Back

Platinum Priority

Reply from Authors re: Emmanuel S. Antonarakis, Howard I. Scher. Do Patients With AR-V7–Positive Prostate Cancer Benefit from Novel Hormonal Therapies? It All Depends on Definitions. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.08.038: Unsplicing a Conflict

By: Julie Steinestela , Christof Bernemanna, Andres J. Schradera and Jochen K. Lennerzb

European Urology, Volume 71 Issue 1, January 2017, Pages 6-7

Published online: 01 January 2017

Abstract Full Text Full Text PDF (479 KB)

Refers to article:

Do Patients With AR-V7–Positive Prostate Cancer Benefit from Novel Hormonal Therapies? It All Depends on Definitions

Emmanuel S. Antonarakis and Howard I. Scher

January 2017 (Vol. 71, Issue 1, pages 4 - 6)

Refers to article:

Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer

Christof Bernemann, Thomas J. Schnoeller, Manuel Luedeke, Konrad Steinestel, Martin Boegemann, Andres J. Schrader and Julie Steinestel

Accepted 14 July 2016

January 2017 (Vol. 71, Issue 1, pages 1 - 3)

In their Platinum Priority editorial, Drs. Antonarakis and Scher [1] — two of the leaders in the field — raise questions regarding the conclusions of our recent study [2]. The intent of our response is to clarify, because the editorial could be perceived as a conflict between two competing groups. Here, we want to empower readers to make their own informed decision about the clinical utility of being identified as AR-V7–positive.

Our recent findings emphasize that a sizeable fraction of prostate cancer patients who are currently deemed unresponsive (by AR-V7+ status) may actually benefit from an otherwise safe medication (arbiraterone or enzalutamide) [3] and [4].

Regarding the difference in assays, we provide a direct comparison in Figure 1A. After capture of circulating tumor cells and isolation of processed RNA using the same commercially available kit, both assays use a reverse transcription–polymerase chain reaction approach specific for AR-V7 transcripts. The basic principle of the TaqMan design is that it requires close proximity of the three oligonucleotides (∼50–150 bp), which increases specificity [5] and [6]. In brief, the Taq polymerase extends the primer and synthesizes the nascent strand whereby the 5′–3′ exonuclease activity degrades the probe (orange in Fig. 1A) that is subsequently detected using fluorescence [5]. We agree that there are currently limitations to computational search tools for templates of exon-spanning oligonucleotides.

gr1

Fig. 1

AR-V7 splice variant detection and response rates in AR-V7–positive patients. (A) Androgen receptor (AR) gene structure with selected transcripts. AR full length (AR-FL) in comparison to AR-V7 variant. AR-V7 consists of canonical exons 1–3 plus 16 amino acids encoded by cryptic exon 3 (CE3). The primary mRNA between the 3′ end of exon 3 and the 5′ end of the coding region in CE3 spans 8753 nucleotides. We also compare two experimental approaches for detection of processed (spliced) AR-V7 mRNA. In the TaqMan approach (yellow and orange) three oligonucleotides have to be in close proximity to lead to a product of 71 bp. The alternative RT-PCR approach (green) leads to a product of 125 bp. (B) Comparison of response rates in AR-V7–positive patients to abiraterone/enzalutamide from two recent studies (see the text). There was no significant difference in response rates (p values from Fisher's exact test); when combined, the data indicate that ∼20% of AR-V7–positive patients are expected to respond. Note the subset of first-line responders.

With respect to the comparability of laboratory-developed tests, one of the key concerns of the US Food and Drug Administration is that patients could forego effective treatment options (http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf). Thus, contradictory data regarding the use of AR-V7 positivity for treatment stratification is paramount to a discussion of clinical utility. We agree that the response criteria in our retrospective study are those of clinical practice rather than those applied in a formal prospective, randomized controlled clinical trial; however, we find it appropriate to incorporate data presented by Antonarakis et al [7] at the 2016 annual American Society of Clinical Oncology meeting into the discussion. Notably, their abstract also reports a number of AR-V7–positive patients who responded to arbiraterone/enzalutamide [7]. Despite the apparent differences in criteria, we found no statistically significant differences in response rates between the two studies (Fig. 1B). Moreover, combination of the data to increase the total number of patients revealed that one in five AR-V7–positive patients may respond to abiraterone/enzalutamide [2] and [7].

