PCa Commentary | Volume 121 – April 2018

Posted by Edward Weber | April 2018

AR-V7: The Clinical Utility of Knowing Your Status … And When the Information Is Most Useful.

A test for the splice-variant AR-V7, Oncotype Dx AR-V7 Nucleus Detect (Genomic Health, Inc.), has become commercially available. This Commentary will focus on the clinical significance of test results — their predictive and prognostic value. 

• The Major Foundation Studies on AR-V7 — The Bases of this Commentary: 

Analyses of the clinical significance of AR-V7 comes from the work of: Emmanuel S. Antonarakis MBBCh., and colleagues: “Clinical Significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells [CTC] of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide,” 1 and from a second article by Bastos and Antonarakis, “CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer”2. 

A second major source is “Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer,” Scher, et al.3 This study is the validation basis for the OncoType Dx AR-V7 Nucleus Detect test now commercially available.

A sentence from Antonarakis states the theme for this Commentary’s discussion:

“Recently, androgen receptor slice-variant 7 (AR-V7) detection has been associated

with worse outcomes for patients with castration-resistant prostate cancer (CRPC)

treated with novel androgen receptor-signaling (ARS) inhibitors such as abiraterone [Zytiga] and enzalutamide [Xtandi] but not taxane chemotherapy.”1

• What is the Splice-Variant AR-V7?:

Discussed in detail in PCa Commentary Vol. 111 https://prostatecancerfree.org/pca-commentary-111-/

(Control + click link above to follow)

AR-V7 is a truncated form of the normal androgen receptor and can be found at low levels in normal and untreated prostates, but is increasingly expressed during the course of prostate cancer treatment, especially occurring in metastatic CRPC. AR-V7, the most common and best studied variant, is an altered version of the native, “full-length” androgen receptor (AR) gene. In this abnormal AR-V7 gene, the functional binding site for testosterone and dihydrotestosterone is missing, i.e. “spliced out.” 

Two consequences result:

1. The absence of this binding pocket renders the newer AR inhibiting drugs, abiraterone and enzalutamide, ineffective for lack of a target. 
2. The AR-V7 gene product is “constitutively active,” meaning that it is self-actuating and activates many genes that promote prostate cancer growth.

• Prevalence of AR-V7 Positivity in Circulating Tumor Cells:

Although present at low levels early in the course of cancer progression, the expression of AR-V7 increases, likely as a result of adaptation to treatment pressures.  Reports of prevalence of AR-V7 positivity in the Scher and Antonarakis articles are relevant to decisions as to the likelihood of benefit from AR-V7 testing at different stages of the disease.

(Scher): AR-V7 positive CTC were found in 3% of men prior to their first therapy for metastatic CRPC (mCRPC); 18% prior to second line therapy; and 31% prior to the third or greater number of therapies.3 

(Antonarakis): Prior to treatment with abiraterone or enzalutamide in mCRPC, CTC+/AR-V7 positivity is found in 12% of men, and in 26.9% prior to second-line use of abiraterone or enzalutamide. (Some of these men had had prior taxane therapy.)1

• Prognostic Value of AR-V7 Positivity in Circulating Tumor Cells:

(Scher): AR-V7 CTC positivity (even one cell) was associated with a shorter time to objective progression, i.e. median 2.3 vs 14.5 months for AR-V7(-). The median overall survival for AR-V7 (+) men was 4.6 months vs “not reached” for AR-V7 negative men.

(Antonarakis): For first line abiraterone or enzalutamide treatment, the median overall survival for CTC AR-V7 positive vs negative was 21.5 vs 29.5 months. For second line usage, median overall

survival was 8.5 vs 13.0 months, respectively. In first-line treatment the median progression-free for AR-V7(+) vs AR-V7(-) was 4.1 vs 10.1 months.1

Taken together, the findings of these studies establish AR-V7 status as an important prognostic biomarker.    

• Results of Taxane Therapy in these Studies:

(Scher): “No association between AR-V7 positivity and PSA response to taxane-based therapy was observed, indicating that patients might respond to taxanes regardless of AR-V7 status.”3

(Antonarakis): The response to taxane therapy was slightly diminished in the AR-V7(+) group compared to AR-V7(-), but was clearly better than their response to abiraterone or enzalutamide therapy.1

The findings of the two studies are not comparable since each used a different assay. Even though both evaluated men with metastatic CRPC, the demographics were not entirely similar. A recently completed PROPHECY study (NCT02269982) of 120 men, soon to be reported, will provide results comparing the performance of the major test methods. 

 [The Johns Hopkins’s test remains available for $900; requisition form upon request.] 

• Findings Common to Both Studies:

1. The percentages of men testing positive for AR-V7 increases as men progress through sequential therapy, suggesting “AR-V7 expression as an adaptive response to systemic therapy over time.”3 Prior to the first line of therapy, Scher found 3% men AR-V7 positive and Antonarakis, 12%. Both studies showed that after failing the first line therapy, AR-V7 positivity rose to 18% (Scher) and 26.9% (Antonarakis).
2. Both studies showed that men having AR-V7 transcripts in CTC have inferior PSA declines. In Antonarakis, using the response criteria of a >50% decline in PSA, 52.2% of CTC         AR-V7(-) men responded vs 13.9% for AR-V7(+) patients, suggesting that the test can be predictive of PSA response to these agents.
3. In both studies, prognoses were significantly worse for CTC AR-V7(+) men.
4. Both studies conclude that taxane treatment confers a better outcome in the face of AR-V7 positivity.

• Considerations as to Whom to Test and When:

In an editorial comment accompanying the Antonarakis article, Bubley and Balk, Beth Israel Deaconess Medical Center, Boston, JCO, July 2017, noted:

“In men who have not been exposed to either abiraterone or enzalutamide, it is less common to have AR-V7 positive CTCs.” Therefore, testing for AR-V7 positive CTCs may not have a major influence on decision making in this population, except possibly in men who are progressing rapidly … ”

However, based on the prevalence data cited in the two studies, after first-line therapy testing may well be indicated. As commented in Scher:

“The clinical implication [of the study] is that, within each line of therapy, once AR-V7 positive cells are detected, the preferred choice of therapy is a taxane rather than an ARS inhibitor (i.e. abiraterone or enzalutamide].”3 

• The Oncotype Dx AR-V7 Nucleus Detect

Genomic Health, Inc. Available as of February 2018.

This test assays for AR-V7 protein in the cell nucleus of CTC. The test is intended for men with metastatic CRPC. The test results are reported as negative or positive, with the explanation “positive: One or more nuclear localized AR-V7 positive CTC identified.”  

A test kit can be obtained by calling 866-662-6897.  In the Northwest, assistance is available by contacting Ms. Connie Porta (206-960-0668 cporta@genomichealth.com).The kit contains instructions and equipment. The “list price” of the test is in the region of $3800. 

• BOTTOM LINE:  In men experiencing metastatic CRPC, particularly after progressing following first-line therapy, awareness of AR-V7 in CTC can beneficially inform clinical management.

References

1. Antonarakis ES, et al. Clinical Significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells [CTC] of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. JCO. April 2017.
2. Bastos DA, Antonarakis ES. “CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer,” Expert Review of Molecular Diagnostics. 2018.
3. Scher HI, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. June 2016.
4. Bubley GJ, Balk SP. Association between androgen receptor splice variants and prostate cancer resistance to abiraterone and enzalutamide. JCO. July 2017.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”