Osteosarcoma is the oldest known form of cancer. It has been found in proto-turtle and dinosaur fossils from hundreds of millions of years ago, early hominid fossils from millions of years ago, and in mummies and skeletons which have been dug up or found throughout the ages going back thousands of years. Unlike some cancers, it occurs in people of all backgrounds, ethnicities, and races, all over the world. It occurs in many vertebrate animals: dogs, cats, rabbits, and a whole host of other animals, and some we probably do not know about because we have no data.
Osteosarcoma occurs more frequently in boys than girls (around 60-65% boys, 35-40% girls) and has been correlated with above average height, but anyone of any background of either sex, tall or short or average can get osteosarcoma. It does not discriminate. The average age at diagnosis of a primary osteosarcoma is about 15-17, but it can occur at any time between the ages of about 5 and 40. The peak distribution is between 10-25 years of age. Girls typically get osteosarcoma at a slightly younger age on average than boys, but the difference on average is maybe a year to a year and half younger. Cases younger than 5 and over 40 do occur but are quite rare.
There is a type of secondary osteosarcoma which generally occurs in older adults which is usually the result of treatment from a previous cancer, usually from radiation or a bone disease such as Paget’s Disease of the Bone. Osteosarcomas are known to have very diverse clinical presentations: some explode like wildfire and kill within months in spite of surgery and chemo, while others linger and smoulder and take many years to kill, and yet others are themselves killed by the chemo and surgery.
It’s a mystery
Some localized osteosarcomas metastasize on treatment, while others which are metastatic at diagnosis clear up on treatment. Some osteosarcomas relapse very quickly off treatment, while others wait many years, sometimes a decade or more before relapsing. Some patients with 100% cell necrosis to MAP relapse and die, and some patients with 0% cell necrosis survive. While most osteosarcomas when they metastasize, metastasize to the lungs, other do not and go to the bone or lymph nodes either in place of or in addition to the lungs. While most osteosarcomas do not respond to standard radiation, some do. Osteosarcomas are among the most mutable and resistant of all cancers and no one knows why.
Osteosarcoma is the prototypical “disordered chromosome” cancer, but is this because of the gene TP53 or something else? The extremely aggressive osteosarcomas appear to disproportionately affect younger patients, and the somewhat slower growing osteosarcomas appear to affect more older patients. However, the shortest time from diagnosis to death that we know of for an osteosarcoma patient was 73 days for a patient in their 30s, while the longest time that we know of between diagnosis and death is 27 years for a patient originally diagnosed as a teenager. The only known genetic difference between younger and older patients is that MYC amplification (aka chromosome 8q22 amplification) which is strongly correlated to an extremely poor prognosis shows up disproportionately in osteosarcoma patients under the age of 25 (about a quarter vs about 3%).
Younger patients are also more likely to have a high number of genetic amplifications in their tumors – some of which may indicate the presence of extrachromosomal DNA (ecDNA). Osteosarcomas have a number of different histologies: osteoblastic, chondroblastic, small cell, giant cell, telangiectatic, mixed, and some other rares histologies. There is no known clear correlation between response to chemo and survival and type of osteosarcoma histology (histology is a categorization of what the tumor cells look like under a microscope to a pathologist — there is no known correlation with the underlying tumor genetics and histology at this time).
No one knows
Why this diverse clinical presentation? No one knows. Why do some osteosarcomas respond to chemo and others do not? No one knows. Why do some patients relapse and others do not? No one knows. Why do some patients with 0% necrosis survive? No one knows. Why do some patients with 100% necrosis relapse and die? No one knows. What is the driving gene behind osteosarcoma? Based on the TARGET study paper publication, as well as other studies done at University of California San Francisco and Dana Farber Cancer Institute, TP53 is the driving gene behind osteosarcoma. What are the driving oncogenes in osteosarcoma? No one knows. Why does the tumor mutate so quickly? No one knows. How is the tumor regulated epigenetically? No one knows. What is the genetic landscape of osteosarcoma and how does it correlate with prognosis? No one knows. What is the epigenetic landscape of osteosarcoma and how does it correlate with prognosis? No one knows. How does the immune system interact with the tumor? No one knows. What effect does the tumor microenvironment have and how does that correlate with prognosis? No one knows. What causes osteosarcoma? Or what series of events cause osteosarcoma? No one knows.
These are very basic and very important questions about osteosarcoma, and the answers are unknown. Some of these questions have theories but no real data. Some have some anecdotal data which might give a clue but as yet have no statistical significance to them. The bottom line is that no one really understands this disease or knows very much about it at all. This is why doctor after doctor has said that this disease is so “difficult” to treat. And we believe that it is because so little is known about this disease that we are in the same situation as we were about 30 years ago with regards to osteosarcoma treatment and outcome. Afterall, how can we logically attempt to find new treatments and more cures if we do not understand basic questions about the disease?
This lack of knowledge and understanding of the disease causes the medical profession to give up, not because they want to and certainly not maliciously, but because they have so many other pressing concerns and issues, and “easier” cancers for which they can advance treatment apparently much more easily. They also have other groups of parents and patients agitating and pushing for research and new treatments and providing funds for that research. We all know that the squeaky wheel gets the most attention. Osteosarcoma has been a very well-oiled wheel, and consequently it has gotten little attention. This has been changing over the last couple of years and the difference in the doctors and researchers is noticeable.
We think difficult is not a reason to stop trying to find answers and improve treatments and cures. Difficult does not mean impossible unless we let it mean impossible. Difficult simply means that we need to think outside the box, approach the problem differently, and see what we can find out with all of us pushing and advocating for our kids and ourselves. The Osteosarcoma Collaborative believes where the parents and patients lead, the doctors will follow; that working together we can and will make a change in the understanding and treatment of this disease. One day, when someone hears the words, “You have osteosarcoma”, it will not result in the incredibly scary, terrifying, and horrifying experience that we have today. Together we can make “difficult” become “possible”.