CONFERENCE SCENE For reprint orders, please contact: [email protected]
Selected news from the 2014 Genitourinary Cancers Symposium: translating novel strategies into clinical practice Maristella Bianconi*,‡,1, Matteo Santoni1, Francesco Massari2, Luca Faloppi1, Michela Del Prete1, Riccardo Giampieri1, Chiara Ciccarese2, Alessandra Modena2, Giampalo Tortora2, Mario Scartozzi‡,1 & Stefano Cascinu1 2014 Genitourinary Cancers Symposium San Francisco, CA, USA, 30 January–1 February 2014 The American Society of Clinical Oncology symposium dedicated to genitourinary tumors represents an unmissable opportunity for the whole oncology community with a special interest in the diagnosis and treatment of genitorurinary tract malignancies, in particular kidney and prostate tumors. The 2014 Genitourinary Cancers Symposium focused attention on the need to find a personalized therapy for metastatic renal cell carcinoma and castration-resistant prostate cancer patients. The development of biomarkers for tumor response and/or resistance will represent a major step in this context and has been the focus of several researches at the symposium. The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium is one of the few key events in which researchers from different countries gather together to show the results of newly acquired knowledge, define and uniform standards of care, debate how recently validated evidences affect clinical practice, and try to identify further research fields to be explored. The 2014 Genitourinary Cancers Symposium, held in San Francisco (CA, USA), has not failed to meet expectations. At present there are two main areas of research: renal cell carcinoma (RCC) issues concern the identification of molecular markers with prognostic and predictive value to guide therapeutic decisions for a foreseeable individualized treatment strategy, reducing ineffective treatments and unnecessary toxicities. Several biomarkers have been identified; none has yet been validated prospectively. The other field of research is to define the appropriate treatment sequence and research for possible biomarkers, as part of a more accurate therapeutic planning strategy in patients with castration-resistant prostate cancer (CRPC); these efforts result from the recent approval of new drugs. The following is a selection of those studies we expect to pave the way towards new therapeutic advances in the near future.
KEYWORDS
• castration resistance • PD-L1 • prostate cancer • renal cell carcinoma
RCC: multiple options for different patients? In 2013, the publication of data from the COMPARZ study, a Phase III trial comparing sunitinib and pazopanib, with the primary end point of progression-free survival (PFS), showed a noninferiority Department of Medical Oncology, AOU Ospedali Riuniti – Polytechnic University of the Marche Region, Ancona, Italy Department of Medical Oncology, University of Verona, Verona, Italy *Author for correspondence: [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.14.185 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2103–2106
part of
ISSN 1479-6694
2103
Conference Scene Bianconi, Santoni, Massari et al. of these two drugs [1] . Thus, biomarkers to separate patients more likely to respond to each of them are strongly needed. Kattan et al. tried to develop and validate prognostic nomograms for predicting the probability of 12-month PFS and 30-month overall survival (OS) for patients who received pazopanib [2] . These predictors included hematological tests (neutrophil count, platelet count, LDH, and alkaline phosphatase, calcium, albumin and hemoglobin) and clinical parameters (Karnofsky score; months from diagnosis to treatment; number of metastatic sites; and presence of lung, liver and bone metastases). This nomogram proved to be able to predict PFS and OS in these patients. Choueiri et al. analyzed the correlation of PD-L1 involved in the apoptotic process, tumor expression and treatment outcomes in the COMPARZ study population [3] . Tumor PD-L1 expression has been associated with poor outcomes in RCC but has not been investigated before as a biomarker of response in RCC patients receiving standard VEGF-targeted therapy. PD-L1 was evaluated through immunohistochemistry expression. In addition, intratumor CD8 - T cells were quantified morphometrically. Increased PD-L1, or increased PD-L1 plus tumor CD8- T cell counts, were associated with shorter OS. PD-L1 was also assessed in non-clear cell (cc) histologies by Fay et al. [4] . PD-L1 expression proved variable in non-ccRCC and depends on histology and tumor versus immune cells scoring. Only PD-L1 positivity in tumor cells was associated with aggressive features. The authors thus suggested that patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway. EVERSUN, a Phase II trial evaluating the alternating administration of sunitinib and everolimus as first-line treatment for advanced RCC patients, was presented at the meeting. This regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. Furthermore, it presented the opportunity to assess circulating biomarkers at baseline in the patients enrolled in this study. Baseline serum was tested for protein biomarkers: bFGF; CAIX; e-selectin; HIF1; IL-8; NGAL; PDGF; PLGF; vCAM; VEGF-A, C and D; and VEGFR1–3. This exploratory study did not find strong statistical evidence for the prognostic value of these circulating baseline biomarkers [5] .
