stages II and III. It is generally recommended for stage IV as well as for anyone with uLMS that wasn't completely removed in surgery.

If a uLMS patient is going to do chemo, the Guidelines recommend doctors try gemcitabine (Gemzar) + docetaxel (Taxotere) first. The Guidelines note a trend to use dacarbazine as a standard treatment for comparison in clinical trials, and say trabectedin (Yondelis) can be useful. However, according to the Guidelines, in the U.S. “trabectedin is currently not available outside of a clinical trial. Enrollment in clinical trials is strongly recommended."

For follow-up, the Guidelines propose a physical exam every 3 months for 2 years and then every 6-12 months. Also, doctors should consider CT imaging of the chest/abdomen/pelvis every 3-6 months for 2-3 years, with other imaging (MRI/PET) as clinically indicated. But they also caution: "Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not delay until the next scheduled appointment."

The Guidelines note that uLMS will return in 50 percent to 70 percent of patients. They urge doctors to educate patients on "symptoms of potential recurrence, lifestyle, obesity, exercise, and nutrition counseling" as well as "sexual health, vaginal dilator use, and vaginal lubricants/moisturizers." They recommend their Guidelines on Survivorship as well as the American Cancer Society's pages on survivorship as an additional resource.

People who are otherwise in good health are likely to get through surgery and other treatment more easily. But Drs. George, Koh and Greer clarified that: “There is no evidence that lifestyle choices impact risk of leiomyosarcoma.”

The Guidelines recommend hormone therapy for "ESS only," but add: "Aromatase inhibitors can be considered for ER/PR-expressing uLMS." They cite a study by Dr. George that says doctors are trying to determine whether suppressing estrogen helps patients with uLMS whose tumors express estrogen and/or progesterone receptors.

Observation without treatment is now an option for stage I ESS after surgery.

You can sign up for free to read this year’s NCCN Guidelines: 

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms V.2.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed Feb. 2, 2015. To view the most recent and complete version of the guideline, go online to NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Saturday, July 18, 2015

Homework for July

By Suzie Siegel

We have until July 23 to collect signatures on our petition asking President Obama to proclaim July as Sarcoma Awareness Month. We are going to fall way short of the 100,000 we're supposed to get. But whatever we get will help the lobbyist who is working for free for the Sarcoma Foundation of America to catch the attention of the White House.

Click here to sign:

We are grateful that the American Association of Clinical Oncology (ASCO), the American Association for Clinical Research (AACR) and the National Cancer Institute (NCI) have recognized July as Sarcoma Awareness Month. They have been tweeting lots of information on sarcoma.

Without government recognition, we can't get some organizations to participate. For example, the American Cancer Society has nearly 50 awareness efforts on its calendar, but nothing about sarcoma. I can't even get any of its PR people to call me back. The next time you donate to ACS or participate in Relay for Life, please ask why they don't do anything to raise awareness about sarcoma.

Another way you can help the sarcoma community is by nominating a doctor, nurse, social worker or other health-care worker for an Outstanding Care Award. Doctors and scientists can win grants and awards for their research. But we want to spotlight those who go beyond technical expertise to show real respect and compassion to patients. Don't worry if you're not the best writer in the world.  Just write from the heart. For more information, go to:

Tuesday, April 28, 2015

Clinical trial will use mice to guide treatment choices in soft-tissue sarcoma

Mice in Champions lab.
By Suzie Siegel

Cancer treatments have been tested on mice for years. Now a new technology uses mice to determine which treatments may best fight an individual patient’s sarcoma.

The TumorGraft technology “provides options for patients in difficult situations when, often as doctors, we are not sure how to treat people,” said medical oncologist Justin Stebbing, a professor of cancer medicine and oncology at London’s Imperial College. “In doing so, it advances the frontiers of science and medicine, but in a practical way, giving clinicians information on treatment choices – what is likely to work, and as importantly, what is likely to not work.”

Champions Oncology soon hopes to open a phase II clinical trial of its TumorGrafts for patients with soft-tissue sarcoma, Chief Medical Officer Angela Davies said. About 200 people whose sarcoma has recurred or metastasized will be enrolled at sarcoma centers across the United States and Canada.

“We have plans for clinical trials in many different tumor types,” she said. “We currently are partnering with academic centers conducting a clinical trial in breast cancer and advanced non-small-cell lung cancer, with plans for a trial in head-and-neck cancer and colorectal cancer to start within the next 12 months.”

