Friday, October 12, 2018

Physics and math bring more precision to treatment

By Suzie Siegel

Dr. Jeremy Mason
My mentor at a cancer conference has taken only one biology class in his life, and that was when he was a freshman in high school. Nevertheless, his knowledge can change the way you think of cancer — and the way doctors treat it.

“Math, physics and computer science have a profound impact on the field of cancer research today,” said Jeremy Mason, who has his doctorate in engineering. “Other scholars with little to no experience in cancer are applying their own knowledge and skills to build detailed and relevant models of the event prediction, cellular birth/death processes, therapeutic responses and much more.

“One day, these models will be used for the common goal of improving patient care and extending lives.”

Dr. Mason, assistant professor of oncology at the University of Southern California in Los Angeles, came from the heart of Cajun country and went to college in Georgia.

“I grew up in a region where diabetes, stroke, and heart attack were discussed more than cancer, so I started down this path with virtually no prior knowledge on the subject. Instead of having to correct any misconceptions I had, I was forced to learn everything from the ground up. Fortunately, since I was classically trained as an engineer, applying math and physics to cancer research allowed me to view the challenges that were arising within the field and helped to quantify the complexity in a manner that made sense to me.

“Cancer research has interested me in a number of ways. It presented a unique challenge that does not have a definitive solution, but has profound impact on numerous people. Both patients and their loved ones. Also, every day I get to work with some truly amazing people.”

Dr. Caligiuri with me
Dr. Mason works on the Convergent Science Initiative in Cancer with USC Professor Peter Kuhn, who has his doctorate in physics.  This is the second year that I won a scholarship to attend the American Association for Cancer Research’s annual meeting as part of its Scientist↔Survivor Program. Drs. Mason and Kuhn were the scientific mentors for the team I was on. We had to do a short presentation on math, physics and evolution in cancer research.

The meeting in April drew 22,500 participants to Chicago. The survivor program gives participants a chance to meet VIPs, such as Michael Caligiuri, MD, then president of AACR, in social settings. Dr. Caligiuri is president of the City of Hope National Medical Center in Duarte, Calif.

Dr. Shihong Zhang
Most doctors and scientists work on carcinoma. I always ask about their research: “Is this the same or different for sarcoma? How could this apply to sarcoma?”

Because sarcoma is rare, I could read the summaries of all the sarcoma research presented. For example, I met Shihong Zhang, PhD, who works on immunology at Fred Hutchinson Cancer Research Center in Seattle. She presented a poster on the use of interferon gamma radiation to heat up the cold microenvironment of synovial sarcoma and myxoid-round cell liposarcoma, both of which express the protein NY-ESO-1. The goal is to make them more susceptible to immunotherapy.

Dr. Jianguo Huang 
Jianguo Huang, PhD, of Duke University Medical Center in Durham, N.C., presented a poster on how long, noncoding RNA NEAT1 promotes lung metastasis in soft-tissue sarcoma.

“Metastasis is the major cause of death from cancers, including sarcomas,” said radiation oncologist David Kirsch, MD, PhD, principal investigator on the NEAT1 study. “We seek to understand how sarcomas spread from their primary site to other parts of the body, such as the lungs. By uncovering the way that sarcomas spread, we hope to develop new approaches for preventing or treating sarcoma metastasis.”

Dr. Kirsch, a Duke professor, thinks it would be a stretch to include this presentation in my topic. Dr. Kuhn did not.

Dr. Peter Kuhn
“Physicists are often trained as high-complexity problem solvers, a k a fancy plumbers with duct tape,” Dr. Kuhn said. “It is not necessarily just about light and energy but really just as much about the body as a complex system (space) that experiences many factors of evolution and lifestyle (time). Understanding this space-time complexity and starting to determine what we need to measure to predict it, is exactly what the physics and math guys are going after.”

“The same mechanisms that allow organisms to adapt and survive are the same mechanisms that cause cancer,” said pathologist Carolyn Compton, MD, PhD, a professor at Arizona State University in Scottsdale and chief medical officer of its Complex Adaptive Systems Institute.

Dr. Carolyn Compton makes a point
Cell mutations drive evolution, she said. They allow some animals to adapt and survive in their environment. But mutations also help cancer cells grow out of control in different environments in our bodies. Thus, humanity takes the bad (cancer) with the good (evolution).

