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Tissue Expression of Androgen Receptor Splice Variant 7 at Radical Prostatectomy Predicts Risk of Progression in Untreated Nonmetastatic Prostate Cancer - Beyond the Abstract

Androgen receptor (AR) splice variant V7 may predict response to new generation androgen signaling inhibitors (i.e. Abiraterone acetate and Enzalutamide), as well as taxane-based chemotherapy.1-2 Although it has been detected in circulating tumor cells (CTCs) of castration-resistant prostate cancer (CRPC) patients, the implementation of CTC-based AR-V7 determination for treatment selection in CRPC into current clinical practice is limited. Indeed, CTCs are usually abundant only in patients with high metastatic tumor burden, and sample processing can require specialized equipment.3


In this study, we first analyzed whether AR-V7 expression is detectable on prostatic tissues in an early stage of untreated non-metastatic PC cases.4 Using a streptavidin-biotin-peroxidase system with two monoclonal antibodies, we separately assessed the expression of AR-V7 and AR-FL (full length) on radical prostatectomy (RP) specimens obtained from 56 patients diagnosed with prostatic adenocarcinoma. At immunohistochemical staining, the positivity of both receptor forms resulted specific for tumoral cells, with an exclusively nuclear localization. A significant correlation between AR-V7 positive staining and the EAU risk classification (p<0.001) was found. Interestingly, only 2 out of 11 low-risk, 4 out of 13 intermediate-risk, and 24 out of 32 high-risk patients resulted AR-V7 positive.

Secondly, we sought to evaluate whether AR-V7 expression can be associated with progression after surgery - all patients were followed for at least 48 months. Our results demonstrated a significant correlation between AR-V7 positivity and biochemical and/or radiological progression after RP. Of note, 17 from 18 men who showed biochemical and radiological progression (i.e. positive imaging for lymph-nodes and/or bone metastases) during the follow-up expressed a strong positive AR-V7 nuclear staining - yet 25 out of 26 men with a negative AR-V7 staining remained without progression (i.e. PSA <0.2 ng/ml; no progression at imaging) (p<0.001).

Although validation of our findings in larger series is needed to draw conclusions, our results showed that, in this setting of untreated and non-metastatic PC patients, AR-V7 is detectable by immunohistochemistry on tumor tissue in more than 50% of cases. At this early stage - independently to androgen deprivation therapy (ADT) - AR-V7 positivity is associated with risk classification, highlighting its possible role in predicting biochemical and radiological progression after surgery. Moreover, it would be noted that all AR-V7 positive cases with radiological progression showed an initial PSA response (PSA decrease >50% from nadir) after starting ADT administration. Although this data should be regarded as preliminary, and did not lead us to a definitive recommendation, it could be used to guide future research.

Written by: Martina Maggi, MD1 Alessandro Sciarra, MD1 Ida Silvestri, MD2 Susanna Scarpa, MD3

  1. Department of Urology, Sapienza University of Rome, Italy
  2. Department of Molecular Medicine, Sapienza University of Rome, Italy
  3. Department of Experimental Medicine, Sapienza University of Rome, Italy

References:

  1. Sciarra A, Gentilucci A, Silvestri I, Salciccia S, Cattarino S, Scarpa S, et al. Androgen receptor variant 7 (AR-V7) in sequencing therapeutic agents for castratrion resistant prostate cancer: A critical review. Medicine (Baltimore). 2019 May;98(19):e15608. doi: 10.1097/MD.0000000000015608.
  2. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol. 2015 Aug;1(5):582-91. doi: 10.1001/jamaoncol.2015.1341.
  3. To SQ, Kwan EM, Fettke HC, Mant A, Docanto MM, Martelotto L, et al. Expression of Androgen Receptor Splice Variant 7 or 9 in Whole Blood Does Not Predict Response to Androgen-Axis-targeting Agents in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2018 Jun;73(6):818-821. doi: 10.1016/j.eururo.2018.01.007.
  4. Sciarra A, Maggi M, Salciccia S, Nicolai A, Tortorella E, Giantulli S, et al. Tissue Expression of Androgen Receptor Splice Variant 7 at Radical Prostatectomy Predicts Risk of Progression in Untreated Nonmetastatic Prostate Cancer. Oncology. 2021 Jan 18:1-5. doi: 10.1159/000512445. Epub ahead of print.

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