Initial work on liquid biopsies used whole genome sequencing to detect somatic copy-number aberrations. This procedure has an estimated sensitivity of 5% to 10% for detecting ctDNA and has been useful in identifying such variationsas focal androgen receptor (AR) amplification at the time of progression, despite castration.
Teams subsequently studied liquid biopsies of mCRPC patients to attempt to understand abiraterone resistance. Using sequential samples from mCRPC patients, biopsies were compared to known alleles that associate with resistance to advanced therapies. These groupings demonstrated a significant temporal heterogeneity of AR variation in terms of copy-number and AR-point mutations. Using these data, researchers have begun to identify specific gains/mutations that temporally relate to abiraterone resistance.
For instance, AR-gain aberrations are strongly associated with enzalutamide resistance. These sorts of irregularities are not uncommon: AR-gain variants occur in 14% to 34% of mCRPC biopsies, and AR-point mutations occur in 2% to 30% of mCRPC biopsies.
In an effort to formulate a clinically useful test for AR variation, Dr. Attard and others developed a multiplex droplet digital polymerase chain reaction test that can be used to detect AR status from liquid biopsies. At minimal cost and providing results in one day, this test has proven quite useful in studying resistance mechanisms and in identifying patients with disease progression. The test has high agreement with whole-genome sequencing for both copy-number alterations and mutations. Furthermore, it has high interlab reproducibility (r = 0.96). A potential downside, however, is that whole-genome data are not obtained from these biopsies since only certain gain and mutation aberrations are identified with this limited technique.
Recent work done using these technologies has demonstrated that AR status strongly associates with outcomes on abiraterone/enzalutamide in both chemo-naïve and post-docetaxel patients. To more completely evaluate these associations, a current biomarker trial is underway by the Spanish GU Oncology Group (SOGUG). The PREMIERE Trial aims to evaluate AR variation with survival outcomes in mCRPC men. Early results have shown that AR-point mutations emerge in 15% to 20% of patients progressing on abiraterone, which may lead to new therapeutic opportunities for those identified with disease progression in this manner, even prior to clinical manifestations. Additionally, plasma AR-copy-number gains strongly associate with worse outcomes on abiraterone or enzalutamide in both chemo-naïve and post-docetaxel mCRPC, a finding that may lead to biomarker development opportunities.
ctDNA is detected in plasma from all progressing mCRPC patients and is representative of clinically progressing metastatic disease. Given this fact, it is a highly important new tool in the struggle to understand and identify PC mutation and resistance. Clinical indicators of PC progression such as PSA kinetics and radiographic changes have dominated the current monitoring paradigm of treatment efficacy in mCRPC patients. Clearly, however, the future of mCRPC monitoring and treatment lies in the use of liquid biopsies, especially when more thoroughly studied biomarkers and AR-variant validation become available.
Presented By: Gerhardt Attard, MD, PhD, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA