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Blood test predicts resistance to androgen receptor therapy for prostate cancer
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Liquid profiling of whole blood rather than circulating tumor cells robustly quantified androgen receptor splice variant 7 levels in men with metastatic castration-resistant prostate cancer, according to study results published in European Urology.
As a result, the approach identified men who may be resistant to treatment with oral adrenal inhibitor abiraterone (Zytiga, Janssen) or androgen receptor inhibitor enzalutamide (Xtandi; Astellas, Pfizer).
Abiraterone and enzalutamide have improved OS among men with metastatic castration-resistant prostate cancer; however, treatment resistance remains a challenge in this patient population.
Research has shown that expression of the most common receptor variant, androgen receptor splice variant 7 (AR-V7), in circulating tumor cells is associated with resistance to abiraterone and enzalutamide.
“If we know in advance whether or not a tumor has developed cells with this receptor, we can provide advice on an individual basis at an early stage — this can spare seriously ill patients from undergoing an ineffective therapy,” co-lead investigator Matthias Heck MD, PhD, specialist for urology at University Hospital TUM Klinikum rechts der Isar in Munich, said in a press release.
Receptor variants can be detected through blood tests of circulating tumor cells, but current approaches can be time consuming, expensive and ineffective.
Heck and colleagues developed a “practical and robust” liquid profiling approach for direct, absolute quantification of AR-V7 and androgen receptor full-length mRNA levels in peripheral whole blood — without the need for circulating tumor cells — to predict resistance to abiraterone and enzalutamide.
“Only minute amounts of RNA are needed in a sample for the test to work,” co-lead investigator Silvia Thöne, PhD, from TUM Institute of Clinical Chemistry and Pathobiochemistry, said in the release. “Additionally, since AR-V7 RNA is present in every tumor cell that possesses the resistant receptors, it means that no tumor cells are slipping by undetected.”
To validate the approach and determine its ability to predict treatment resistance in this patient population, the researchers analyzed whole blood samples from a prospective biorepository of 85 men with castration-resistant prostate cancer prior to starting treatment with abiraterone (n = 56) or enzalutamide (n = 29).
PSA response — defined as a decline of 50% or more — served as the primary endpoint. Secondary endpoints included PSA-PFS, clinical PFS and OS.
The first researchers assessed the analytical validity of the droplet digital polymerase chain reaction assay and then quantified AR-V7 and AR full-length transcript levels in peripheral whole blood samples from the treatment cohort and a control cohort comprised of 28 healthy men.
Using 0.6% — the maximum AR-V7 fraction observed among healthy men — as a cutoff, researchers dichotomized patients into “high” (n = 15) and “low” (n = 98) groups of AR-V7 levels.
Overall, 41% of patients achieved PSA response. No patient with high AR-V7 levels achieved PSA response, compared with 50% of men with low AR-V7 levels (P < .001).
Multivariable logistic regression analysis demonstrated an association between AR-V7 status and PSA response. Results confirmed high levels of AR-V7 predicted no PSA response following treatment with abiraterone or enzalutamide (P = .03).
High AR-V7 expression appeared associated with shorter median PSA-PFS (2.4 months vs. 3.7 months), clinical PFS (2.7 months vs. 5.5 months) and OS (4 months vs. 13.9 months; P < .001 for all).
Multivariable Cox regression analysis showed high AR-V7 expression independently predicted shorter PSA-PFS (HR = 7; 95% CI, 2.3-20.7), clinical PFS (HR = 2.3; 95% CI ,1.1-4.9) and OS (HR = 3; 95% CI, 1.4-6.3).
“We were able to demonstrate that we can accurately predict whether or not resistance against abiraterone or enzalutamide is present in a patient,” Cristof Winter, MD, PhD, physician and bioinformatician at TUM Institute of Clinical Chemistry and Pathobiochemistry, said in the release.
The researchers acknowledged the study was limited by its retrospective design and low number of patients with high levels of AR-V7. Further, they noted that, because 50% of men with low levels of AR-V7 failed to achieve PSA response, other resistance mechanisms contributed to therapy failure that were not captured by their approach.
“Nevertheless, the optimal method for determining AR-V7 status has yet to be determined,” the researchers wrote. “Moreover, a randomized controlled trial is urgently needed to determine the clinical utility of AR-V7 as a resistance marker and quantify the survival benefit of AR-V7-guided therapy selection.” – by Kristie L. Kahl
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Nima Sharifi
Prostate cancer dependency on the androgen receptor (AR) is the major known pathway that drives tumor progression and is the basis for the clinical development of enzalutamide and abiraterone, potent blockers of the AR signaling pathway. AR variants, including AR-V7, have been shown to stimulate tumor growth in the absence of androgens, and expression of such variants are thought to make tumors impervious to treatment with abiraterone and enzalutamide.
Seitz and colleagues investigated an approach to determine the presence of AR-V7 in peripheral whole blood and its association with treatment-specific outcomes for patients with castration-resistant prostate cancer treated with abiraterone or enzalutamide. Researchers found that AR-V7 status is an independent predictor of PSA response in multivariable logistic regression analysis.
This study provides additional confirmatory data on AR-V7 as a biomarker of poor outcomes among patients with castration-resistant prostate cancer treated with abiraterone or enzalutamide. The approach used by these investigators circumvents the need for circulating tumor cell capture, which has merits for ease of analysis. However, it also makes it more challenging to determine whether AR-V7 detection in this study is confounded by the number of circulating tumor cells and other factors associated with clinically aggressive disease that are independent of AR-V7 function and may not otherwise be captured by patient characteristics. Yet again, this study demonstrates a clear signal that AR-V7 detection in blood portends poor clinical outcomes for patients treated with enzalutamide or abiraterone. Determining how these patients should instead be treated remains the challenge.
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