Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns

11530 Background: Androgen receptor splice variant 7 (AR-V7) is linked to a priori resistance to abiraterone acetate and enzalutamide. However, AR-V7 negativity does not necessarily indicate responsiveness and up to 20% of AR-V7 positive patients do demonstrate moderate response to these second-line endocrine therapies. Methods: Peripheral blood samples from patients with CRPC (n = 30) starting a new line of systemic therapy were subjected to comprehensive profiling of AR. AR splice variant (ARV) profiling for eight isoforms was performed by targeted RNA-Seq on CellSearch-enriched circulating tumour cells. Low-pass whole-genome and targeted sequencing of the entire AR gene in plasma-derived circulating cell-free DNA allowed the assessment of copy number status and structural rearrangements, respectively. ARV expression, structural variation, copy number alterations and ligand-binding domain mutations were combined and correlated to clinicopathologic parameters. Results: Twenty-five out of 30 patients (83%) demonstrated an aberration in AR. Twenty out of 30 patients (66.7%) demonstrated AR amplifications. Interestingly, 15/30 patients had intra-AR structural variants, of whom 14 expressed ARVs. In the context of endocrine treatment, 15/26 (57.7%) patients were ARV-positive with 13/15 patients having less than 6 months benefit from their therapy (Fisher’s exact test, p = 0.0115). ARV expression was heterogeneous with 10/15 ARV-positive patients expressing several ARV. Notably, AR-V7 was most frequently detected, however AR-V3 was 3.5x more abundant (Wilcox signed rank, p = 0.0029). In 17 patients, a baseline AR profile was available and demonstrated how having any ARV was associated with progression-free survival (HR: 4.53, 95%CI: 1.424–14.41; p = 0.0105). In the poor response group, 6/17 (35.2%) were AR-V7 negative, of whom 4 carried other AR aberrations. Conclusions: Comprehensive AR profiling on liquid biopsies is feasible and provides new insights into the mechanisms driving endocrine resistance. Clinical validation, by means of a non-interventional, prospective and multicentric study, is essential and currently ongoing.

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Current status of circulating tumor cell androgen receptor splice variant-7 in metastatic castration-resistant prostate cancer

Annals of Translational Medicine ◽

10.21037/atm.2019.12.137 ◽

2019 ◽

Vol 0 ◽

pp. S375-S375

Author(s):

Shinichi Sakamoto

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Tumor Cell ◽

Splice Variant ◽

Circulating Tumor Cell ◽

Current Status ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Androgen Receptor Splice Variant

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Combinatorial expression of androgen receptor splice variants: No predictive value in castration-resistant prostate cancer patients treated with enzalutamide (enza) or abiraterone (abi).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17547 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17547-e17547

Author(s):

Katrin Schlack ◽

Konstantin Seitzer ◽

Martin Boegemann ◽

Laura-Maria Krabbe ◽

Andres Jan Schrader ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variant ◽

Predictive Power ◽

Splice Variants ◽

Statistical Significance ◽

Therapy Response ◽

Hormonal Treatment ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

e17547 Background: Playing an important role in prostate cancer, androgen receptor (AR) signaling is a common therapeutic target. Novel hormonal treatment (NHT) using enza or abi prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, biomarkers predicting therapy response are limited. AR-V7, as the most abundant AR splice variant, has gained clinical interest. Nonetheless, current discussions on its predictive power are diverse. Given that AR-V7 as a sole biomarker is not efficient in predicting response to NHT, we aimed to increase the predictive potential by analysis of combinatorial AR splice variant (AR-V) expression in mCRPC patients undergoing NHT. Methods: We prospectively enrolled 60 patients who started on either abi or enza. Presence of circulating tumor cells (CTC) as well as expression of AR-V3, -7 and -9 were assessed. Outcomes in CTC-, CTC+/AR-V- and CTC+/AR-V+ patients were analyzed considering PSA reduction, PSA-PFS, PFS and OS. Results: PSA reduction of 50% was predominantly found in CTC- patients (78.5%) compared to CTC+/AR-V- (55.5%) and CTC+/AR-V+ (39.3%) without statistical significance (P = 0.059). When taking co-expression of two or more AR-V into account there was no difference in PSA response either (one AR-V 42.9%, two AR-V 33.3%, three AR-V 41.6%, P = 0.154). Median PSA-PFS was 17 months (95%CI 15.7 – 18.3), 13 months (95%CI 6.8 – 19.2) and 5 months (95%CI 3.6 – 6.4) for CTC- pts, CTC+/AR-V- pts and CTC+/AR-V+ pts, respectively (P = 0.005). However, comparing CTC- and CTC+ pts, differences become even more apparent (P = 0.004), CTC+/AR-V- and AR-V+ pts showed less statistically significant differences (P = 0.029). Median PFS and OS were not reached for CTC- pts. PFS was 10 months (95%CI 6.2 – 13.8) for CTC+/AR-V- pts and 9 months (95%CI 1.1 – 16.9) for CTC+/AR-V+ pts (P = 0.004, only CTC- vs. CTC+ P = 0.002). OS was 28 months (95%CI 16.8 – 39.2) for CTC+/AR-V- pts and 15 months (95%CI 7.9 – 22.1) for CTC+/AR-V+ pts (P = 0.014, only CTC- vs. CTC+ P = 0.006). Regarding PFS and OS, there was no difference comparing only CTC+/AR-V- and AR-V+ pts (P = 0.356 and P = 0.244). Conclusions: AR splice variants have prognostic power in stratifying mCRPC patients suffering from a more advanced stage of disease. Nonetheless, our study clearly demonstrates the lack of predictive power of AR splice variants for response to NHT. Additionally, we prove the importance of CTC analysis rather than AR-V expression being more valuable in mCRPC.

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