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Editorial: Circulating biomarkers of NEPC – an unmet challenge

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Prostate cancer is a global health issue and, although the overwhelming majority (>95%) of metastatic castration-resistant prostate cancers (CRPCs) have adenocarcinoma histology [1], a subset of tumours acquire histopathological and immunohistochemical evidence of neuroendocrine differentiation, with a variety of morphological classifications being reported [1]. Nonetheless, the term ‘neuroendocrine prostate cancer’ (NEPC) should be reserved for tumours with absent or minimal androgen-signalling modulated transcription [2]. NEPC arising in the castration-resistant scenario (treatment-related NEPC or tNEPC) [2] is a disease of unknown prevalence and without an optimum treatment regime. Autopsy studies have shown at least focal neuroendocrine differentiation may be present in up to 33% of patients [3]. The cellular precursor of tNEPC is still debated, but a common clonal origin from adenocarcinoma CRPC (adeno-CRPC) is likely [2]. The assumption of negligible androgen signalling in these tumours implies resistance to agents such as abiraterone and enzalutamide. In this setting, research focused on identifying biomarkers of tNEPC is to be welcomed.

Heck et al. [4] determined the prognostic impact of elevated circulating neuroendocrine biomarkers chromogranin A (CGA) and neuron-specific enolase (NSE) in the serum of patients with CRPC treated with abiraterone in the post-chemotherapy setting. Although CGA and NSE did not predict PSA response, they correlated with clinical and radiographic progression-free survival (PFS), as well as overall survival (OS). The association between these biomarkers and clinical outcomes in metastatic CRPC has been confirmed in retrospective studies [5]. According to the authors, this association, independently of PSA response, underlines the sub-clonality of this disease, and the key role of androgen receptor (AR) signalling, even in advanced disease [4].

The marker NSE is considered to be generic, with high sensitivity but low specificity; CGA is a more specific neuroendocrine tumour biomarker and a common constituent of neuroendocrine tumour secretory granules. Abnormal CGA levels have, however, been significantly associated with intake of proton pump inhibitors in patients treated with abiraterone for metastatic CRPC rather than with duration of treatment [5]. Unfortunately, the use of proton pump inhibitors in that study was not disclosed and may have affected the reported results. Moreover, compared with previous experience, the rate of abnormal NSE was significant higher, probably in keeping with the low specificity of this biomarker.

Interestingly, the authors report an OS and PFS of 12.7 and 3.7 months, respectively [4]. These data are significantly different from the results of the COU-AA 301 study, in which treatment with abiraterone resulted in improved OS (14.8 vs 10.9 months) [6]. Surprisingly, there was no difference in PFS between abiraterone in the study by Heck et al. and the control arm of the COU-AA 301 trial (3.6 months) [6]. This discordance could be attributable to the small sample size of their study rather than the high PSA level at initiation of abiraterone, as claimed by the authors. In support of this alternative possibility, a post hoc analysis of the AFFIRM trial [7] showed consistent benefits in OS and PFS with second-generation hormonal treatments, regardless of baseline disease severity as assessed by PSA level.

Nevertheless, identifying patients with tNEPC is an urgent clinical need; genomic germline and somatic DNA next-generation sequencing as well as transcriptomic analysis of metastatic biopsies should now be considered a key approach to better understanding the heterogeneity of metastatic CRPC and to personalize treatment in order to maximize benefit.

There is substantial genomic overlap between adeno-CRPCs and tNEPC. TMPRSS2-ERG is the most common genomic aberration in prostate cancer and has been reported in NEPC with a similar frequency [2]. Furthermore, both adeno-CRPCs and tNEPCs are enriched for the inactivation of key tumour suppressor genes, such as RB1 and TP53, compared with hormone-sensitive prostate cancer, albeit in different proportions [2]. Although genomic amplification and activating point mutations of the AR in tNEPCs are notably absent, the presence of AR-splicing variants, including ARv7, is still detectable, suggesting that AR signalling is still present in at least a proportion of tNEPCs [2].

Despite a common background of genomic aberrations, tNEPCs have also been reported to have significant overexpression and copy number gains of AURKA and MYCN (40% of NEPC vs 5% of primary prostate cancer tumours), although these findings remain unsubstantiated [3]. As such, these have been postulated to be drivers of this disease phenotype and are under investigation as targets of novel agents.

Genome-wide DNA methylation analysis has, however, also shown that there are marked epigenetic differences between NEPC and adeno-CRPC, suggesting that epigenetic modifiers play a major role in the induction and maintenance of the neuroendocrine status [2].

In conclusion, the identification and definition of NEPC remains challenging. Blood biomarkers such as NSE and CGA cannot be considered to be proven prognostic biomarkers of NEPC as they have only been evaluated in small retrospective studies not adhering to REMARK criteria [8]. Genomic profiling from tissue biopsies or circulating DNA remains a preferable way to identify NEPC and is increasingly feasible, although still not affordable or a standardized procedure for the definition of NEPC.

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Pasquale Rescigno*,†, Daniel Nava Rodrigues*,† and Johann S. de Bono*,†

 

*Institute of Cancer Research, London, UK and †Royal Marsden NHS Foundatio n Trust, London, UK

 

References

 

1 Epstein JI, Amin MB, Beltran H et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 2014; 38: 756–67

 

2 Beltran H, Prandi D, Mosquera JM et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016; 22: 298–305

 

3 Mucci NR, Akdas G, Manely S, Rubin MA. Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression. Hum Pathol 2000; 31: 406–14

 

4 Heck MM, Thaler MA, Schmid SC et al. Chromogranin A and neurone- specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration-resistant prostate cancer undergoing abiraterone therapy. BJU Int. 2017; 119: 30–7

 

5 von Hardenberg J, Schwartz M, Werner T et al. Influence of abiraterone acetate on circulating neuromediators in chemotherapy-naıve castration- resistant prostate cancer. Prostate 2016; 76: 613–9

 

6 de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005

 

7 Saad F, de Bono J, Shore N et al. Efficacy outcomes by baseline prostate- specific antigen quartile in the AFFIRM trial. Eur Urol 2015; 67: 223–30

 

8 McShane LM, Altman DG, Sauerbrei W. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93: 387–91

 

Article of the Week: Predicting complications in partial nephrectomy for T1a tumours: does approach matter?

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Predicting complications in partial nephrectomy for T1a tumours: does approach matter?

Daniel Ramirez, Matthew J. Maurice, Peter A. Caputo, Ryan J. Nelson, Onder Kara, Ercan Malkoc and Jihad H. Kaouk

 

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

 

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Objectives

To assess differences in complications after robot-assisted (RAPN) and open partial nephrectomy (OPN) among experienced surgeons.

Patients and Methods

We identified patients in our institutional review board-approved, prospectively maintained database who underwent OPN or RAPN for management of unifocal, T1a renal tumours at our institution between January 2011 and August 2015. The primary outcome measure was the rate of 30-day overall postoperative complications. Baseline patient factors, tumour characteristics and peri-operative factors, including approach, were evaluated to assess the risk of complications.

aotwdec-5-results

Results

Patients who underwent OPN were found to have a higher rate of overall complications (30.3% vs 18.2%; P = 0.038), with wound complications accounting for the majority of these events (11.8% vs 1.8%; P < 0.001). Multivariable logistic regression analysis showed the open approach to be an independent predictor of overall complications (odds ratio 1.58, 95% confidence interval 1.03–2.43; P = 0.035). Major limitations of the study include its retrospective design and potential lack of generalizability.

Conclusions

The open surgical approach predicts a higher rate of overall complications after partial nephrectomy for unifocal, T1a renal tumours. For experienced surgeons, the morbidity associated with nephron-sparing surgery may be incrementally improved using the robot-assisted approach.

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Editorial: Open partial nephrectomy is still alive

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In this issue of BJUI, Ramirez et al. [1] assess the peri-operative outcomes of patients with small renal tumours treated with robot-assisted or open partial nephrectomy [1]. Their study retrospectively compared transperitoneal robot-assisted partial nephrectomy (RAPN) and retroperitoneal open partial nephrectomy (OPN) in a series of 714 patients (545 RAPN and 169 OPN) with cT1a parenchymal tumours of the kidney. Although the RAPN group had a higher mean RENAL nephrometry score, the authors observed a significantly higher overall complication rate in patients in the OPN group (30.3 vs 18.2%; P=0.038). On multivariable analysis, the open approach was an independent predictor of overall complications (odds ratio 1.52; CI 1.03–2.43, P=0.035) besides race, body mass index (BMI) and Charlson comorbidity index. Notably, when complications were stratified by grade, the worse outcome for OPN compared with RAPN was related to minor complications (i.e. Clavien–Dindo 1 and 2) only, with the most relevant difference represented by wound problems. No statistically significant difference between the two approaches was observed with regard to estimated blood loss (EBL) or genitourinary complications. Surprisingly, the RAPN group also had a shorter median warm ischaemia time (WIT; median 22.1 vs 28.6 min).

The authors should be commended for this very interesting comparative study; however, some criticisms should be considered.

First, the authors claim that all procedures were performed by surgeons beyond their learning curve over a period of >4.5 years. Considering the OPN group, the number of procedures/year is <40. If the series was multi-surgeon (the authors do not specify this), then yearly caseload does not meet the standards for defining ‘high’ surgical volume, especially when compared with the RAPN cases (>100/year).

Second, the main complication in the OPN group was wound problems. One has to consider that patients included in this study were mostly overweight to obese, as reflected in the BMI values (median 29.6 kg/m2). This characteristic could have played an important role in the OPN group and may represent a bias.

Third, it seems curious that the same group of authors recently published another comparative study of RAPN vs OPN for ‘completely endophytic tumours’ [2], where the only statistically significant difference between the two approaches was lower EBL and shorter length of stay, in favour of RAPN. Interestingly, no statistically significant difference was reported between two groups with regard to either postoperative complications or WIT.

In 2014, Ficarra et al. [3] compared RAPN and OPN in a multicentre series of 400 cases (200 RAPN and 200 OPN) using a matched-pair analysis [3]. The robot-assisted approach resulted in a lower rate of minor postoperative complications and a lower intra-operative EBL. Notably, in that analysis, the open approach resulted in a shorter WIT despite the fact that 14.5% and 13% of RAPN and OPN patients, respectively, were complex cases (i.e. had cT1b tumours). As pointed out above, in the present study, Ramirez et al. [1] reported a median (interquartile range [IQR]) WIT of 22.1 (17–26) min for the RAPN group and 28.6 (22–35) min for the OPN group [1].

Robot-assisted surgery confers an evident advantage to the surgeon, especially during the renorrhaphy phase as a result of the freedom of movement of the robotic needle driver compared with conventional laparoscopic instruments. It has been shown that the learning curve for RAPN is relatively short, allowing WIT of <20 min to be achieved [4]. In our opinion, the real competitor with regard to RAPN for WIT is OPN. A recent systematic review and meta-analysis based on 16 series showed, in fact, longer WIT for RAPN compared with OPN [5].

Taken together, all these results suggest that OPN maintains its role in the robotic era, especially when complex cases require treatment. Although RAPN is now widespread and has expanded its indications, it is still able to provide excellent performance in terms of postoperative complications at least equal to OPN in tertiary referral centres where a high volume of robotic renal surgery is performed, as indicated by Ramirez et al. [1]; however, several aspects of RAPN still await evaluation. The learning curve for RAPN, in terms of operating time and WIT, has been previously evaluated [4, 6], and the advantages of robotic surgery have been convincingly demonstrated when compared with pure laparoscopy [7]. Despite this, all the studies that have evaluated the learning curve for RAPN involved a tumour size <3 cm. The learning curve for OPN, especially in complex cases, should also be considered. Despite its impressive dissemination, RAPN is still in evolution, and OPN remains alive.

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Alessandro Crestani, Marta Rossanese and Gianluca Giannarini
Academic Medical Centre Hos ital ‘San ta Maria della Misericordia’, Urology Unit, Udine, Italy

 

References

 

1 Ramirez D, Maurice MJ , Caputo PA et al. Predicting complications in partial nephrectomy for T1a tumors: does approach matter? BJU Int 2016; 118: 940–5

 

2 Kara O, Maurice MJ, Malkoc E et al. Comparison of robot-assisted and open partial nephrectomy for completely endophytic renal tumours: a single centre experience. BJU Int 2016; 118: 946–51

 

3 Ficarra V, Minervini A, Antonelli A et al. A multicentre matched-pair analysis comparing robot-assisted versus open partial nephrectomy. BJU Int 2014; 113: 936–41

 

4 Mottrie A, De Naeyer G, Schatteman P et al. Impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumours. Eur Urol 2010; 58: 127–32

 

5 Shen Z, Xie L, Xie W et al. The comparison of perioperative outcomes of robot-assisted and open partial nephrectomy: a systematic review and meta-analysis. World J Surg Oncol 2016; 14: 220

 

6 Benway BM, Wang AJ, Cabello JM, Bhayani SB. Robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. Eur Urol 2009; 55: 592–9

 

7 Pierorazio PM, Patel HD, Feng T et al. Robotic-assisted versus traditional laparoscopic partial nephrectomy: comparison of outcomes and evaluation of learning curve. Urology 2011; 78: 813–9

 

Article of the Week: Detecting PSMs – using LRS on ex vivo RP specimens

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens

Aaron H. Lay*, Xinlong Wang†, Monica S. C. Morgan*, Payal Kapur‡, Hanli Liu†,Claus G. Roehrborn* and Jeffrey A. Cadeddu*

 

*Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, †Department of Bioengineering, University of Texas at Arlington, Arlington, TX, and ‡Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

 

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Abstract

Objective

To assess the efficacy of light-reflectance spectroscopy (LRS) to detect positive surgical margins (PSMs) on ex vivo radical prostatectomy (RP) specimens.

Materials and Methods

A prospective evaluation of ex vivo RP specimens using LRS was performed at a single institution from June 2013 to September 2014. LRS measurements were performed on selected sites on the prostate capsule, marked with ink, and correlated with pathological analysis. Significant features on LRS curves differentiating malignant tissue from benign tissue were determined using a forward sequential selection algorithm. A logistic regression model was built and randomised cross-validation was performed. The sensitivity, specificity, accuracy, negative predictive value (NPV), positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) for LRS predicting PSM were calculated.

aotwdec-4-results

Results

In all, 50 RP specimens were evaluated using LRS. The LRS sensitivity for Gleason score ≥7 PSMs was 91.3%, specificity 92.8%, accuracy 92.5%, PPV 73.2%, NPV 99.4%, and the AUC was 0.960. The LRS sensitivity for Gleason score ≥6 PSMs was 65.5%, specificity 88.1%, accuracy 83.3%, PPV 66.2%, NPV 90.7%, and the AUC was 0.858.

Conclusions

LRS can reliably detect PSMs for Gleason score ≥7 prostate cancer in ex vivo RP specimens

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Editorial: Light reflectance spectroscopy is one more emerging technique with the potential to adjust excision limits during radical prostatectomy

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In this issue of BJUI, Lay et al. [1] report that light reflectance spectroscopy (LRS) can detect Gleason ≥7 positive surgical margins (PSMs) with 92.5% accuracy. In this initial study, the authors have reported the use of LRS in an ex situ setting to analyse the prostate surface; however, this technology could ultimately be developed to identify PSMs before choosing the surgical plane of dissection, which could allow the surgeon to immediately perform a wider complementary excision.

As long as PSMs are detected ex situ, it is not clear why spectroscopy should be preferred to frozen sections. NeuroSAFE, for example, is a standardized and validated margin evaluation procedure in pathology [2]. It does not lengthen operating time, does not require any new equipment and provides a pathological assessment which is the best level of evidence for PSM status; however, as a conventional pathological procedure, it is not conceivable in situ, and real-time detection of PSMs that ensures the safest oncological resection during a nerve-sparing dissection is needed.

In this effort to examine in vivo/in situ prostate PSMs, several other technologies can be considered. During radical prostatectomy, optical coherence tomography (OCT) has been used in situ in humans, but only to identify the neurovascular bundles [3]. Field of view and depth of penetration were limited and OCT has never been evaluated in situ for prostate PSM detection. Confocal endomicroscopy has recently been reported during robot-assisted radical prostatectomy [4]. With this technique, optical biopsies were feasible in situ but the PSM detection rate and the overall efficiency of this confocal endomicroscopy in prostate specimens remain unknown. Similarly, illumination microscopy has been used to generate gigapixel images of the full prostate circumference in vivo for the detection of PSMs [5]. Illumination microscopy allows images to be interpreted readily by pathologists, but the feasibility series was too small to assess the accuracy of this technique for PSM detection. Ex situ multi-photon microscopy (MPM) is an optical technique that enables the imaging of prostatic and periprostatic tissue at sub-micron resolution to a depth of up to 0.5 mm [6]. On a fresh specimen, it generates three-dimensional images of periprostatic nerves, blood vessels and capsule, but also underlying acini and pathological changes such as prostate cancer. MPM technology has also been miniaturized and its accuracy in situ is currently under investigation.

