Daniel A. Haber, MD
A particular assay could determine when patients with metastatic prostate cancer who have received primary or secondary androgen deprivation therapy (ADT) begin to relapse, and which patients may respond better to second-line therapies.
The findings suggest that a response to therapy could be monitored in approximately real time, thus expediting a targeted and personalized approach to treatment, according to researchers. The results of their analysis were published in the journal Cancer Discovery
ADT is a standard treatment for patients with metastatic prostate cancer and is often initially effective, while secondary hormonal therapies are prescribed to suppress androgen receptor (AR) reactivation and therefore reduce the risk of relapse. However, no reliable biomarkers have been identified to determine how a patient will respond to secondary hormonal therapy.
To determine the level of AR signaling prior to and after treatment, researchers used microfluidic capture of circulating tumor cells (CTC) and then employed single-cell immunofluorescence analysis to determine AR status among those cells. The researchers selected prostate-specific antigen (PSA; KLK3
) and prostate-specific membrane antigen (PSMA; FOLH1
) as disease-specific gene products for which reliable antibodies were available, and because those antigens were the most consistently upregulated after AR activation and AR suppression, respectively.
Once the CTCs were isolated, untreated patients with newly diagnosed metastatic prostate cancer were found to have predominantly “AR-on” CTC signatures, meaning that they tested PSA-positive and PSMA-negative (median 99.1%, range, 75%–100%). Once these patients were treated with first-line ADT, the researchers noticed that the signaling switched to an “AR-off” phenotype, or PSA-negative and PSMA-positive, within 1 month, followed by the complete disappearance of CTCs within 3 months of initial therapy.
However, after progression of the disease, patients had some CTCs that were “AR-off” (median 51.9%); others identified as “AR-mixed,” or PSA-positive and PSMA-positive (median 17.6%); and a relatively small fraction of “AR-on” (median 11.1%).
“This study is a proof of principle that it is possible to monitor, in patients with metastatic prostate cancer, the androgen receptor signaling pathway in real time, repeatedly and noninvasively,” said Daniel A. Haber, MD, PhD, director of the Massachusetts General Hospital Cancer Center in Boston, project leader of the Stand Up To Cancer Bioengineering and Clinical Applications of Circulating Tumor Cell Chip Dream Team, and corresponding author of the study, in a statement. “Our approach allowed us to monitor whether initial androgen-deprivation therapy was keeping the androgen signaling pathway shut down or whether the tumor was becoming resistant, and if so, by what mechanism.”
Additionally, the researchers looked at the response after administration of abiraterone acetate, which is marketed under its brand name Zytiga by Janssen Biotech. Abiraterone is a relatively new drug and a selective androgen biosynthesis inhibitor that is designed to target androgen receptors to block an enzyme, CYP17A1, which is heavily implicated in AR signaling and the synthesis of testosterone. Abiraterone acetate is designed to block all sources of production of testosterone and therefore delay progression of the disease.
The investigators found that the presence of more than 10% of “AR-mixed” among CTCs prior to treatment with abiraterone was associated with decreased overall survival (P
< .05). Once abiraterone was administered, the presence of “AR-mixed” and an increase in “AR-on” CTCs were associated with adverse treatment outcomes and decreased overall survival.
Specifically, the authors reported that 4 of 17 (24%) patients with castration-resistant prostate cancer who were treated with abiraterone acetate exhibited a 50% or greater decline in the percentage of “AR-on” CTCs within 2 to 5 weeks of therapy, suggesting that a reduction in systemic androgen levels suppressed a subset of their metastatic tumor cells. However, 2 of 17 (12%) patients in the same group experience a two-fold or more increase of “AR-on” CTCs within the same 2 to 5 weeks of therapy.
“As more drugs are developed that target the different pathways that drive the recurrence of metastatic prostate cancer in different patients, it will become essential to know which drug and which pathway is relevant in each patient,” Haber said. “Our assay will be an effective way to interrogate the tumor and follow it during the course of treatment to monitor therapy response and the emergence of drug resistance.”
Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer [published online ahead of print October 23, 2012]. Cancer Discov. DOI:10.1158/2159-8290.CD-12-0222.