A place to start if you or your child has been diagnosed with SEF.
If you are reading this and you, your child, or loved one has recently been diagnosed with Sclerosing Epithelioid Fibrosarcoma (SEF), first let me say I am deeply sorry. I know how it feels; it is excruciatingly difficult to cope with; you may feel helpless; you may feel overwhelmed by the many difficult decisions that lie ahead. This is normal and to be expected.
Second, let me say that we are here to help you. I hope you will find this letter as a good place to start, and that it will be encouraging rather than overwhelming. As the cliché goes, this is the start of a marathon, not a race. It is a marathon that I have already started and I have gotten pretty far. I am here to welcome you and hopefully help you start this challenge much further along than if you had started it alone. This marathon also may have many forks in the road and potholes along the way, but we hope to be able to provide guidance and information that may help in your decision-making along your path.
I often wonder if I could go back in time when Rucker was first diagnosed, and knowing what I know now, whether or not it would have made a difference. During the two and a half year fight to save my son, I learned not only just about cancer and rare diseases, but also how to learn about them. I learned how to navigate medical journals and literature and how to seek out and find experts in the field. I want to share some of these practical skills here. Although the subject matter below is about SEF, this framework may be helpful to anyone facing a rare disease of any kind (and collectively there are many). Accordingly, please feel free to share this with anyone you know facing a rare disease.
Step One: Get The Correct Diagnosis.
With rare cancers, getting the correct diagnosis is challenging. Your oncologist should have already begun this search for a “diagnosis” or a label for your cancer. You need to be certain that it is the correct one, and the most specific one you can get. Many of the more difficult-to-diagnose forms of cancer might be grouped into a larger catch-all bucket, such as “undifferentiated sarcoma.” While this may be the correct starting place, I believe that continuing to search for the most specific diagnosis you can find will prove to be instrumental, especially if you face a recurrence after frontline treatment. It may not change your initial treatment plan (but in our case it did!), but it will almost certainly help you later if you need it.
You need to advocate for and seek out expert opinion(s) in order to ensure that you receive an informed and hopefully precise diagnosis. The tumor tissue should be evaluated by a capable pathologist and in some cases even an expert soft tissue sarcoma pathologist. After that, appropriate genetic profiling should be performed, if called for. For example, in Rucker’s case, we started with a diagnosis of “sarcoma otherwise unspecified” from our home pathologist. We then had Rucker’s biopsy sent to several leading pathology institutions to help in the hunt for the correct diagnosis. But even after all of that brainpower was used to look at the slides of Rucker’s tumors, the best guess we had at that point was Clear Cell Sarcoma of the Kidney. It was not until we had genomic testing done that we were able to better refine the diagnosis and be certain that it was, in fact, Sclerosing Epithelioid Fibrosarcoma (SEF). Rucker’s tumors have a chromosomal translocation, or what is commonly referred to as a fusion (where one gene is fused with another in error). About a third of all sarcomas are driven by these translocations. In Rucker’s case, his fusion was called EWSR1-CREB3L1. Most SEF cases have this fusion or a couple of others (more on that in the literature section). The primary point is that genomic testing can be vital to ensure the correct diagnosis is made, which will determine which path you begin down for therapy. Having an expert pediatric soft tissue sarcoma pathologist lead the diagnostic workup may make it much faster to reach the correct diagnosis than what we went through. Through our Medical Advisory Board and their knowledge of the experts, we would be happy to make a referral to you and your oncologist if we can.
Step Two: Find the Experts.
Perhaps the most vital step in your journey is to find the most experienced and appropriate expert in your type of cancer. The key is to find an expert who can tell you how to learn more about your or your child’s tumor and who can help you uncover new and potential treatment options.
So, search for the best experts on SEF (or whatever disease you are facing). At a minimum, find a provider who specializes in rare sarcomas, or seek out a Sarcoma Center. While it is extremely rare . . . some doctors have direct experience treating SEF (I have provided a list below from my personal experience). If your oncologist does not have any background treating SEF, reach out to one who does. Your oncologist will, and should, encourage this and can help you make the proper connections. If not, you can do it on your own.