In this context, the study by Lay et al. [1] shows that, for the time being, LRS is one more promising technique on the road to real-time PSM detection. More will undoubtedly be done to overcome the spectroscope’s light absorption in the presence of blood and, subsequently, to evaluate its reliability in situ; however, the recent developments of these protocols and technologies (endomicroscopy, illumination microscopy, OCT, MPM, LRS) show a progressive effort amongst clinicians to obtain intra-operative feedback on the PSM status. Fortunately, this is taking place while the urological community is increasingly considering surgical treatment even for the high-risk disease, where oncological adequacy is of paramount importance. While we are witnessing these promising evolutions in high-grade prostate cancer, the optimum technique which will safely end margin-blind radical prostatectomy in an actual surgical field (filled with blood and often distorted because of inflammation) still needs to go through clinical trials and validation; however, the future is bright as a result of these newer developments.

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Thomas Bessede*†‡ and Ash Tewari*

 

*Department of Urology, Icahn School of Medicine at Mount Sinai, New York , NY, USA, †U1195, INSERM, Universite Paris-Saclay, and ‡Department of Urology, APHP, Hopitaux Universitaires Paris-Sud, Le Kremlin-Bicetre, France

 

References

 

1 Lay AH, Wang X, Morgan MSC et al. Detecting positive surgical margins: utilisation of light-reflectance spectroscopy on ex vivo prostate specimens. BJU Int 2016; 118: 885–9

 

2 Beyer B, Schlomm T, Tennstedt P et al. A feasible and time-efficient adaptation of NeuroSAFE for da Vinci robot-assisted radical prostatectomy. Eur Urol 2014; 66: 138–44

 

3 Aron M, Kaouk JH, Hegarty NJ et al. Second prize: preliminary experience with the Niris optical coherence tomography system during laparoscopic and robotic prostatectomy. J Endourol 2007; 21: 814–8

 

4 Lopez A, Zlatev DV, Mach KE et al. Intraoperative optical biopsy during robotic assisted radical prostatectomy using confocal endomicroscopy. J Urol 2016; 195: 1110–7

 

5 Wang M, Tulman DB, Sholl AB et al. Gigapixel surface imaging ofradical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy. Sci Rep 2016; 6: 27419

 

6 Tewari AK, Shevchuk MM, Sterling J et al. Multiphoton microscopy for structure identification in human prostate and periprostatic tissue: implications in prostate cancer surgery. BJU Int 2011; 108: 1421–9

 

Article of the Week: VEGFR1 rs9582036 as a predictive biomarker in m-ccRCC patients treated with sunitinib

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

If you only have time to read one article this week, it should be this one.

Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib

Benoit Beuselinck*,†,‡, Johnny Jean-Baptiste*,†, Patrick Schoffski‡, Gabrielle Couchy*,†, Clement Meiller*,†, Frederic Rolland§, Yves Allory, Steven Joniau**, Virginie Verkarre††, Reza Elaidi‡‡, Evelyne Lerut§§, Tania Roskams§§, Jean-Jacques Patard¶¶, Stephane Oudard†,‡‡, Arnaud Mejean***, Diether Lambrechts†††,‡‡‡ and Jessica Zucman-Rossi*,†,‡‡

 

*Inserm, UMR-1162, Genomique fonctionnelle des tumeurs solides, IUH, Paris, †Sorbonne Paris Cite, Facultede Medecine, Universite Paris Descartes, Paris, France, ‡Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, §Department of Medical Oncology, Institut de Cancerologie de l’Ouest, Saint Herblain, Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Henri Mondor, Creteil, France, **Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, ††Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants malades, Paris, ‡‡Department of Medical Oncology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, §§Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ¶¶Department of Urology, Hopital Bicetre, Le Kremlin-Bicetre, ***Department of
Urology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, †††Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, and ‡‡‡Vesalius Research Center, VIB, Leuven, Belgium

 

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Abstract

Objectives

To validate vascular endothelial growth factor receptor-1 (VEGFR1) single nucleotide polymorphism (SNP) rs9582036 as a potential predictive biomarker in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib.

