Dr George D. Demetri, MD, Quick Family Chair in Medical Oncology, Dana-Farber Cancer Institute; Professor of Medicine, Harvard Medical School, Director, Ludwig Center at Harvard; Associate Director for Clinical Sciences, Dana-Farber/Harvard Cancer Center
“I fully believe that we will have the chance to control at least 75% of cancers in the next 10 – 20 years. And I remain completely optimistic that everything we learn in cancer research will give us insights to provide better care in other diseases, including infectious diseases, blood diseases, heart disease, kidney diseases, and even neurologic diseases such as multiple sclerosis and Alzheimer’s disease. We live in a global community and the technology allows us to work across borders for the good of patients around the world. Just as democracy started in Greece and spread across the world, we see the scientific and medical advances spread across the world with breathtaking speed. We want to push that as fast as possible, because time really matters for each and every patient.”
Dr Demetri, you were included in the Thomson Reuters’ list for 2015, as one of the 27 most important Greek scientists in the world. How did you feel about this distinction?
I feel blessed to be serving in the medical profession and to have had the opportunity to practice research and clinical cancer medicine at a time when we could develop breakthrough therapies based on the application of science to patient care. It is a tremendous honor to have been included in that list which is based on how many time one’s work has been cited in the publications of other researchers. My professional satisfaction comes from having developed medicines which help people and give hope where there had been very limited hope in the past, and that is deeply fulfilling. Additionally, it has always been a great privilege to work collaboratively with so many talented and dedicated physicians and scientists around the world to advance the quality of scientific medicine and perform research rapidly with the needs of patients as our primary focus.
How close do you feel to Greece?
My Greek heritage is very important to me, it shaped so much of who I am today. Honestly, as a second-generation Greek-American, I always wish that I had learned to speak the Greek language better than I do, but Yiayia would speak to me in Greek, and while I understood, I would always answer in English – a typical 2nd generation pattern that limits my ability to find words on my own. I am so proud of our Greek heritage, and the democratic, philosophic and scientific principles that still serve as the foundation of our Western civilization.
What piqued your interest in your first professional steps and decided to deal with research on cancer and particularly sarcomas? To what extend did your family experiences influenced you in your decision?
When I was growing up in the mid-Hudson Valley of New York state there was always some member of my family who was undergoing therapy for some form of cancer. Those treatments were quite harsh in the late 1960’s and 1970’s, with many more side effects from radiation or chemotherapy than we routinely see today due to advances in technology. The personal losses of family members taught me, sadly, the needs of caregivers and family members as well as those of the patients. I was honored to be the first person in my family ever to get a University education, and then also to be able to go on to medical school. The mentorship of scientists and physicians at Harvard College and Stanford Medical School was key to my academic success, and the support of my family and loved ones has kept me focused on my work while balancing the importance of having a family and personal life. My research and clinical work on sarcomas was driven by the scientific pathways that were being uncovered in those fields in the late 1980’s and late 1990’s. It was clear to me that my generation had a huge opportunity to revolutionize the way sarcoma patients could be treated, and my collaborators and I seized those opportunities to help patients. It was an incredible time for “on the job training” as well, since we paved the way for efficient and effective academic-industrial research collaborations with large biotechnology and pharmaceutical firms who could help us develop our academic concepts into international clinical trials that could change the standard of care for patients around the world. This has been a humbling and wonderful experience, and I feel so grateful for the opportunity to have played the roles I have in the research and clinical care of these trials.
Why do you think it is important for both patients and their families to be acquainted with all treatment options?
Research is moving so quickly, and time is always of the essence. That is so clear to me, and it needs to be clear to patients. Our former US Vice President, Joe Biden, who lost his son to brain cancer, made it clear in his efforts to stimulate cancer research that time matters, that people’s lives depend upon expertise and time-sensitive studies to learn about cancer, and then share our learnings and apply those lessons to change the outcomes for cancer patients. It is key for patients and families to be viewed as partners with physicians and researchers, and not simply as passive “consumers” of “medical services”. I have learned an infinite amount from my patients and their families, and I have always viewed medicine as a two-way street. Communication is key to that process. The root of the English word “physician”, as I do not need to tell you, derives from the Greek “physiki” for one who studies nature, and who teaches others about that. This includes “human nature” and communication is such an important part of medicine, I cannot overemphasize that. Patients and families need to feel that they are hearing about all the options from their care team, and referrals to experts in rare diseases such as sarcomas are essential to top-quality care and optimal outcomes.