Upon Rucker’s recurrence, after we learned that his frontline therapy did not work and his disease had spread, I put together a handout in PDF form, with the intent to circulate it and get it in the hands of someone that could help us. In it, I outlined Rucker’s clinical synopsis (with input from our oncologist, Dr. Wadhwa) and what we were searching for and in need of. I circulated this PDF to people whose papers I had read or who were referred to me as specialists in pediatric soft tissue sarcomas. Through this method, I eventually found Dr. Sheri Spunt, who is thought of by many as a leading expert in pediatric soft-tissue sarcoma. I’ll save you some time . . . if your child has SEF or another rare soft-tissue sarcoma, contact Dr. Spunt. Here are a few oncologists that we have personally been to see for Rucker, all of whom would be highly recommended by us:
Dr. Aman Wadhwa Children’s of Alabama Birmingham, AL https://www.childrensal.org/dr-aman-wadhwa-md-msph-hematology-oncology
Dr. Sheri Spunt Lucile Packard Children’s Hospital/Stanford Palo Alto, CA https://profiles.stanford.edu/sheri-spunt
Dr. Steven DuBois Dana-Farber Cancer Institute/ Harvard Boston, MA http://www.danafarberbostonchildrens.org/finddoctor/details.aspx?ID=30260
Dr. Douglas Harrison MD Anderson Cancer Center Houston, TX https://faculty.mdanderson.org/profiles/douglas_harrison.html
This is a framework you can use for any rare disease. Ask your treating oncologist who the known sarcoma experts are, or seek out those who write papers on the subject, and ask for a quick phone call. Get to know them and ask for their advice. You will find experts willing and able to help. They will point you in the right direction. For example, after Rucker’s second and third lines of treatment did not work, we began to search for treatments that were truly novel and at that point worth exploring and considering. Through that search I was introduced to Dr. Charles Keller, who founded the Children’s Cancer Therapy Development Institute in Portland, Oregon or CC-TDI. Through Charles, I further expanded my network and met quite a few parents in similar situations. I had many calls with them to hear their stories and learn from their experiences. Next, I went to meet with Charles and visit their lab in Portland. I liked what I saw and found Charles to be an extremely knowledgeable and helpful ally in my fight for Rucker.
The main point is that you should find the experts to better inform, or better yet, lead your clinical decision-making.
Step Three: Learn the Material and Read the Literature
There is no substitute for knowledge. If you read the following pieces of literature (linked here and on this page below) and begin to understand the science of your disease, you will very likely end up knowing as much (or more) about SEF as most practicing oncologists do. Practically, they do not have enough time in the day to deeply understand the specifics of each cancer they must treat on a day-to-day basis. You are your best advocate. Through your knowledge and understanding of your disease, you can direct your clinical decision-making with your oncologist in a way that you would not have imagined at the beginning.
I have linked below many of the papers I have read in order to better understand cancer, sarcoma, SEF, immunotherapy and targeted therapies. If you find a particular paper of interest to your specific case, do not be afraid to reach out to the authors. They are real people – people who care about the subject matter enough to put their life’s work into it in some cases. They can help! I made many connections through this method that proved helpful in our search for the next best treatment for Rucker. Also, if you read a portion of a paper that interests you, look up the sources (documented throughout the footnotes). Then read that source material . . . and so on. This practice will take you down many avenues worth exploring and will further your knowledge of the subject.
As a side note, these pieces of literature are not always free. If you find an article that requires payment in order to access the full document, first try copying and pasting the title into Google Scholar to see if it may be available for free somewhere else. You also may need to ask your doctor or anyone who works for a medical organization to use their subscription to download them for you. Another way to potentially access it for free is to email the author and request a re-print. And, if you are not afraid of breaking the rules to help yourself or your child (which I was certainly not), then google “Sci-Hub” and go to it to find free copies of medical literature (they claim to “remove all barriers in the way of science”). Knowledge is power. The only way to properly advocate for yourself or your child is to learn as much as you can about their disease.
Step Four: Consider Getting Genomic Testing and Stay Informed of Cutting Edge Technology.
Because targeted therapy is a hopeful treatment option for SEF and other rare cancers, genomic testing of the tumor is extremely important. Advocate for genomic testing to be done now on your tumor. If your oncologist has not already, I suggest that you push for it to get done. Your oncologist should know how to do this; if he or she does not you need to find one that does. Consult with an expert who can ensure that the tumor is profiled and evaluated with the latest technology. Again, if you have found the experts, they will already be aware of genetic profiling and the latest technologies available.
Genomic testing will not only help to ensure that you have the correct diagnosis, but it will also help guide any targeted therapies you might consider down the road. This information can become vital in your treatment. Importantly, you should also ask for a copy of the data underneath the general report you get back from this testing. This data can be mined by genomic analysts for potential treatment targets. If possible, ask for deep sequencing of both DNA and RNA. DNA provides some of the answers, and especially may help in your diagnosis; RNA further shows expression levels of genes that may prove to be good targets for therapies.