Materials and Methods

m-ccRCC patients receiving sunitinib as first-line targeted therapy were included. We assessed response rate (RR), progression-free survival (PFS), overall survival (OS), and clinical and biochemical parameters associated with outcome. We genotyped five VEGFR1 SNPs: rs9582036, rs7993418, rs9554320, rs9554316 and rs9513070. Association with outcome was studied by univariate analysis and by multivariate Cox regression. Additionally, we updated survival data of our discovery cohort as described previously.

aotwdec3-results

Results

Sixty-nine patients were included in the validation cohort. rs9582036 CC-carriers had a poorer PFS (8 vs 12 months, P = 0.02) and OS (11 vs 27 months, P = 0.003) compared to AC/AA-carriers. rs7993418 CC-carriers had a poorer OS (8 vs 24 months, P = 0.004) compared to TC/TT-carriers. rs9554320 AA-carriers had a poorer RR (0% vs 53%, P = 0.009), PFS (5 vs 12 months, P = 0.003) and OS (10 vs 25 months, P = 0.004) compared to AC/CC-carriers. When pooling patients from the discovery cohort, as described previously (n = 88), and the validation cohort, in the total series of 157 patients, rs9582036 CC-carriers had a poorer RR (8% vs 49%, P = 0.004), PFS (8 vs 14 months, P = 0.003) and OS (13 vs 30 months, P = 0.0004) compared to AC/AA-carriers. Unfavorable prognostic markers at start of sunitinib were well balanced between rs9582036 CC- and AC/AA-carriers.

Conclusion

VEGFR1 rs9582036 is a candidate predictive biomarker in m-ccRCC-patients treated with sunitinib.

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Editorial: SNP of the VEGFR – a promising biomarker in mRCC

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Despite earlier detection of localised renal tumours, the resultant tumour down-staging, and an ever-increasing armamentarium of systemic therapies available for metastatic RCC (mRCC), population-level RCC mortality data has failed to show significant improvement in survival. The increasing understanding of RCC biology, specifically the tyrosine kinase signalling pathway, has sparked the development and USA Food and Drug Administration (FDA)-approval of four tyrosine kinase inhibitors (TKIs) and one anti-vascular endothelial growth factor receptor (VEGFR) antibody. Additionally, immunotherapies in the form of interferon, interleukin 2 cytokine therapy and the advent of checkpoint inhibitors further expands the options for treatment of mRCC. This poses a clinical dilemma; although clinical trials are showing improved survival outcomes, there is uncertainty about to how best to sequence the available therapies. In lieu of long, expensive clinical trials exploring all possible permutations and in order to personalise therapy for specific patients, we are hopeful the exploration of biomarkers (such as the authors have performed) will fill this void and aid in the selection of therapies based on likelihood of patient response.

While studies do not seem to show a reliable correlation between von Hippel-Lindau gene status or expression levels of hypoxia-inducible factor and response to targeted therapy [1], recent exploration of single nucleotide polymorphisms (SNPs) of the VEGFR has yielded promising results with certain VEGFR1 SNPs (in particular, SNP rs9582036 with CC alleles) associated with a significantly worse overall survival when treated with a TKI [2-4]. The authors previously published on a discovery cohort of patients with mRCC treated with sunitinib and found results consistent with the aforementioned exploratory studies; the CC-variant in rs9582036 was associated with worse response rate, progression-free survival (PFS), and overall survival (14 months vs 31 months; P = 0.008) on multivariate analysis [5, 6].

This current study [7] represents their findings of a validation cohort of the potential predictive association of the VEGFR1 SNP rs9582036 in mRCC treated with sunitinib. In all, 69 patients were genotyped and clinical outcomes analysed; results were consistent with their previous discovery cohort, and in their pooled analysis of 157 patients they confirmed that the allelic status of the rs9582036 SNP was significantly associated with clinical outcomes. Patients with the CC-variant had poorer response rates (8% vs 49%), worse PFS (8 vs 14 months), and worse overall survival (13 vs 30 months).

This finding certainly could have profound implications in guiding choice of systemic therapies and exploration of the biological meaning of these SNP variants could shed light on why certain tumours or patients fail to respond to targeted therapy. However, further study is warranted. In this current study, VEGFR1 mRNA expression levels at the onset of therapy correlated positively with response to treatment; however, there was no association between the SNP genotypes explored and initial VEGFR1 expression, thus providing no clear mechanistic rationale between this association and clinical outcomes. Furthermore, this rs9582036 sub-group represented a minority (9%) of the patients studied and most patients were Caucasian, limiting the applicability of this genotyping. Additionally, the lack of a placebo control group prevents a conclusion about what to do in the case of a CC-variant rs9852036 patient, i.e. a diminished response to TKIs does not mean TKIs are necessarily ineffective, nor does it mean another therapy will be preferentially more effective.

