Is AR-V7 Testing Pointless?

[pjoshea13]

Recent paper below [1].

Interest in AR-V7 was aroused in 2014 when it was reported that AR-V7 was often associated with Abiraterone (Zytiga) & Enzalutamide (Xtandi) resistance, & that used in either sequence, the second drug might fail quickly if AR-V7 was present.

In a 2014 Hopkins paper [2]:

"Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53% ...) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months ...), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months ...), and overall survival (median, 5.5 months vs. not reached ...).

"Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68% ...) and shorter PSA progression-free survival (median, 1.3 months vs. not reached ...), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached ...), and overall survival (median, 10.6 months vs. not reached ...)"

The message was clear: why waste time & money on the second drug, when it offered a median progression-free survival of a little over a month.

AR-V7 is a truncated form of the androgen receptor [AR]. It lacks the structure where androgen & AR antagonists attach, yet remains fully functional. Neither abiraterone nor enzalutamide can have therapeutic activity against AR-V7 cells.

Interestingly, "In all patients with detectable AR-V7, full-length androgen receptor mRNA was also expressed and at higher levels (with one exception) than the levels of AR-V7; increased expression of AR-V7 was generally (but not always) coupled with that of full-length androgen receptor mRNA ..."

So there wasn't even a preponderance of AR-V7 over normal AR in most of the cases.

In a 2016 follow-up paper [3]:

"We calculated the cost savings of performing AR-V7 testing in mCRPC patients prior to starting abiraterone/enzalutamide (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC patients empirically with abiraterone/enzalutamide (without use of the biomarker)."

"We determined that AR-V7 testing would result in substantial cost savings as long as the true prevalence of AR-V7 was >5%. In our prior studies, we estimated that approximately 30% of mCRPC patients may have detectable AR-V7 in circulating tumor cells (CTCs). In this population, upfront testing of AR-V7 status (at a price of $1,000 per test) would result in a net cost savings of $150 Million in the United States per year."

In a 2017 paper [4]:

"Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients (circulating tumor cells not detected), intermediate for CTC+/AR-V7- patients (circulating tumor cells detected, but no AR-V7), and worse for CTC+/AR-V7+ patients."

"CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 .., metastatic disease at diagnosis .., higher PSA .., prior abiraterone or enzalutamide use .., prior taxane use .., and Eastern Cooperative Oncology Group ≥ 1 ..."

How has the Hopkins AR-V7 test been used [5]:

"Providers used AR-V7 testing to influence clinical decision making more often than not. Physicians reported that men with AR-V7+ results had the most treatment changes, and such men were preferentially managed with taxane therapy or offered a clinical trial, which may have improved outcomes."

...

The abstract of the new study was posted by "Hidden" 16 days ago in response to:

"AR-V7, Zytiga(abiraterone) and Xtandi (enzalutamide)" [Cmdrdata].

The link below [1] is to the full text.

The authors devised a new way of testing for AR-V7 [6].

"We next applied our assay to a prospectively collected cohort of 37 mCRPC patients, commencing abiraterone or enzalutamide, across three institutions. Blood samples were taken immediately before the commencement of therapy."

"we found that positive AR-V7 expression using a novel whole blood reverse transcription PCR assay was not linked to poorer clinical outcomes in mCRPC patients receiving abiraterone or enzalutamide. Critically, our results are in keeping with the findings of the pivotal ARMOR3-SV clinical trial in which AR-V7 expression was evaluated in CTCs. These data collectively suggest that AR-V7 expression in either CTCs or whole blood is not a negative predictive biomarker for patients commencing abiraterone or enzalutamide, and therefore testing should not be incorporated into routine clinical practice, a position supported by recent international consensus guidelines ..."

...

In the 2014 paper, we have men who first became resistant to ADT, & then to abiraterone or enzalutamide before being tested. In the new study, the men were mCRPC when tested, but yet to begin abiraterone or enzalutamide. (If I have read this correctly.)

And so it seems that the mere presence of AR-V7 cells is not predictive unless one is CRPC AND have failed abiraterone or enzalutamide.

-Patrick

[1] europeanurology.com/article...

[2] ncbi.nlm.nih.gov/pmc/articl...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] ncbi.nlm.nih.gov/pubmed/283...

[5] ncbi.nlm.nih.gov/pubmed/291...

[6] "We have developed an assay for detecting AR-V7 and AR-V9 that requires only 2.5 ml of whole blood collected in PAXgene RNA tubes. Immediate sample processing is not required, and tubes can be stored frozen for up to 7 yr without loss of RNA integrity. RNA is isolated and subject to reverse transcription using a primer specific for the AR-V7 or AR-V9 transcript (Supplementary material). Quantitative polymerase chain reaction (qPCR) is then performed using Taqman chemistry, and a probe/primer is set for specifically targeted unique sequences within the AR-V7 or AR-V9 transcript (Supplementary Fig. 1). Importantly, the combination of gene-specific reverse transcription and Taqman probe qPCR detection allows for both high specificity and sensitivity. By serially diluting RNA from VCaP prostate cancer cells (which are known to express AR-V7), we established that the lower limit of detection of our assay for AR-V7 is 0.1% (Supplementary material). The assay also exhibits 100% specificity with neither AR-V7 nor AR-V9 detected in any of the 13 healthy male controls (data not shown)."

[snoraste]

Interesting. Looking at contradictory results, it shows that it really doesn’t make a difference, or their models are misspecified. Doesn’t seem to be an actionable item.

[Dan59]

Very Interesting, My expert at Dana told me a few years ago He was not a fan of the ARV7 test in determining xtandi sensativity. It has not affected me personally, but to those who did not do zytiga or xtandi because of the ARV7 ,may have hurt them. I plan to return to xtandi after chemo.

Dan