Many people have cancer cells in their bodies, but they don’t know it because the cells haven’t found a hospitable environment in which to grow. It takes about a billion cancer cells to make a tumor that is 1 centimeter cubed, Dr. Compton said. The cells in a cancerous tumor may not be all the same, she said, and some may survive treatment.

“Cancer is the ultimate complex, adaptive system. It does new things that you did not expect. If we think of weather, there’s all this math modeling to make predictions, but we’re not there yet” in cancer research.

Sometimes treatment isn’t strong enough to kill cancer. Sometimes doses are stronger than they need to be, causing unnecessary damage to healthy cells, she said. Sometimes cancer treatment can cause so much damage that people develop new cancers.

Dr. Kuhn is working to develop liquid biopsies — blood samples that could make treatment more precise and predict a patient’s future. These samples would be more accurate in screening for cancers. They could predict which treatment would work for a patient, monitor the cancer for resistance to treatment, and predict what treatment might work if the cancer returns.

For many sarcoma patients, treatment can feel like a gamble. I'm glad that math and physics can give us better odds.

Thursday, August 30, 2018

We loved the Sarcoma Exchange!

By Suzie Siegel

The Sarcoma Exchange proved so successful that even before it ended, survivors were asking about the next one. 

“We were so encouraged by the outpouring of participation by the sarcoma patient, caregiver and survivor community. We had 147 attendees, but many more expressed that they wanted to attend,” said Alyssa O’Driscoll, executive director of the Sarcoma Alliance. “We’re planning to make this a regular part of our programming should funding continue.” 

The Alliance, founded in 1999, is an international nonprofit dedicated to the education, guidance and support of people affected by sarcoma. Although survivors and families meet each other at Alliance events, this the first time it has held a patient-education conference. 

The conference was July 20-22 in Atlanta. Patients and caregivers came from 29 states and represented 21 subtypes. The patient who had survived the longest was Susie Wright of Cairo, GA, who was diagnosed with synovial sarcoma 48 years ago. The subtype with the most survivors in attendance was leiomyosarcoma (LMS).  

LMS survivor Sharee Whitmer (left) and Lisa Kessler, whose husband survived LMS, but their son did not.    

"The information gleaned from the sarcoma oncologists and researchers empowered me in a way that really let me feel I have some options that I have not exhausted," said Sharee Whitmer of Madisonville, VA, an LMS survivor. She came with her husband and their therapy dog, Stella. "It reassured us that the sarcoma oncologist and team that I am with now are staying well-informed and that I am indeed in good hands. And when and if the time comes to move on and find another team, I have many other choices.

"For us to have some idea of how up-do-date our care and our options, including trials, really are, it is imperative to attend conferences aimed at educating and empowering patients. Not everyone is seen at a large sarcoma center.

"The BIG take away from the conference for us was to really be able to connect in person with other sarcoma patients and their caregivers that we have met through online support groups. And during the conference to be able to meet so many more that we would not have met if it were not for attending the conference. Knowledge is incredibly valuable for patients like us, and having the opportunity to exchange our experiences while enduring this diagnosis and the treatments that follow are invaluable."  

Mary Prince, Lea Custer and me
Mary Prince of Portland, OR, came from the farthest away. Her sister, another LMS survivor, lives in Murrayville, GA. 

“Attending this wonderful event with my longterm-thriver/ BFF / sister, Lea Custer, was the highlight of the year for me. Meeting other LMS survivors and meeting all the wonderful medical professionals and hearing what's coming up on the horizon made it an incredible conference. Love was everywhere; you could feel it!" Mary said. "A special shout out to Dr. Gina D'Amato, Lea's primary sarcoma physician, who made it all happen.”  

Dr. D’Amato, a Sarcoma Alliance board member, practices at Northside Hospital’s Cancer Institute in Atlanta. She’s grateful that sarcoma specialists from across the South volunteered to speak, along with her colleagues from Northside.

The medical oncologists who spoke were Dr. Robert Benjamin and Dr. Shreyaskumar Patel from MD Anderson Cancer Center in Houston, Dr. Jonathan Trent from the Sylvester Cancer Center in Miami, and Dr. Richard Riedel from Duke Cancer Institute in Durham, N.C. Dr. Scott Davidson, a surgical oncologist, and Dr. Hamilton Williams, a radiation oncologist, attended from Northside.

Breakout sessions covered patients in treatment, survivors and caregivers.

