Hormone Therapy Response Associated with Signaling Activity in Circulating Cancer Cells

A study monitoring hormone receptor activity in tumor cells from patients being treated for resistant metastatic prostate cancer has found that such monitoring may be useful for indicating which patients will be more likely to respond well to continued therapy.

Treatments that inhibit the androgen receptor (AR) pathway, androgen-deprivation therapy (ADT), are initially highly effective in most patients with metastatic prostate cancer (MPC); however, since cancer cells often develop resistance, secondary hormonal therapies are being tested to suppress androgen receptor reactivation. There are variable responses to such secondary therapy, but no reliable biomarkers are available to guide the use of AR pathway inhibitors in treating resistant MPC. A collaborative team of researchers led by Prof. Daniel A. Haber, MD, PhD, and director of the Massachusetts General Hospital Cancer Center (Charlestown, MA, USA) have now established a method using microfluidic capture of circulating tumor cells (CTCs) to isolate cancer cells from the blood of patients with MPC and single-cell immunofluorescence analysis to measure androgen receptor signaling activity in the individual CTCs.

Monitoring was performed on CTCs from patients with castration-resistant prostate cancer (CRPC), before and after therapeutic interventions. Prior to the initiation of ADT, the AR pathway was turned on in most CTCs from newly diagnosed patients. Initiation of first-line ADT induced a profound switch from “AR-on” to “AR-off” CTCs. In patients whose cancer had become resistant after initially responding well to androgen-deprivation therapy, the CTCs population became highly variable - some CTCs were AR-on, others AR-off, and still others had characteristics of both AR-on and AR-off. The presence of cells with a mixed AR signaling pattern was associated with an adverse treatment outcome. In addition, in patients treated with a new drug, abiraterone acetate, which achieves more complete androgen deprivation than earlier treatments, an increased percentage of AR-on CTCs despite abiraterone treatment was associated with decreased overall survival.

The assay may provide a valuable marker to help target such treatments to patients more likely to respond to second-line therapies. "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 Prof. Haber. He added, "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. 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."

The study was published early online October 23, 2012, in Cancer Discovery, a journal of the American Association for Cancer Research.

Related Links:
Massachusetts General Hospital Cancer Center
American Association for Cancer Research