Genomic testing should be covered by insurance; however, sometimes it is not. If that is the case, do not give up. Your doctor should be able to make a solid appeal for why it is necessary to diagnose and treat your rare cancer. If he/she fails to get it covered, do not quit. Ask the company for a compassionate use or financial assistance programs, which they have. Another route is to find a trial where they are doing sequencing as part of it. Although we had already gotten DNA sequencing done through Foundation Medicine in order to get the proper diagnosis of Rucker’s tumor, we also put him in a trial at Stanford to get the RNA sequencing.
Then if all of that fails . . . we want to help. We believe it is that important. We will get your out of pocket expenses taken care of through our foundation. The point is . . . do not accept no as the answer. Demand genomic testing; it may just save your life.
Here are a few links on genomic testing that may be informative:
https://www.cancercenter.com/treatment-options/precision-medicine/advanced-genomic-testing
https://www.cancer.gov/about-cancer/treatment/types/precision-medicine/tumor-dna-sequencing
https://www.foundationmedicine.com/test/foundationone-cdx
Step Five: Prepare for Recurrence or Progression and Start Forming Plan B, C, D and E, NOW.
Due to SEF being considered an “aggressive” cancer, oncologists are usually (rightfully so) eager to start treatment. Therefore, if you have received a diagnosis of SEF you are likely already underway with some form of frontline treatment, whether it be surgery, radiation, chemotherapy, or a combination thereof. If you catch it early and your cancer is localized (prior to it metastasizing or spreading to other parts of your body from where it originated) then surgery has proven to be the most effective form of treatment. For SEF, as with most sarcomas, if you can safely cut it out – do it! However, if it has already metastasized, then you are likely under a combination treatment of all three of the above-mentioned therapies because you will likely need a systemic (or full body) approach to treat your cancer.
There will be a general playbook that most oncologists begin with, and it is important to discuss your treatment plan with your treating oncologist. For SEF, treatment will most likely be under a broader sarcoma protocol. They would refer to this as “front-line treatment” or following the “standard protocol.” This approach is the most proven, best treatment to try based on the current evidence available. While ethically and logically that is what oncologists are obligated to do, practically, I believe you need to prepare for what to do next, should this initial treatment prove to be ineffective. I do not want to scare you, but the reality is that SEF is considered to be “aggressive” and if you don’t get it all out it will likely spread. Moreover, when the disease has spread, it is not historically responsive enough to the accepted front-line chemotherapies to be eradicated from your system. It is always good to be working on your next plan of attack, should the current one prove to be ineffective. That is how oncology works . . . you try something . . . then if the cancer spreads . . . you try something else. It is logical, but something you should prepare for in advance. The moment you learn that your disease has progressed is a time that may be filled with emotions and stress and grief and despair. Having already made the plan for what is next will save you critical time and the stress of having to rush and make another major clinical decision. Below are examples of secondary and/or alternative treatments that might end up replacing the historically recognized frontline protocols for rare sarcomas.
Immunotherapy
Given that traditional forms of therapy have proven not to be very effective against metastatic SEF, immunotherapy is a very interesting area of potential future effective treatments. Study up on it. Learn about how to harness your own immune system to fight your cancer. CAR-T therapy is one such form, where they engineer your own immune cells (T-Cells) with an antibody that sticks to the known antigen that is highly expressed in the cells of your cancer. Thus guiding your own immune cells to kill the cancer. I believe in the next 10 years, this very area will provide a cure for SEF and many other cancers as it is already doing for blood cancers.
Immune Checkpoint Blockades (ICBs)
There are also other systemic immunotherapies, such as immune checkpoint blockades (ICBs). They work by knocking down immune checkpoints (things that effectively tell your immune system to leave the cell alone). These ICBs did not prove to be very effective in many sarcoma or cancers like SEF as monotherapy, but they are being tried in combinations that are beginning to show efficacy in similar solid tumors and may be worth exploring in a trial setting such as:
https://clinicaltrials.gov/ct2/show/NCT04416568?cond=Epithelioid+Sarcoma&draw=2&rank=6
Important Update (1/13/2021): Please read our news post on this therapy showing clinical benefit. Also this recent publication on two case studies can be found here:
https://ascopubs.org/doi/abs/10.1200/PO.20.00201
This is big news!
Antibody Drug Conjugates (ADCs)
Targeted therapies are a very promising area of oncology. Some forms of cancer that were once deadly can be cleared with something as simple as taking a pill daily. Some routine infusions of very low side effect medications are effective as well. Antibody Drug Conjugates (ADCs) are another such targeted therapy, using antibodies to home in on specific antigens found on target cells. However, instead of immune cells as in CAR-T, there is another payload, such as a cytotoxic chemical or radioactive material. We used this when Rucker’s disease spread to his leptomeninges (brain and spine linings) in the form of Omburtamab, a radioactive monoclonal antibody targeting B7H3 (which was shown to be highly expressed in his RNA sequencing). Think of ADCs as a guided missile instead of an atom bomb (traditional chemotherapy).