Amanda Smith with the late Roger Henderson
"Never quit the fight. That was my mindset," said Amanda Smith of Havelock, NC, who facilitated the caregiver section. She lost her boyfriend, Roger Henderson, to chondrosarcoma. An LPN, she's in school to become an RN. 

Sarcoma Alliance board member Marites Tullius, a nurse practitioner, spoke on palliative care. From Northside, registered dietitian Rebecca Perez spoke on nutrition; social worker Myra Bazell, stress management; RN Debbie Bickes, patient navigation; and occupational therapist Melora Rennie, exercise and fatigue.

Osteosarcoma survivor Woody Roseland, whose "S#!%Cancer Patients Say” brought knowing laughs, entertained us one afternoon. That night, hypnotist Ricky Kalmon evoked a great deal of silliness from his targets.  

Sponsors were drug companies Lilly, Eisai, Ignyta, Novartis, Immune Design and Epizyme as well as  Northside Hospital’s Sarcoma Program. Thanks to them, we had free rooms at the Marriott Perimeter Center Hotel and delicious meals. 
Presentations from the conference are posted here: Here are a few tidbits:

Dr. D'Amato with Dr. Benjamin
"Stage 4 has a bad connotation. I don't even use it in clinic,” Dr. D’Amato said. The problem with "stage 4" or "terminal" is that these labels include people whose sarcoma has spread far and wide as well as those with oligometastatic disease, which means they have only a few small tumors in one or two distant locations. Some people think "stage 4" or "terminal" means they are going to die soon. They may decline treatment that could help them live longer.

Dr. D’Amato noted that "remission" applies to people who no longer have any evidence of sarcoma after their initial treatment. The term for people who have no evidence of disease after they have been treated for metastatic sarcoma is NED. For example, my original leiomyosarcoma was 2C. Soon after, one small lung metastasis was found; 18 months later another appeared. Thanks to radiation, chemo and surgery, I’m NED from oligometastatic disease.

Dr. Riedel
“When you’re educated, you’re empowered,” said Dr. Riedel, who spoke on immunotherapy. “The future is bright.” 

Don’t let community doctors take you off of a drug just because your tumors aren’t shrinking, he said. His mantra is: “Stable disease is a good thing.”

“Patients want their sarcomas to shrink and disappear, but doctors are happy with stability,” Dr. D’Amato stressed. Sarcoma specialists may try new treatments only if tumors start to grow. 

Some times the tumor stays the same, or even looks larger, but is actually dead after treatment. Some tumors shrink, but not enough to meet the definition of shrinkage in clinical trials. 

Researchers refer to “progression-free survival” (PFS) when tumors stay stable. Some people don’t think the FDA should approve drugs based on stability. They want clinical trials to prove that the people who got the new drug lived longer, which is called “overall survival” (OS). 

Dr. Benjamin thinks PFS can be a good sign that a drug is working. The problem with OS is that it measures  things that weren’t part of the clinical trial, he said. For example, the clinical trial on doxorubicin (adriamycin) + olaratumab (Lartruvo) compared it with dox by itself. But people who got olara may have gone on to get better treatment, improving their survival.  That’s why MD Anderson is doing a clinical trial to compare dox + olara to the older combination of dox + ifosfamide.

Dr. Patel
Dox + ifos is a common treatment for sarcomas, and some community doctors may try to treat all sarcomas with it, Dr. Patel said. They shouldn’t, he added. They need to look at each subtype individually because some, such as alveolar soft part sarcoma (ASPS), don’t respond to this chemo combo. 
Because immunotherapy is in the news, he spends a lot of time educating patients on why chemo may be better than immunotherapy for their particular sarcomas. He also discusses the advantages of a clinical trial vs. standard treatment.

“Patients must have information to make a decision,” Dr. Patel said.

A variation on doxorubicin, called aldoxorubicin, “clearly has less cardiac toxicity. It’s a very good drug,” Dr. Benjamin said. We await the results of clinical trials and a decision by the FDA. 

Dr. Trent
Dr. Trent joked about the crazy names that pathologists give to sarcoma subtypes, such as dermatofibrosarcoma protuberans (DFSP). Nevertheless, medical oncologists like Dr. Trent greatly respect sarcoma pathologists. You can’t get the best treatment without an accurate diagnosis. 

For example, most sarcoma cells look like spindles under the microscope, Dr. Benjamin said. If pathologists cannot identify the tumor’s subtype, they may use the catch-all term of “spindle-cell sarcoma.” 

