For cancer patients, liquid biopsy is a term that is applied when the fluid in blood, saliva, or urine is used identify tumor cells, tumor DNA, or tumor RNA.  Blood is perhaps the most commonly used source and, in the case of thyroid cancer patients, provides an opportunity to compare with the traditional tumor markers used to monitor patients, such as thyroglobulin or calcitonin. There are several perceived clinical benefits of liquid biopsy.  These include roles in early detection of cancer, molecular diagnosis, prognosis, detection of progression or response to treatment, and finally in uncovering mechanisms of resistance.  Compared with tissue biopsy, it is considered a less invasive approach because patients do not need to be subjected to additional biopsy of the tumor itself for the purpose of studying tumor genetics.  Furthermore, liquid biopsy provides an opportunity to study tumor when biopsy is not possible because of tumor location or previously removed specimens are not available for testing.   These perceived benefits are slowly becoming a reality for management of thyroid cancer patients.

 

At MD Anderson Cancer Center our group is exploring the role liquid biopsy as a clinical tool for patients with papillary (PTC), medullary (MTC), and anaplastic (ATC) thyroid carcinoma.  At the ITOG meeting, I presented our findings related to the analysis of circulating tumor DNA, which is released into the bloodstream when tumor cells die. Circulating tumor DNA is detected by looking for specific mutations that may have caused the cancer to grow, known as “somatic driver mutations”, using either cutting-edge digital polymerase chain reaction (PCR) or DNA sequencing techniques.  PCR provides a more sensitive tool for detecting known mutations like BRAF V600E or RET M918T, while DNA sequencing provides a broad discovery tool typically to examine a panel of “hot spot” mutations.  Neither of these tools is currently sensitive enough to play a singular role in early detection or molecular diagnosis. In PTC and MTC patients with tumor-defined driver mutations, the concordance between the digital PCR-based liquid biopsy and mutations actually found within the patient’s tumor is less than 50%. However, in ATC patients, where growing tumor burden is typically much higher, the concordance between tissue and liquid biopsy has exceeded 80%.  As a result, the Anaplastic Thyroid Cancer (“FAST”) team at MD Anderson is now able to put patients on appropriate targeted therapy in greatly shortened time frames, a major victory when trying to treat a rapidly growing and fatal cancer.  Where liquid biopsy is likely to have more of an impact in all three cancer types is in detection of progression and response to treatment.  For example, in MTC patients we have found that the detection of circulating DNA containing RET M918T mutation is a better predictor of survival than calcitonin doubling time. Furthermore, for all three cancer types we are starting to see examples where a reduction in the level of circulating tumor DNA detected by liquid biopsy coincides with a response to treatment. In ATC, where there is no existing standard tumor marker, liquid biopsy could be utilized as an early indicator of response, or lack thereof, to treatment. These studies are underway under the direction of Maria E. Cabanillas.

 

Where we are now is that we have evidence that validates that liquid biopsy, at least the measurement of circulating tumor DNA, can guide how we treat some thyroid cancer patients with systemic therapy. Where we are heading is trying to determine how best to implement these findings into routine clinical care.