If given the proper molecular target, small molecules, antibody-drug conjugates, CAR-T cells, and other targeted therapies give me reason to be optimistic about the future of oncology. There will come a day where we will look back and think it to be very crude and archaic that we once used toxic chemicals systemically to treat cancer.
Become familiar with this site. On it you can search for your specific diagnosis, which in the case of SEF will be very limited or non-existent. However, you can use search for broader terms like “Soft-Tissue Sarcoma”, or “Refractory Solid Tumors”, or “Sarcoma” to find trials for which you might qualify. You can also search for targets (targets you have identified from your genomic analysis). This is a free public tool that may be where you find the next best therapy to try for you or your child.
Step Six: Research the Targets.
What I found through my research on SEF is that while there isn’t much literature or research specifically on SEF therapies, there are genomic characteristics of Rucker’s tumors that are similar to those of more common cancers, that do have a lot of funding and research around potential therapies. Once you find that certain genes are very highly expressed in your tumors, you can then search backward for therapies that might be targeted to those same genes or proteins, albeit with a different diagnosis in mind. I think of this as bottom-up research, starting with the genomic profile of your cancer irrespective of the diagnosis. I believe this is how most cancers will be treated 10 years from now.
For instance, Rucker’s tumors and other SEF tumors in the literature have a common genomic expression, CD24, with ovarian cancer and triple-negative breast cancer. CD24 is a very compelling target for therapy; however, it is still too early for CD24 targeting therapies to be ready for clinical use. I studied this target extensively and I recommend that you should stay informed of its developments and be prepared for them to come out over the next few years. This is a highly promising target for SEF!
CD276 (or B7H3): This is a very promising target as well. It is being used in several immunotherapy drugs already in existence, one of which is a CAR-T therapy that I am very interested in. I have gotten to know two researchers who worked extensively in the lab on it (Dr. Rimas Orentas, of Seattle Children’s and Dr. Robbie Majzner of Stanford).
They believe it to be very promising and are very excited to see their work brought to the clinic. CD276/B7H3 was highly expressed in Rucker’s tumors according to the RNA sequencing, which is why we were optimistic about its potential as a therapeutic target. We were planning to enroll him in the Seattle trial (mentioned below) as soon as they opened up enrollment for his age group. Unfortunately, while we were waiting, Rucker’s disease spread into his central nervous system (into his leptomeninges), which caused us to have to change our treatment course and attack his LM disease. Although he did not make it to the trial, it is now open and very worthy of consideration.
Please read more at clinicaltrials.gov about them and ask your oncologist if it makes sense for you.
https://clinicaltrials.gov/ct2/show/NCT04483778?term=STRIvE-02&draw=2&rank=1
Gaining access to targeted therapies:
If you find a targeted therapy that overlaps with a specific genomic characteristic of your tumor and there is a compelling scientific rationale for its use in your case, then here are a few steps you may want to take:
Step One: Inquire with your oncologist whether or not it is FDA approved for use. If it is, your oncologist may be able to prescribe it for another diagnosis. If not, it is likely only available through a clinical trial.
Step Two: Use clinicaltrials.gov to search for available clinical trials for this drug therapy. Usually the website of the drug manufacturer will have links to available trials. The best and safest way to use these drugs would be through a clinical trial, so if you qualify for one of those, start there. However, you will likely find that you don’t qualify for the trial due to not having the specific diagnosis they are treating, such as “Ovarian Cancer.” Also, there are often many inclusion criteria that you must meet and exclusion criteria that you must not have in order to qualify for trial. It is very likely if you have a rare cancer, such as SEF this will keep you from participating in many trials.
Step Three: Don’t give up, there is still a way forward. You can go to the manufacturer and ask for “expanded access,” sometimes referred to as “compassionate use” of the drug. This is how we gained access for the use of Omburtamab for Rucker. Y-Mabs Therapeutics, who makes the drug, allowed us this use even though Rucker didn’t have Neuroblastoma, the diagnosis for which the drug is FDA approved. I knew Rucker’s tumors highly expressed B7H3, which is the target that Omburtamab is engineered to attack. With the help of many of the experts that I counted on for advice, I also knew this was worthy of trying for Rucker, and the only targeted therapy for leptomeningeal disease which made sense for us to try. First, I went to the website of Y-Mabs, and started down the list of the leadership’s biographies. After reading the Founder and President’s biography (Thomas Gad), I knew he was who I needed to talk to. He is the father of a neuroblastoma survivor, and she is doing well today in large part due to Omburtamab. I sent him an email detailing our request, and outlining the scientific rationale for the use of Omburtamab for Rucker. He and I then had a phone conversation, and he was more than willing to help. If you are successful at gaining this access, next you’ll need to find a clinician, or oncologist, to run the single-patient investigational new drug (IND) trial. The drug manufacturer’s clinical team will help you find an oncologist with experience in the specific drug. In our case we chose Dr. Douglas Harrison, of MD Anderson. He was on the list that Y-Mabs provided us with experience in Omburtamab and we knew him from our previous trips to Houston. I called him and told him our intentions and he was also very willing to help. He and his team then did the hard work of writing the single-patient IND and getting the FDA to approve its use for Rucker. I tell you all of this to demonstrate that with good scientific rationale, and persistence, you can make it happen and gain access to drugs that at first glance do not seem available.
For more information you can explore the Compassionate Use Navigator, which a great resource for expanded access/compassionate use. https://www.kidsvcancer.org/compassionate-use/
Some Practical Tips and Advice
What do these codes mean?
A good resource for researching targets is Genecards. On it you can type in a gene or protein expression or something else that shows up in your genomic data and learn more about it as well as other aliases. To further complicate this issue, they can be called by different names. It would be shame if you missed out on the Seattle trial because they refer to the target as B7H3, only because you were searching for CD276 (even though they are synonymous). Genecards can help you figure out these targets and their various labels. https://www.genecards.org/
Set up Google Alerts:
Google is a great free resource that can connect you to all the relevant news and research articles about your cancer. Use their alert system to automatically alert you to news and publications on specific keywords. These alerts can give you the most up to date information on research and clinical developments, and takes a lot of the research burden off of you. For example, I get alerts almost daily based on the following keywords:
“Sclerosing Epithelioid Fibrosarcoma” “Soft-Tissue Sarcoma” “Advanced Soft-Tissue Sarcoma” “Immunotherapy for Soft Tissue Sarcoma” “CD24” “CD276” “B7H3” “MUC4” “NOTCH”
Facebook Groups:
Another great resource that my wife Katie found extremely helpful were Facebook groups. Under “groups” in Facebook, search for the name of the cancer you have and see if any groups have been formed for it. In our case, Katie found the “SEF Sarcoma Support” group. Many of these groups are not public so that patients can freely ask questions and support each other, so just click on the “join” button and ask to become a member. It is very helpful to find a network of those who face the same disease as you or your child. From there, you can ask others what doctors and hospitals have treated them and what experts are the most recommended.
Step 8: Let’s continue the fight to find a cure for SEF.
Although we lost the battle for Rucker’s life, we are not stopping our fight. In late 2019 we started a pilot study of SEF at CC-TDI in Portland. We realized that no big pharmaceutical company or other large research institution would spontaneously take on SEF as the subject of their research. Simply put, because rare and pediatric cancers arguably have small patient populations, they are not considered profitable for drug companies, which is why the more “mainstream” adult cancers (like breast and prostate) get much more attention. We knew that no one else was going to take on our cause for us. So we did it ourselves. Through our connection with Charles Keller at CC-TDI, we were able to fund and set up what is now the only known institutional research study on SEF. This research program is actively working to build a national registry of SEF patients, create genomic datasets, generate SEF cell lines and mouse models, and, most importantly, it is earnestly exploring therapeutic strategies which might be effective against SEF. Please read more on that here, as well as how to participate in this study if you or your loved one has SEF.
I hope that you will use my story and this framework to jumpstart you on your way to fighting for a cure for SEF (or any rare disease you may face). We want to help you start further in this marathon than where you would be without our experience. Please let us know if we can be of assistance to you as you face your own battle. This is our way of honoring our beloved Rucker; to carry on the work we have been doing. If we are a part of saving one life . . . and keeping one family from bearing the pain we are feeling now . . . all of this will be worthwhile.
Sincerely,
John Collier- Rucker’s Dad
SEF Study
In late 2019 we started a pilot study of SEF at CC-TDI. Through this program, we aim to create a patient registry, generate cell lines and mouse models, create genomic datasets, and, most importantly, explore therapeutic strategies which might be effective against SEF. Please read more on that here, as well as how to participate in this study if you or your loved one has SEF.
Literature
Here you can find the literature that I found helpful in my search for understanding and knowledge. Hopefully it will start you on the right path.