Instead of taking a tissue sample, some doctors are looking at tumors’ DNA circulating in the bloodstream (called ctDNA). They want to see which treatments are working and which might work for the patient in the future. Although these “liquid biopsies” are still experimental, Dr. Trent said: 
“This is what the future is.”

Monday, July 2, 2018

Let's make Sarcoma Awareness Month official!

Sarcoma nonprofits are seeking U.S. senators to introduce a resolution naming July as Sarcoma Awareness Month. We have been working on this since 2007 and have been successful in getting recognition from the Sarcoma Alliance for Research through Collaboration, National Cancer Institute, American Association for Cancer Research, the American Society for Clinical Oncology and the American Cancer Society.

U.S. Rep. Kathy Castor, D-FL, has introduced the resolution in the House in past years, to no avail. We’ve also tried White House petitions, but that didn’t work either. That’s why we’re focusing on the U.S. Senate this year.

We would be grateful if you would contact your U.S. senator! Here’s the suggested wording for the resolution:

A resolution declaring July to be Sarcoma Awareness Month

WHEREAS, Sarcoma is a cancer of connective tissues, such as nerves, muscles, joints, fat, bones and blood vessels, and it can arise anywhere in the body; and 

WHEREAS, the American Cancer Society estimates 13,040 cases of soft-tissue sarcoma will be diagnosed this year, with 5,150 Americans expected to die from it. 

WHEREAS, 3,450 new cases of bone sarcomas are estimated for this year, with 1,590 deaths.
WHEREAS, 1 percent of the cancers diagnosed in adults and 20 percent of cancers diagnosed in children each year are sarcoma; and  

     WHEREAS, More than 50 subtypes of sarcomas have been identified; and

WHEREAS, Nonprofit sarcoma organizations want to raise awareness in hopes that more patients will get earlier diagnosis and treatment, and these organizations have agreed upon July as Sarcoma Awareness Month; and

     WHEREAS, the National Cancer Institute, the American Society of Clinical Oncology, the American Association for Cancer Research, the American Cancer Society, the Sarcoma Alliance for Research through Collaboration, the National Comprehensive Cancer Network and many others recognize July as Sarcoma Awareness Month;


Be It Resolved by the U.S Senate: 

That the Senate recognizes July as Sarcoma Awareness Month. 

Tuesday, February 13, 2018

Big Data research includes sarcoma

By Suzie Siegel

Dr. Bill Dalton is betting on Big Data.

In 2006, when he was CEO of the Moffitt Cancer Center in Tampa, he led the development of the Total Cancer Care Protocol and M2Gen, a for-profit subsidiary.

As part of Total Cancer Care, more than 140,000 patients — including 3,392 with sarcoma — have given permission to have their blood and tissue samples stored and analyzed at Moffitt and to be followed throughout their lives. This produces huge amounts of data that researchers and M2Gen can analyze further.

“We have one of the oldest and largest databases of its kind, especially in molecular genomics,” said Dr. Dalton, MD, PhD, now executive chair of M2Gen, a health-informatics company. “We are continually updating patients’ data to try and learn from each patient’s experience.”

Researchers group patients' de-identified data by their similarities, and then break out the groups with more and more similarities. For example, they might start with patients whose cancers had NTRK gene mutations, and then create a subset that have Ras mutations, too. Because some patients may have the same genetic mutations, patients with different kinds of cancer might be able to take the same drug.

Sarcoma is rare, and doctors often struggle to enroll enough patients in the clinical trials needed to gain FDA approval of a new drug. We may benefit from trials that enroll patients with different cancers who have the same mutations. Targeting these mutations in a person’s cancer is called precision or personalized medicine.

In sarcoma, the first targeted treatment was imatinib (Gleevec) for gastrointestinal stromal tumor (GIST), which often shares the same mutation as chronic myeloid leukemia (CML). The FDA approved imatinib for CML in 2001 and GIST patients followed soon after.

In the past, GIST had often been classified as gastrointestinal leiomyosarcoma (GI LMS). Although my LMS was vaginal, I was checked for the mutation when I was diagnosed in 2002, just in case. My first sarcoma oncologist, Dr. Andy Burgess, now retired from MD Anderson Cancer Center in Houston, told me that imatinib for GIST was the best thing that had ever happened to him in his life.

One of Dr. Dalton’s sons was diagnosed with GIST last year and is doing well on imatinib. “I’m becoming a student again,” Dr. Dalton said, as he learns more about sarcoma. As a physician, he treated patients with multiple myeloma.

