Prostate cancer biomarker research gains momentum, but challenges remain
Recent research has revealed various potential biomarkers for metastatic castration-resistant prostate cancer (mCRPC), but several challenges remain in fully utilizing them in clinical practice.
“The pivotal multicentre study by the SU2C-PCF Dream Team group looking at the integrative genomics of mCRPC revealed that nearly 90 percent of the patients had clinically actionable mutations. Androgen receptor [AR] gene alterations accounted for most of these mutations,” said Dr Ravindran Kanesvaran of National Cancer Centre, Singapore. [Cell 2015;161:1215-1228] “This was the first study to provide evidence for the role of genomic sequencing in the management of mCRPC and has charted the path for the development of numerous biomarker-driven clinical trials.”
“Characterizing predictive biomarkers in mCRPC with tissue biopsy is faced with a lot of challenges. Alternatively, analyses of circulating tumour cell [CTC] and cell-free DNA [cfDNA] are promising and minimally-invasive approaches in this regard,” he noted.
In a small study (n=31), researchers were able to identify AR splice variant 7 (AR-V7) messenger RNA in CTCs as a biomarker for outcomes with enzalutamide and abiraterone treatment in patients with CRPC. “Results showed that AR-V7 positivity was associated with resistance to enzalutamide and abiraterone, and hence poor outcomes with these drugs,” Kanesvaran noted. [N Engl J Med 2014;371:1028-1038]
These results were further confirmed in a study in 202 patients who were on abiraterone or enzalutamide. Results showed that CTC-negative patients had the best prognosis, while patients who were CTC-positive and AR-V7–positive had the worst prognosis. [J Clin Oncol 2017;35:2149-2156]
The use of AR-V7 as a negative predictive biomarker of outcomes with enzalutamide and abiraterone treatment was also validated in the PROPHECY trial. [J Clin Oncol 2018;36 (15_suppl):5004]
“Another study showed that taxanes appeared to be more efficacious than enzalutamide or abiraterone in AR-V7–positive mCRPC patients. This suggests that AR-V7 may serve as a biomarker for treatment selection in mCRPC,” highlighted Kanesvaran. [JAMA Oncol 2015;1:582-591]
“Our team is also conducting a study to investigate AR-V7 as a biomarker in Asian patients with mCRPC,” he said.
Genomic changes, such as AR aberrations, can also be detected through cfDNA assays. Similar to studies in CTCs, AR aberrations in cfDNA were found to be associated with resistance to enzalutamide and abiraterone in mCRPC. [Clin Cancer Res 2015;21:2315-2324; Sci Transl Med 2015;7:312re10]
In addition, a higher number of circulating tumour DNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with poor clinical outcomes in patients with mCRPC. “Importantly, the frequency of genomic alterations detected via cfDNA analysis was similar to that previously reported in tumour tissues,” Kanesvaran highlighted. [Cancer 2019, doi: 10.1002/cncr.31959]
“However, many challenges remain in fully utilizing these biomarkers in clinical practice,” he noted.
“For example, most circulating biomarker assays in mCRPC are still at the discovery stage or under validation. The assays’ sensitivity also needs to be improved. Instead of individual biomarkers, future studies should focus on the effect of multiple biomarkers,” he suggested.