Detecting predictive androgen receptor modifications in circulating prostate cancer cells.

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5067 Background: Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) and chemotherapy in prostate cancer patients. When resistance to therapy ensues, lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications and some patients may thus receive ineffective therapy. Methods: We devised a single-tube assay to detect the two most common AR-modifications (AR-V7 splice variants and ARpoint mutations) in circulating tumor cells (CTC) using immunomagnetic CTC isolation followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 prostate cancer patients with PSA progression and molecularly uninformed therapy switch. Comparison of newly administered therapy and CTC-AR-status allowed effect size estimation. Results: Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Specifically, 17 patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We found a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. We estimated the overall benefit from molecularly informed therapy switch by subtracting the molecularly uninformed (31%) and the AR-status unmatched (6%) response rates from the AR-status matched response rate (72%). Thus, for prospective clinical trial planning our data suggest an estimated effect size of ~33%. Conclusions: In summary, the ability to detect key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.

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