My tour to learn more about Total Cancer Care began at Moffitt, where I peered into the pathology lab near the operating rooms. If possible, a diagnosis is made while the patient is in surgery to help the surgeon know how to proceed. With sarcoma, for example, surgeons try to take some normal tissue around the tumor — just in case some microscopic cancer cells have spread that far. In ovarian cancer, surgeons often take much more.

Tissue donated for research is snap-frozen, usually with liquid nitrogen. When tissue is needed for patient care, hospitals store tissue in wax, technically called formalin-fixed paraffin-embedded (FFPE) tissue blocks, said Michelle Fournier, manager of Moffitt’s central biorepository (also known as a tissue bank).

“But that isn’t the best for genomic sequencing,” she said. Ten years ago, Moffitt couldn’t extract good quality genetic information from paraffin blocks, but it now has the technology, Dr. Dalton noted. This matters because Moffitt often receives FFPE samples from other hospitals when patients seek second opinions.

If a patient may benefit from genomic testing, most Moffitt doctors use FoundationOne, Fournier said, which is not always covered by insurance. She said Moffitt wants to create its own genomic-testing lab.

Samples of blood and other bodily fluids are also important parts of Total Cancer Care, she said. Like their colleagues elsewhere, Moffitt researchers hope to develop technology to allow the use of liquid biopsies. Drawing blood for a biopsy would be easier on patients than minor surgery to remove tissue.

Genesis Blanco, left, and Michelle Fournier, right
“I have a lot of patients who say they came to Moffitt because of the research,” said Genesis Blanco, a Total Cancer Care research coordinator.

Total Cancer Care draws from electronic medical records (EMR) created by clinic staff, as well as results of surveys from patients. This two-part system helps ensure accuracy, Dr. Dalton said. “I’d sometimes trust patient-reported outcomes for such things as patient’s pain over EMR.”

M2Gen, built on 30 acres near the main Moffitt campus, promotes research using the Total Cancer Care data. The data are de-identified so that researchers don’t know who the patients are. M2Gen partners with five pharmaceutical and biotech companies, which provide funding for further analysis of the data.

M2Gen also looks into the future. Researchers use statistical algorithms to predict how someone’s cancer might change if it spreads and what treatment options might be available.

In 2014, Moffitt and the Ohio State Comprehensive Cancer Center in Columbus, cofounded the nonprofit ORIEN (Oncology Research Information Exchange Network). M2Gen manages the network.  Seventeen cancer centers participate.

"We’ll be up in Canada next month, and then in Europe,” seeking more partners, Dr. Dalton said.

M2Gen is leading the Avatar Research project within ORIEN that does whole exome sequencing, which looks at the part of DNA that encodes protein, as well as RNA sequencing on tissues collected as part of TCC. Dr. Dalton would like to create a portal so that patients could learn how their donations of tissue and data are advancing research.

ORIEN is using resources on a focused group of Total Cancer Care tissues. “For Avatar we’re looking at a subset of high-risk patients who may be in need of clinical trials,” explained Erin Siegel, MPH, PhD, Scientific Director of TCC.

In this Avatar Research project, researchers in and outside of the ORIEN network can ask to use the data for specific projects. For example, Dr. Damon Reed is looking at teenagers and young adults up to age 40. Dr. Reed, MD, is director of the Adolescent and Young Adult Program at Moffitt and medical director of its Sarcoma Department. Working with Dr. Reed, Moffitt will include over 250 sarcoma tumors in the Avatar project.

"We need champions in this research, like Damon,” Dr. Dalton said.

Wednesday, February 7, 2018

Sarcoma Awareness Month needs your help

By Suzie Siegel

Once again, we need your help to get Congress or the White House to recognize July as Sarcoma Awareness Month.

Many of us had never heard of sarcoma before our diagnosis. Our first doctor may have seen few, if any, cases. We may have felt alone, with no idea about the resources available to patients and their families.

Increased awareness could help patients get a correct diagnosis and better treatment and support earlier.

July may seem far away, especially for those still digging out from winter, but we need to start contacting Congress and the White House now.

Here's how to contact the White House: Here's how to find your Senator: If you don't know who your U.S. House Representative is, put your zip code into the box on the top righthand corner of this page:

Please keep all communication positive. Remember that we need bipartisan support. If you can't talk directly with your Representative or Senator, you may want to call their offices to see if they have a staff member who handles health issues. After talking to someone, follow up with an email or letter. Check back with them periodically to see if a decision has been made. Visit them in person if possible.

