Dr. Himisha Beltran
Biomarkers and Disease Settings
In recent years, researchers have made substantial progress in understanding the molecular and genomic landscape of prostate cancer in both the localized and advanced settings. “As a field, we have started to use this information to develop biomarkers as well as fuel preclinical research. An important next step is to better translate these ‘-omics’ into clinical practice,” Dr. Beltran explained.
The natural history of prostate cancer can make this challenging, as longitudinal studies have shown that the molecular biology of prostate cancer can change over the typically long course of the disease. Tissue samples from the primary tumor, which are often the only samples available, are “not likely representative of what is going on several years later when we are trying to make a treatment decision,” Dr. Beltran added. She noted that incorporating metastatic biopsies into clinical trials will help identify biomarkers relevant to advanced disease.
In the setting of localized disease, no single genomic mutation has been shown to have prognostic value for use in risk assessment. It is now recognized that prostate cancer is a multifocal disease characterized by independent primary tumors with distinct biologic features; this presents another challenge to biomarker analyses. Questions remain regarding which tumor nodule should be evaluated in the primary setting.
In the setting of advanced prostate cancer, biomarkers have been identified that have significant prognostic and, in some cases, predictive value, showing a potential role not only for risk assessment but also for guiding the selection of therapy.
The Role of AR-V7
Studies investigating the biology of metastatic castration-resistant prostate cancer (CRPC) have shown that reactivation of AR signaling is a major mechanism of resistance to current therapies. The androgen receptor can be reactivated through a variety of genetic events. One particular splice variant, AR-V7, has gained particular attention due to its detection in circulating tumor cells (CTCs), its association with drug resistance, and its potential role in treatment selection.
Discussing the biology and significance of AR-V7 was Emmanuel S. Antonarakis, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Dr. Antonarakis explained that AR-V7 is created when abnormal gene splicing of AR creates an AR protein that lacks the ligand binding domain, which is the target of both abiraterone and enzalutamide. Despite the absence of the ligand binding domain, AR-V7 remains constitutively active. This creates resistance to both enzalutamide and abiraterone.
Prospective biomarker-driven trials are currently being conducted in order to assess the clinical validity of AR-V7 as a biomarker, as are efforts to develop a standardized, certified AR-V7 assay.
Dr. Antonarakis added that AR-V7 may also be a suitable therapeutic target. Several novel AR-targeting drugs are under development that share some mechanisms of abiraterone and enzalutamide but also target the androgen receptor through inhibition or degradation, allowing these agents to potentially retain activity in patients with AR-V7. Preliminary data suggest that the strategy is active against AR variants, and clinical trials are ongoing.
Analyzing Tumor DNA
Another line of biomarker research involves the analysis of tumor DNA isolated from the bloodstream of patients with prostate cancer. Gerhardt Attard, MD, PhD, of the Institute of Cancer Research and the Royal Marsden NHS Hospital, United Kingdom, discussed the potential biologic and clinical significance of circulating tumor DNA in prostate cancer.
The technique involves the molecular analysis of plasma DNA isolated from the blood of patients with prostate cancer. “This is a noninvasive, easy-to-perform approach,” Dr. Attard explained, and he added that it is amenable to sequential analysis performed throughout the course of disease. The potential clinical applications of CTC plasma DNA analysis are numerous, from risk stratification, treatment selection, and drug resistance analysis to response monitoring and detection of early disease progression. However, Dr. Attard acknowledged that there are challenges, including low amounts of DNA, the fact that plasma tumor DNA represents all tumors present, and the variable nature of the tumor DNA-to-normal DNA ratio.
Dr. Attard also discussed the potential use of plasma DNA testing as a monitoring tool during treatment. Longitudinal studies have shown enrichments of AR variants during a course of therapy prior to the development of clinical response.
Plasma DNA technology has not been adequately studied or standardized to be able to be incorporated into clinical practice. The ultimate goal is to be able to change treatment based on plasma DNA findings that are detectable prior to the onset of clinical symptoms. Next steps towards this goal include the conduct of prospective trials to validate current findings and determine clinical applicability and the development of an optimized, standardized assay for analyzing plasma DNA in a clinically accredited environment.
Imaging in Prostate Cancer
Imaging represents another area in which biomarkers can be used in prostate cancer care. Michael J. Morris, MD, of the Memorial Sloan Kettering Cancer Center, provided an update on the use of biomarkers in prostate cancer imaging. He noted that there has been much progress in the 8 years since a working group proposed definitions for disease progression as detected by bone scans. Since then, bone scan imaging has been shown to be associated with clinical outcomes, has been recognized by regulatory authorities, and has been the basis for drug approval in metastatic CRPC.
Dr. Morris noted that multiple molecular imaging tracers are now available with a variety of proposed uses including response assessment, detection of disease and relapse, and assessment of prostate-specific antigen levels following prior treatment. When considering the use of these biomarkers in prostate cancer imaging, Dr. Morris suggested that for clinicians, the important issues relate not as much to the imaging technology, but rather to the clinical applicability of the images obtained—determining what is actionable and clinically relevant to improve patient care.
“Even though we now have the capacity to order scans that are molecularly targeted,” Dr. Morris explained, “that does not mean that we know how to use them, how to read them, what to do about those images, or even what the informative pieces of information that’s embedded in those images are.”
Clinical qualification studies are crucial to answering these questions. In order to be clinically applicable, Dr. Morris said that a biomarker requires a quantitative parameter such as the absolute value or change in lesion number, standard uptake value, and disease distribution, among other factors. Prospective trials are needed to further evaluate possible imaging biomarkers and assess their clinical utility.
Overall, experts agreed that much progress has been made in the identification of biomarkers that have the potential to guide risk stratification, treatment planning, and response assessment in patients with advanced prostate cancer, but additional work is needed, particularly in the context of prospective clinical trials. Dr. Beltran expressed hope that in the near future, “we will be able to use molecular biomarkers, whether it is tissue, liquid, imaging-based, or a combination to improve our treatment decisions for patients.”
– Melinda B. Tanzola, PhD