How critical is the time factor for the treatment of bone tumors from the moment of diagnosis until the time actual treatment starts?
Sarcomas originate in the bones only about 12% of the time. In most cases, sarcomas are tumors that can arise virtually anywhere in the body. The key for physicians is to be aware of these rare diseases and to keep them in what we call the “differential diagnosis” of any tumor. Most doctors may only see one or two patients with a sarcoma in their entire life’s practice. Here at Dana-Farber Cancer Institute, our team will see over 1,000 new sarcoma patient referrals each year, from all over the world. In addition to that, we perform internet-based, online formal consultations for patients around the world for whom travel to Boston may not be possible. There are at least more than 50 types of sarcomas and bone tumors – I actually think that number is far too low, and I often state that there are more than 500 different kinds of sarcomas. They vary from very slow-moving diseases which can subtly change over a decade to rapidly moving diseases which could prove lethal within weeks. We cannot oversimplify the complexity of sarcomas, which represent only 1% of cancers in adults and around 15% of cancers in children. Thus, the most important thing is for doctors to be aware that sarcomas exist and to consider them, while for patients to ask questions and to see whether referral to an expert center is a reasonable option.
Why do sarcomas are considered particularly hard to deal with?
Some sarcomas are among the most curable diseases, including many bone sarcomas called osteosarcomas or others called Ewing Sarcoma. The sarcoma known as GIST (Gastrointestinal Stromal Tumor) used to be one of the worst and most feared sarcomas because no therapy worked at all. That all changed with the drug called Glivec (spelled “Gleevec” in the USA), based on new scientific understanding of what fundamentally drives that type of sarcoma. By blocking that driving force (which came from a mutated gene and an abnormal enzyme inside the tumor cells), we could effectively shut down the tumor, often for many years. I still see some of the patients who originally started taking the Glivec in the year 2000, 17 years ago. That is a transformational thing for a patient, but also for an oncologist.
Why isn’t tumor biopsy a safe indication for the type of tumor?
Expert biopsy of sarcomas is, in fact, safe: please let’s be clear on that so that patients and families are not scared inappropriately. However, if the biopsy is done in the wrong way, there can be a risk of spreading the tumor in the area of the biopsy so that more extensive surgery might be needed. That can adversely impact function for the patient, and that is to be avoided of course. We are doing so well these days to help patients keep normal function, and surgical expertise in sarcomas is a very important skill.
How do new technologies open “new paths” to the understanding and development of tumors and lead to better treatment options?
The best example is the GIST example above. As soon as the “driving force” known as a mutation in an enzyme called “KIT” was identified in GIST, we used a pill that was identified as a KIT inhibitor to shut down the tumors. Similarly, there are several other such “smart drugs” that have been developed for GIST, and also for other sarcomas. The key is in taking clues from the molecular biology of the individual sarcoma to make the right diagnosis, and then to use the best current technology and science to see whether we can address that mechanism to improve the outcomes for that patient. It sounds easy, and it should be simple, but biology is dauntingly complex – nonetheless, our team has gotten at least 5 new drugs for sarcomas approved by the European Medicines Agency as well as by the US Food and Drug Administration to make safe and effective new therapies available to patients and improve the standard of care around the world. The pace of research is accelerating too, as success breeds more success. The application of science to sarcomas in patients is very exciting, with potential to increase cures and certainly improve how well patients can live.
In your research field, you study the possibility of finding the patient’s tumor type with a simple blood draw, and not using tumor biopsy. Tell us about this technique called BEAMING.