In the sarcoma trial, she said, patients will start standard treatments while waiting for results from the TumorGraft process, which can take 4-6 months. The trial will accept only patients who are expected to survive at least six months and who are healthy enough to undergo systemic therapy, such as chemo. If the initial treatment fails, the TumorGrafts may help a doctor choose which treatments to try next.

Until a clinical trial validates the process, a U.S. doctor can’t use it to justify delaying or changing treatment in a patient with advanced sarcoma, said Sujana Movva, a sarcoma medical oncologist at Fox Chase Cancer Center in Philadelphia.

Dr. Sujana Movva

Dr. Movva helped design the trial, which was discussed last fall at the annual meeting of the Connective Tissue Oncology Society in Berlin. Other physicians involved in the research were from Massachusetts General Hospital in Boston; University of Michigan, Ann Arbor; Oregon Health & Science University, Portland; Mount Sinai Hospital, New York; Rutgers Cancer Institute of New Jersey, New Brunswick; Johns Hopkins University, Baltimore; M.D. Anderson Cancer Center, Houston; Sarcoma Oncology Center, Santa Monica, Calif.; University of California, Los Angeles; and University of Pennsylvania, Philadelphia.  

Dr. Stebbing serves on Champions’ Scientific Advisory Committee, as does medical oncologist George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston.

Before surgery, patients can ask for a piece of their tumor and its surroundings to be saved for Champions. The fresh tissue will be implanted into one or more immunodeficient mice. If the graft grows, it will be divided again and implanted in more mice. Grafts also will be preserved for future testing.

These grafts are called patient-derived xenografts (PDX) or patient-derived tumor xenografts (PDTX).

“Champions can test chemotherapy, targeted agents, monoclonal antibodies and antiangiogenics as single agents or in combination,” said Dr. Davies, a medical oncologist. Immunotherapies cannot be tested now, but scientists are working on a mouse model with a humanized immune system engrafted.

“No model system is perfect,” Dr. Movva said, “but it is the best ‘in-vivo’ testing available so far.”

The Hackensack, N.J., company began testing different cancers in 2007, with the greatest number of tests in sarcoma, Dr. Davies said. “The rare and heterogeneous nature of sarcomas and the lack of well-defined treatment strategies make sarcoma well-suited to a personalized approach.”

More than 150 sarcoma patients have tried TumorGrafts, she said. “We managed to grow approximately 100 tumors. Currently, we have 60 successful mice models for sarcoma patients.” That translates into a 65-percent success rate for growing sarcomas in mice, she said, “and 67 percent of patients for whom a model was successfully developed decided to proceed with drug sensitivity testing in the model.”

Implantation costs about $2,000, she said. Testing one therapy costs an additional $2,500-$3,000, and the cost mounts as more therapies are tested. The upcoming clinical trial would be free to patients, however. A successful phase III trial could lead to insurance coverage for TumorGrafts.

Some sarcoma patients choose to do chemosensitivity or chemoresistance tests in which their cancer cells are grown in a Petri dish. TumorGrafts have an advantage because they preserve the biological characteristics of the original human tumor, Dr. Davies said.

“Previous work has shown that implanted tumors are able to spontaneously metastasize,” Dr. Movva said. “This suggests that there is interaction between the tumor and its microenvironment, which may therefore mimic the patient response better.”

Genetic testing can help people with certain cancers, but researchers have found few targeted therapies for people with sarcoma, she said. There are more than 70 subtypes of sarcoma, and chemo is less effective in many of them than in more common cancers.

“A recent paper by Stebbing et al. summarizes the clinical experience of 29 patients,” she said. “A few of these patients did have DNA sequencing of their tumors, which guided the physician in selection of drugs for the sensitivity testing.”

In 13 cases, treatments that worked in the mice also helped the patients. “A few patients derived benefit from drugs not normally prescribed for patients with soft-tissue sarcoma,” Dr. Movva said. Grafts failed for seven patients. Six died before data from the mice became available. In three cases, there was no correlation between the mice and the patients.

“It is unclear, therefore, if this approach (using a PDX model to direct care) is better than participating in a phase I trial, for example,” Dr. Movva said. Nevertheless, “patients should definitely consider participating in the TumorGraft clinical trial when it becomes available. This will help determine how well the PDX model predicts patient response and also help sort out some of the issues related to engraftment rates and feasibility.”

Other companies have developed PDX models for research. But Champions is the only one that sells them to individual patients, Dr. Davies said.