Despite these issues, if we are to ever realise the promise of personalised medicine, it will be through efforts such as these, which explore the genetic variation in our germline (and tumour) genome that may affect treatment response and to integrate the findings of genomics and epigenomics with clinical outcomes to tailor future therapies.

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Solomon L. Woldu and Vitaly Margulis
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

 

References

 

1 Choueiri TK, Fay AP, Gagnon R et al. The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma. Clin Cancer Res 2013; 19: 5218–26

 

2 Dornbusch J, Walter M, Gottschalk A et al. Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. J Cancer Res Clin Oncol 2016; 142: 1171–82

 

3 Hansen TF, Christensen R, Andersen RF, Garm Spindler KL, Johnsson A, Jakobsen A. The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer: results from the Nordic ACT trial. Int J Colorectal Dis 2012; 27: 715–20

 

4 Lambrechts D, Claes B, Delmar P et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol 2012; 13: 724–33

 

5 Beuselinck B, Karadimou A, Lambrechts D et al. VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib – a multicentric retrospective analysis. Acta Oncol 2014; 53: 103–12

 

6 Beuselinck B, Karadimou A, Lambrechts D et al. Single- nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2013; 108: 887–900

 

7 Beuselinck B, Jean-Baptiste J, Schoffski P et al. Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib. BJU Int 2016; 118: 890–901

 

Video: VEGFR1 rs9582036 as a predictive biomarker in m-ccRCC patients treated with sunitinib

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Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib

Benoit Beuselinck*,†,‡, Johnny Jean-Baptiste*,†, Patrick Schoffski‡, Gabrielle Couchy*,†, Clement Meiller*,†, Frederic Rolland§, Yves Allory, Steven Joniau**, Virginie Verkarre††, Reza Elaidi‡‡, Evelyne Lerut§§, Tania Roskams§§, Jean-Jacques Patard¶¶, Stephane Oudard†,‡‡, Arnaud Mejean***, Diether Lambrechts†††,‡‡‡ and Jessica Zucman-Rossi*,†,‡‡

 

*Inserm, UMR-1162, Genomique fonctionnelle des tumeurs solides, IUH, Paris, †Sorbonne Paris Cite, Facultede Medecine, Universite Paris Descartes, Paris, France, ‡Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, §Department of Medical Oncology, Institut de Cancerologie de l’Ouest, Saint Herblain, Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Henri Mondor, Creteil, France, **Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, ††Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants malades, Paris, ‡‡Department of Medical Oncology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, §§Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ¶¶Department of Urology, Hopital Bicetre, Le Kremlin-Bicetre, ***Department of Urology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, †††Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, and ‡‡‡Vesalius Research Center, VIB, Leuven, Belgium

 

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Abstract

Objectives

To validate vascular endothelial growth factor receptor-1 (VEGFR1) single nucleotide polymorphism (SNP) rs9582036 as a potential predictive biomarker in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib.

Materials and Methods

m-ccRCC patients receiving sunitinib as first-line targeted therapy were included. We assessed response rate (RR), progression-free survival (PFS), overall survival (OS), and clinical and biochemical parameters associated with outcome. We genotyped five VEGFR1 SNPs: rs9582036, rs7993418, rs9554320, rs9554316 and rs9513070. Association with outcome was studied by univariate analysis and by multivariate Cox regression. Additionally, we updated survival data of our discovery cohort as described previously.

aotwdec3-results

Results

Sixty-nine patients were included in the validation cohort. rs9582036 CC-carriers had a poorer PFS (8 vs 12 months, P = 0.02) and OS (11 vs 27 months, P = 0.003) compared to AC/AA-carriers. rs7993418 CC-carriers had a poorer OS (8 vs 24 months, P = 0.004) compared to TC/TT-carriers. rs9554320 AA-carriers had a poorer RR (0% vs 53%, P = 0.009), PFS (5 vs 12 months, P = 0.003) and OS (10 vs 25 months, P = 0.004) compared to AC/CC-carriers. When pooling patients from the discovery cohort, as described previously (n = 88), and the validation cohort, in the total series of 157 patients, rs9582036 CC-carriers had a poorer RR (8% vs 49%, P = 0.004), PFS (8 vs 14 months, P = 0.003) and OS (13 vs 30 months, P = 0.0004) compared to AC/AA-carriers. Unfavorable prognostic markers at start of sunitinib were well balanced between rs9582036 CC- and AC/AA-carriers.