The confirmation of a subgroup of responders amounting to 20% has to be accounted for on several levels. First, the fact that 20% of the AR-V7+ subset are responders has important implications for prospective trial design (eg, effect size prediction). Second, the findings are a possible contributory factor in the recent discontinuation of the ARMOR3 study (http://tokaipharmaceuticals.com/patients-and-physicians/clinical-trials/) comparing the efficiency of galaterone versus enzalutamide in AR-V7+ patients [8]. Third, there is an urgent need for prospective trials delineating the clinical utility and predictive properties of AR-V7 positivity. Fourth, the subset of responders should be incorporated in cost-benefit analyses [9]. Fifth, we need to clarify the underlying basis for the responses in a subgroup of AR-V7 mRNA positive patients. One possibility entertained by Drs. Antonarakis and Scher is that AR-V7 mRNA–positive patients may lack AR-V7 protein expression, which is possible, but to the best of our knowledge has not been reported in the literature. There is fortunately agreement in the field that more integrated molecular tests — that go beyond AR-V7 mRNA positivity — are needed [10]. Most importantly, however, we should not categorically withhold a potentially safe treatment option from a vulnerable patient population.

In summary, delineation of the true clinical utility of a biomarker rarely ever happens without a meaningful discussion. In the case of castration-resistant prostate cancer, AR-V7 positivity may be a current example.

Conflicts of interest

The Anneliese Pohl Foundation sponsored the study and played a role in study design and conduct. The authors have nothing further to disclose.

References

  • [1] E.S. Antonarakis, H.I. Scher. Do patients with AR-V7–positive prostate cancer benefit from novel hormonal therapies? It all depends on definitions. Eur Urol. 2017;71:4-6
  • [2] C. Bernemann, T.J. Schnoeller, M. Luedeke, et al. Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer. Eur Urol. 2017;71:1-3
  • [3] J.S. de Bono, C.J. Logothetis, A. Molina, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005 Crossref
  • [4] H.I. Scher, K. Fizazi, F. Saad, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197
  • [5] M. Arya, I.S. Shergill, M. Williamson, L. Gommersall, N. Arya, H.R. Patel. Basic principles of real-time quantitative PCR. Expert Rev Mol Diagn. 2005;5:209-219 Crossref
  • [6] J. Luo. Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer. Asian J Androl. 2016;18:580-585
  • [7] E.S. Antonarakis, C. Lu, B. Luber, et al. AR-V7 and efficacy of abiraterone (Abi) and enzalutamide (Enza) in castration-resistant prostate cancer (CRPC): expanded analysis of the Johns Hopkins cohort. J Clin Oncol. 2016;34(Suppl):5012
  • [8] D.A. Bastos, E.S. Antonarakis. Galeterone for the treatment of advanced prostate cancer: the evidence to date. Drug Des Dev Ther. 2016;10:2289-2297
  • [9] Markowski MC, Frick KD, Eshleman JR, Luo J, Antonarakis ES. Cost-savings analysis of AR-V7 testing in patients with metastatic castration-resistant prostate cancer eligible for treatment with abiraterone or enzalutamide. Prostate. In press. http://dx.doi.org/10.1002/pros.23232.
  • [10] Steinestel J, Luedeke M, Arndt A, et al. Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget. In press. http://dx.doi.org.10.18632/oncotarget.3925.

Footnotes

a Clinic of Urology, University Hospital Münster, Münster, Germany

b Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

Corresponding author. Clinic of Urology, University Hospital Münster, Albert-Schweitzer-Campus 1, Münster 48149, Germany. Tel. +49 251 8347442; Fax: +49 251 8349739.

Place a comment

Your comment *

max length: 5000