One of the most exciting applications of science to medicine is the field known as “liquid biopsy”, or using a blood sample to detect tumors that are deep within the body. This sounds like magic, but it is all based on the fact that DNA is remarkably stable (that is why we can extract dinosaur DNA from bits preserved in amber, for example). A tumor deep in the body has cells that are constantly dying and being born, and as that happens, they release bits of tumor DNA into the bloodstream: that tumor DNA floats away from the tumor and can be sampled in a bit of blood from a vein in the arm, for example. Using sophisticated machines, we can “read” the DNA code (written in 4 “letters” of chemicals called A, T, G and C) which is like reading the sequence of pearls on a necklace. We know what a normal human code is, and we can find abnormalities in the code that we read in the tumor DNA from the blood. One version of this test that we have used is called BEAMing, but there are several ways to do this now. It allows us to appreciate the incredible diversity of tumor cells in any one patient, and to track the evolution of cancer in every person with a simple tool. It is still investigational, but in 10 years, I suspect this will be one part of the standard of care to help doctors track patients over time, and possibly even to screen for the first appearance of a cancer even before it could be found with the most powerful CT scanners.
How can BEAMING technology help “unlock” other type of cancers as well? Where has you research led you so far?
The “liquid biopsy” tools can help us to understand the full complexity of cancer in ways we never thought possible. We know that each person’s DNA is different (except in identical twins – and even in twins there are subtle differences). We certainly know that the tumors of different people are different, since their DNA is different. But we are beginning to realize just how different tumors are: even in one tumor from one patient, if you look at the DNA in different corners of the same tumor, you may see dramatic differences in the DNA code. That is because most tumors do not copy their DNA with high fidelity: they make mistakes, and so each cell in a tumor will differ. Some people use the “snowflake” analogy – each snowflake is subtly different, but if you get a lot of them together, you get a snowball and cannot see the variations. Same for tumor cells. By examining the genetic code of tumors in the tumor DNA found in a person’s blood, one can analyze the summation of all tumor cells in the body. You take a “national census” of the tumor burden, rather than just knocking on the door of one house and asking questions of that one person who answers the door (to use a clumsy metaphor). This has the potential to advance our cancer research just as global search engines such as Google have changed our ability to access information about life in general.
Why do you think it is more valuable to study the DNA of tumors of patients who are not responsive to a specific treatment?
We are looking at the DNA and other codes of tumors that do not respond, as well as those that respond exceptionally well, to understand the basic mechanics of cancer. We still do not know all the rules that govern how cancer cells grow or survive, and how that varies across cancer cells as heterogeneous as they are, and across tumor types, and across individuals in populations. We would love to PREVENT even more cancers than we do today, and by understanding the mechanisms, perhaps we can do that better and at a much more reasonable price than the high prices of cancer therapies today. Most importantly, we are all looking for the most effective ways to manage cancer, and that is likely in preventing cancer in the first place whenever possible, and catching it early if not possible to prevent it completely.
How do you think medical practice will be carried out in the near future? Which will be the role of new technologies?
It is clear that the most exciting new technology is the activation of the human immune system to fight cancer. We are just beginning to understand how to do this safely and with great effectiveness. We just published a report about the very first patient in the world with a type of a sarcoma called leiomyosarcoma who had an exceptional response to one of these new immune-activating drugs. This patient had metastatic sarcoma in several places in her body, but after this treatment started, most of the tumors rapidly shrank – only one large tumor continued to grow, and eventually that was taken out and studied. We now think we understand why the growing tumor was resistant to the treatment, and why the other tumors were able to be controlled. And the good news is that this patient is still on the immune drug, living a healthy and productive life, more than two years after starting the therapy. That is a major step forward. This type of immune therapy is much more active in other types of cancers, like lung cancers and the skin cancer called melanoma, and understanding how to make it work better for all cancers will be a key step forward.
Which illnesses do you think man will be able to “beat” in the near future?
Define “near” when you say “near future”. I think there are several other rare cancers, like epithelioid sarcomas and sarcomas with an NTRK gene translocation, which will be controlled and successfully managed even in the next 1 – 5 years. I fully believe that we will have the chance to control at least 75% of cancers in the next 10 – 20 years. And I remain completely optimistic that everything we learn in cancer research will give us insights to provide better care in other diseases, including infectious diseases, blood diseases, heart disease, kidney diseases, and even neurologic diseases such as multiple sclerosis and Alzheimer’s disease. We live in a global community and the technology allows us to work across borders for the good of patients around the world. Just as democracy started in Greece and spread across the world, we see the scientific and medical advances spread across the world with breathtaking speed. We want to push that as fast as possible, because time really matters for each and every patient. ⨯