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.
Highlights
Therapy of advanced prostate cancer is based on interference with androgen receptor (AR) signaling and androgen deprivation therapy (ADT) has been firmly established as the principal therapeutic approach [1]
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)
The group did, not assess point mutations of the AR gene in CTCs, while there is an implicit understanding that treatment decisions based on both AR-splice variants and point mutations would significantly improve therapy response rates. This point formed a rationale for our study, and we propose that treatment decisions based on CTC assessment should consider both AR-modifications (Figure 1)
Summary
Therapy of advanced prostate cancer is based on interference with androgen receptor (AR) signaling and androgen deprivation therapy (ADT) has been firmly established as the principal therapeutic approach [1]. All patients develop resistance to primary ADT (surgical/medical castration) as well as novel hormonal therapies (nextgeneration ADT), which either suppress the synthesis of extragonadal androgens (e.g. abiraterone) or target the androgen receptor directly (e.g. enzalutamide). Resistance to both primary and next-generation ADT is frequently caused by molecular AR-modifications. The most common AR-modification is an AR splice variant (AR-V7) that renders cancer cells resistant to otherwise effective therapy (e.g. abiraterone and enzalutamide) [2].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