Get your friends in on the fun. Put this on Facebook, Instagram, etc. Talk to your bridge club or your religious institution. Be creative.

Here are facts to mention:
  • Sarcoma nonprofits decided at a meeting in 2007 to support July as Sarcoma Awareness Month. We don't know anyone opposed to this. 
  • The National Cancer Institute, the American Cancer Society, the American Association for Cancer Research, the American Society of Clinical Oncology, the Sarcoma Alliance for Research through Collaboration and the Connective Tissue Oncology Society recognize July as Sarcoma Awareness Month. But no one in Congress or the White House has chosen to make this official ... yet!
  • Sarcoma is one of the major types of cancer. Although it represents only 1% of adult cancer cases, it is 20% of childhood cancers. 
  • Sarcomas occur in connective and supportive tissues, including bone, muscle, fat, nerves, etc., anywhere in the body. There may be more than 200 subtypes. People of all ages can get sarcoma, including babies in the womb. Lifestyle choices, such as smoking and drinking, have not been linked to sarcoma.
  • The American Cancer Society estimates 13,040 cases of soft-tissue sarcoma will be diagnosed this year, with 5,150 Americans expected to die from it. For bone sarcomas, the figures are 3,450 new cases and 1,590 deaths.
The movement to designate a special time for sarcoma awareness started in 2001 with the late Suzanne Leider, founder of the Sarcoma Alliance. She proposed a Sarcoma Awareness Week in June. Its sister organization, the Sarcoma Foundation of America, adopted that, as did Sarcoma-UK and other nonprofits and sarcoma centers. Then Bruce Shriver, founder of the Liddy Shriver Sarcoma Initiative, decided to have an International Sarcoma Awareness Week in July.

In 2006, I wondered why we couldn't all agree on the same time period. Bruce didn't want to change his week in July. So, the Sarcoma Alliance and others switched to July for the sake of unity. Sarcoma nonprofits agreed on July at the Connective Tissue Oncology Society (CTOS) meeting in Seattle in 2007.

I created a Care2 petition on the topic. A legislative liaison at Moffitt Cancer Center in Tampa helped me draft the wording for a House resolution, and U.S. Rep. Kathy Castor, D-FL, sponsored it 2011.

The former Republican leadership of the House wanted no more resolutions recognizing days, weeks, months, etc. I talked with the leadership’s staff to no avail. The result was we couldn’t get Rep. Castor’s resolution out of committee.

I was a journalist before being diagnosed with leiomyosarcoma. In 2012, I wrote an editorial for my former newspaper, the Tampa Tribune. The next year, I wrote this. In 2015, I wrote another editorial and created a White House petition. The Sarcoma Foundation of America took over the petition in 2016 and 2017.

At the CTOS meeting this November, sarcoma advocates decided to consider collaborating on the effort to gain federal recognition of Sarcoma Awareness Month. The National Leiomyosarcoma Foundation has partnered with Rare Disease Legislative Advocates.

Of course, the Sarcoma Alliance and Sarcoma Foundation of America will work hard on this issue once again -- with your help! Please tell us who you've contacted in comments on this blog post or on the Sarcoma Alliance Facebook page: 

Wednesday, June 21, 2017

A rare opportunity

I presented the Alliance's poster at AACR.
By Suzie Siegel
Someday all cancers will be rare.

So says Rick Pazdur, MD, director of the FDA's Oncology Center of Excellence. As physicians and scientists learn more about genetics, they are breaking down cancers into smaller and smaller categories that may respond to specific drugs.

Dr. Pazdur spoke this spring to a group of advocates who won scholarships to attend the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C. I was the only sarcoma advocate in the Scientist↔Survivor Program, but that’s not surprising, considering sarcoma represents only 1 percent of adult cancer cases.

Carcinomas – what most people call cancer – are named for where they occur in the body, such as breast cancer or colon cancer. Sarcomas are named for the cells in which they are thought to come from. But sarcoma subtypes are now being divided still further.

Histological classifications are now supplemented by molecular subclassifications, which strongly influence prognosis and guide treatment decisions. More than ever, sarcomas are regarded as a complex and fragmented collection of uncommon entities, altogether rare and often extremely rare,” Jean-Yves Blay, MD, PhD, director of the Centre Léon Bérard in Lyon, France, wrote in Future Medicine. An example is liposarcoma, which arises in fat cells. It has been separated into well-differentiated, dedifferentiated, myxoid and pleomorphic liposarcoma.

