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. 2015 Apr 23;10(41):4213-4223.
doi: 10.18632/oncotarget.3925. eCollection 2019 Jun 25.

Detecting predictive androgen receptor modifications in circulating prostate cancer cells

Julie Steinestel #  1   2 , Manuel Luedeke #  1 , Annette Arndt #  3 , Thomas J Schnoeller  1 , Jochen K Lennerz  4 , Carina Wurm  1 , Christiane Maier  1 , Marcus V Cronauer  1 , Konrad Steinestel  5 , Andres J Schrader  1   2
Affiliations

Detecting predictive androgen receptor modifications in circulating prostate cancer cells

Julie Steinestel et al. Oncotarget. .

Abstract

Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two most common AR modifications (AR-V7 splice variant and AR point mutations) in circulating tumor cells (CTCs). We devised a single-tube assay to detect AR-V7 splice variants and AR point mutations in CTCs using immunomagnetic cell isolation, followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 patients with PSA progression awaiting therapy switch. Comparison of response to newly administered therapy and CTC-AR-status allowed effect size estimation. Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Seventeen 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 estimated a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. Based on a conservative calculation, we estimated the effect size for molecularly-informed therapy switches for prospective clinical trial planning to ~27%. In summary, the ability to determine key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.

Keywords: androgen receptor modification; castration-resistant prostate cancer; circulating tumor cells; splice variants.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Study rationale.
Current practice: Therapy switch at progress (PSA progress or progressive disease) occurs molecularly uninformed. Personalized approach: Evaluation of androgen receptor status in circulating tumor cells (CTC-AR-status) at time of progression enables matching of therapy to the individual resistance profile.
Figure 2
Figure 2. Study flow chart depicting the timeline of therapy switch, blood draw, circulating tumor cell (CTC) analysis and evaluation of response rates.
For estimation of effect size according to molecularly matched and unmatched therapy switches see results. Abbreviation: AR, androgen receptor gene (here assessed in CTCs).
Figure 3
Figure 3. Study results.
A. Overview of prior and new therapies along with the androgen receptor status in the circulating tumor cells (CTC-AR-status) for each study patient. Therapy switch in our study occurred molecularly uninformed (see Figure 2); however, comparison of newly administered therapy and CTC-AR-status allowed assignment as molecularly AR-matched vs. AR-unmatched. We defined ‘response’ as PSA reduction ≥50%. Abbreviation: ADT, androgen-deprivation therapy. B. Comparison of response rates between uninformed and molecularly/AR-status matched vs. unmatched. Abbreviations: TP, true positive; FP, false positive; FN, false negative; TN, true negative. C. Effect size estimation for planning of a molecularly stratified, controlled clinical trial. Note, we account for the 7% response rate in the AR-unmatched subgroup.
See this image and copyright information in PMC

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