Conclusion

VEGFR1 rs9582036 is a candidate predictive biomarker in m-ccRCC-patients treated with sunitinib.

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Article of the Week: Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant PCa affects PSA flare

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare

Masaki Shiota*, Akira Yokomizo*, Ario Takeuchi*, Keijiro Kiyoshim a*,Junichi Inokuchi*, Katsunori Tatsugami*, Ken-ichiro Shiga†, Hirofumi Koga†, Akito Yamaguchi†, Seiji Naito† and Masatoshi Eto*
*Department of Urology, Graduate School of Medical Sciences, Kyushu University, and †Division of Urology, Harasanshin Hospital, Fukuoka, Japan
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Abstract

Objective

To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10–20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. In the world of fat-burners, Clenbuterol has a place of importance among bodybuilders and others. Several athletes also utilize the drug for its long list of potential benefits. While great care should be taken with something like this, there are nonetheless some advantages that should be considered. For example, understand that Clenbuterol is not a steroid, Red Thai Kratom is one of the most widely used for beginners.

Patients and Methods

This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease.

aotwdec2-results

Results

PSA flare was recognized in 7.0–23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure.

Conclusions

Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.

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Editorial: What is behind the flare phenomenon?

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In the present issue of BJUI, Shiota et al. [1] propose a potential explanation for the PSA ‘flare’ observed in many patients as they initiate docetaxel chemotherapy. The PSA flare or ‘surge’ phenomenon has been noted for years, and may affect up to one-fifth of patients treated with docetaxel. Multiple reviews have concluded that the development of flare does not influence disease-specific outcomes [2, 3], which is further supported by the present paper [1]. However, there are no pragmatic analyses of how this flare is interpreted in real-world practice. As treatment of prostate cancer becomes more complex, and definitions of progression on treatment continue to evolve, practitioners must be aware of this laboratory pattern to avoid unnecessary discontinuation of therapy based on early PSA change alone.

The cause of such flare has only been postulated. Many suggest that it could be caused by PSA release from lysed cells or by aberrant androgen receptor (AR) activation, but other theories are also proposed. The present paper supports the hypothesis that transactivation of the AR by corticosteroids contributes to the flare. Further translational work may provide additional insight into this mechanism, but we have long discussed the influence of steroid administration on the AR. Similar flare phenomena have been observed with cabazitaxel [4] and abiraterone acetate, two regimens that are reliant on concomitant steroid use. Interestingly, patients in the present cohort treated with steroids before treatment initiation had less flare. This is a unique observation in that steroid activation may occur, but at an earlier time point, mitigating the coincidental rise when starting chemotherapy. Just as one must be aware of the existence of flare to avoid premature abandonment of a regimen, perhaps we now must take into account previous steroid use and interpret a PSA rise slightly differently. The present work is certainly hypothesis-generating and larger series may offer additional insight.

Recent data have shown significant survival gains using docetaxel in the hormone-sensitive metastatic setting, in which patients received chemotherapy without daily prednisone use [5]. Practitioners may find themselves managing patients on docetaxel chemotherapy who may or may not be taking corticosteroids. These recent data will probably also contribute to a ‘resurgence’ of sorts in the use of chemotherapy, and remembrance of the flare is important. We may find ourselves interpreting PSA flare in multiple steps: we will assess the agent (i.e. a taxane) and the use of prednisone (i.e. present prior to treatment or initiated at the start) and then interpret the results accordingly. The work of Shiota et al. in this observational study continues to highlight the flare phenomenon and the fact that the use of steroids before, or during, chemotherapy may further complicate our approach to the care of patients on chemotherapy. The field is moving forward and, as we work to understand the intricacies of PSA response, we also create more and more reliance on providers to really marry the art and science of medicine.

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Elizabeth R. Kessler

 

Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

 

References

 

1 Shiota M, Yokomizo A, Takeuchi A et al. Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare. BJU Int 2016; 118: 880–4

 

2 Sella A, Sternberg CN, Skoneczna I, Kovel S. Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer. BJU Int 2008; 102: 1607–9

 

3 Nelius T, Klatte T, de Riese W, Filleur S. Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy. Int Urol Nephrol 2008; 40: 97–104

 

4 Angelergues A, Maillet D, Flechon A et al. Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer. Eur J Cancer 2014; 50: 1602–9

 

5 Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–46

 

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