Results of the largest study of sarcoma genetics were published last year, with more data coming from the Garvan Institute in Sydney, Australia. It leads the International Sarcoma Kindred Study, which is looking at the genetics of more than 1,000 people.

We also await more results from The Cancer Genome Atlas, a project of the National Cancer Institute in Bethesda, Md. Anna Barker, PhD, chair of the AACR survivor program, helped conceive and develop TCGA when she was deputy director of the NCI.  She is now co-director of Complex Adaptive Systems and director of the National Biomarker Development Alliance at Arizona State University in Tempe.

At the recent American Society of Clinical Oncology (ASCO) meeting in Chicago, a study was presented on an experimental drug named larotrectinib that targets TRK gene fusions. Some sarcoma patients should benefit.
The clinical trial was done basket-style, enrolling patients with different types of cancer. Getting enough sarcoma patients for meaningful research takes time; I think we benefit from basket studies that include people with other cancers. In a sense, many clinical trials in sarcoma have been basket studies because they enrolled people with different sarcoma subtypes.

Dr. Rick Pazdur
Companies need clinical trials to get their drugs approved. But Dr. Pazdur believes: “Clinical trials are here to serve the patient. Patients are not here to serve clinical trials.”

The FDA used to require companies prove that their drugs would help patients live longer. This can be hard to measure, in part because some patients have very advanced cancer by the time they go on a clinical trial. The FDA now approves some drugs if patients can go longer without their cancer progressing than they could on a standard drug. This change allowed trabectedin (Yondelis) to be approved for liposarcoma and leiomyosarcoma, for example.

I hope the FDA will use similar criteria to approve aldoxorubicin, which I wrote about in 2014.

Dr. Pazdur wants to expand access to clinical trials for patients who might not qualify because of how advanced their cancer is. He has suggested other innovations here and here. But he said he can do only so much because drug companies pay for almost all clinical trials. They control eligibility requirements, except where safety and a few other issues are concerned.

His desire to expand access stops at the “Right to Try” laws, which allow people with terminal illnesses to take unapproved drugs outside of trials. He said these laws directly contradict the Food, Drug and Cosmetic Act, which requires the FDA to oversee drug safety.

Trials are much more likely to be done in North America, Europe and Asia than in South America or Africa. That needs to be rectified, Dr. Pazdur said, to see if different populations respond differently to new drugs.

The AACR meeting drew 22,850 people from 60 countries, said CEO Margaret Foti, MD, PhD. She has spent 35 years with the organization and sees a much greater emphasis on cancer prevention.

Sarcoma researchers have been active in the AACR since its founding 110 years ago. The founders included Dr. William Coley, considered the father of immunotherapy, and Dr. James Ewing,  AACR’s first president. Dr. Ewing discovered the bone sarcoma that bears his name.  

George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston, is on AACR’s current board. He decries cuts in federal funding for cancer research. “I do not believe for one second this is what the public wants.” 

Dr. Drew Pardoll
Recent gains in immunotherapy show the importance of investing in science even when the payoff isn’t immediate, said Drew Pardoll, MD, PhD, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University in Baltimore. He has been working in the field more than 30 years.

“Cancer genetics has married immunotherapy,” said Dr. Pardoll, discussing how pembrolizumab (Keytruda) works in people with DNA mismatch-repair deficiency (MMR), which causes microsatellite instability (MSI).

After approving Keytruda last month for this genetic defect, the FDA noted: “This is the first time the agency has approved a cancer treatment based on a common biomarker.”

Stefanie Joho
The evidence for supporting immunotherapy stood by Dr. Pardoll’s side: Stefanie Joho of Philadelphia, whose colon cancer disappeared after she joined a clinical trial for Keytruda. She recalled when she was inoperable: “The doctors say there’s nothing they can do. There’s no more hope. I’m ready to give up. I basically feel dead.”

Then her sister found the study at Hopkins. “The public has a misconception of clinical trials. I did, too. I was under the impression they were the last resort. I’d just be a guinea pig. But right now, you could be getting the most precise treatment for your specific kind of cancer.

“How do you go through an experience like this and not want to advocate, not just for other patients, but for cancer research?”

Suzie Siegel, a 15-year survivor of leiomyosarcoma, is a former board member of the Sarcoma Alliance. 

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 Renée 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.