Chondrosarcoma is the most common form of primary bone cancer occurring in adulthood, but it is underfunded and difficult to accurately diagnose. Improvements in diagnosis are desperately required in order to advance treatment planning and in turn, improve patient outcomes.
Background of the research
Chondrosarcomas are classified as low, intermediate, or high grade, and the treatments for these classifications are different. Low-grade tumours are treated with less invasive surgically techniques. Whereas high grade tumours are treated more aggressively and require surgery that removes a section of the affected bone. The difference in treatment is because high grade tumours have a higher risk of recurrence and spread to other parts of the body. However, distinguishing between low-grade and high-grade tumours visually (which is done by pathologists using a microscope) is not always straight forward. Therefore, deciding on the extent of the surgery that is required can be challenging.
The purpose of this research was to identify a biomarker that could be detected and quantified in the blood of chondrosarcoma patients that could be correlated to the severity of the disease and therefore could be used to predict the grade of the tumour more accurately, allowing surgeons to be correctly informed on the surgery each patient requires. It was also hoped that the blood test could be used to monitor patients routinely and detect the very early stages of recurrence and catch this before the chondrosarcoma begins to spread.
Results
Chondrosarcoma tumours, particularly higher-grade ones, present mutations in the IDH1 or IDH2 genes.
Small pieces of DNA find their way from cells into the blood stream. The DNA fragments that are released by tumour cells into the circulation are known as Circulating tumour DNA (ctDNA). Circulating tumour-derived DNA (ctDNA) can be measured and characterised using sensitive techniques from a simple blood sample and are therefore ideal biomarker candidates.
The project, led by Professor Adrienne Flanagan at University College London was a multi-institutional study. Thanks to Infrastructure Grant funding from the Bone Cancer Research Trust, samples donated by chondrosarcoma patients were collected by the bone cancer specialist centres at Newcastle, Birmingham, Stanmore, and Oswestry. The study opened in October 2017 and closed at the end of December 2020, which included a six-month extension due to the COVID pandemic. The study recruited 145 patients.
Professor Flanagan and her research group have developed a promising new blood test which detects circulating tumour DNA (ctDNA) containing the IDH1/2 mutations. The levels detected are seen to be high before surgery and drop off after surgery. IDH1/2 mutations were detected in 80% of tumours. Detection of ctDNA containing IDH1/2 mutations was more accurate than pathology for identification of high-grade tumours and was associated with a poor prognosis. ctDNA containing IDH1/2 mutations was never associated with chondrosarcoma grade 1/atypical cartilaginous tumours (ACT) in the long bones, in tumours of the small bones of the hands and feet or in tumours measuring less than 80mm.
These very promising results offer pathologists an accurate and reproducible tool to diagnose and stage chondrosarcoma, informing clinical management and deciding the type of surgery a patient needs. They also provide a non-invasive way to monitor patients and detect the early stages of recurrence, before the disease spreads, allowing further surgical intervention. However, they are still based on a relatively small number of patients.
The introduction of this minimally invasive blood test into clinical practice would allow the research to be assessed more stringently and hopefully developed for a more personalised approach for the treatment of patients with chondrosarcoma.
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