2104
Future Oncol. (2014) 10(14)
Escudier et al. conducted another biomarker analysis on patients included in the GOLD study, a Phase III trial comparing dovitinib and sorafenib as third-line treatment [6] . As previously reported, dovitinib did not improve PFS and OS compared with sorafenib. Plasma samples were obtained longitudinally throughout the study. Baseline plasma biomarker levels were not predictive of dovitinib or sorafenib PFS or OS. However, strong prognostic effects, particularly for OS, were observed. High baseline cKIT and low baseline FGF2, HGF, PlGF, sVEGFR1, VEGFA and VEGFD were associated with better OS for both dovitinib and sorafenib. The authors thus stated that baseline plasma biomarkers are prognostic but not predictive in the third-line. The exonic single nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in ccRCC [7] . Hakimi et al. suggested that the exonic MET variant rs11762213 is an independent predictor of adverse cancer-specific survival and time-to-recurrence in ccRCC and could be integrated into clinical practice for prognostic stratification [8] . Gene-expression analysis showed that inherited variation of MET influences expression of the gene in normal kidney tissue, as well. Another proposed prognostic molecular marker that needs further validation is PBRM1/ BAP1 protein expression. Joseph et al. were able to quantify PBRM1/BAP1 through immunohistochemistry in the vast majority of tumors examined (87%), and found that PRBM1/BAP1 expression strongly associates with both cancerspecific survival and pathologic tumor characteristics, such as tumor size, stage, grade and tumor necrosis [9] . Prostate cancer: beyond castration resistance at last At the 2014 Genitourinary Cancers Symposium, Beer et al. presented the results from the interim analysis of the PREVAIL trial, a large Phase III trial evaluating enzalutamide against placebo in chemotherapy-naive men with metastatic CRPC (mCRPC) progressed on androgen deprivation therapy [10] . Enzalutamide was associated with a 30% risk reduction for death and an 81% risk reduction for radiographic progression or death. The estimated median OS in the enzalutamide arm was 32.4 months compared with 30.2 months in the placebo arm. Median
future science group
Selected news from the 2014 Genitourinary Cancers Symposium radiographic PFS had not yet been reached at the time of the analysis in the enzalutamide arm but was 3.9 months in the placebo arm. Notably, enzalutamide delayed the median time to chemotherapy initiation by 17 months when compared with placebo. Armstrong et al. [11] performed a genomic analysis on circulating tumor cells (CTCs) from men with mCRPC treated with enzalutamide. They developed a novel method for CTC array comparative genomic hybridization (CGH) that identified genomic alterations, such as androgen receptor (AR) amplification or focal deletions; deletions of CHD1, Rb, PHLLP, FGFR2, FOXA1 and NCOA2; and amplifications of EZH2 and MYC, previously reported in mCRPC. AR amplification was noted in a man with mCRPC who responded to enzalutamide; loss of AR amplification and gain of MYCN and c-MET amplification were present at progression. Whole-exome sequencing demonstratedd acquired PTEN, MAGI1, SMAD4 and RB1 mutations, as well as AR region deletion detected by CGH in a patient who progressed to enzalutamide. Altogether, these data open the door to the employment of CGH and whole-exome sequencing for the identification of previously validated and novel genomic alterations predictive of enzalutamide efficacy and resistance in the clinical practice. The enumeration and molecular characterization of CTCs may allow sequential evaluation of drug-induced changes and mechanisms of drug resistance. Ferraldeschi et al. [12] utilized the Epic Sciences platform to identify and characterize traditional CTCs (CK-CD45 +) and other CTC subpopulations (CK- CD45 - CTCs and small CTCs) in sequential samples obtained from mCRPC patients treated with abiraterone acetate, enzalutamide or cabazitaxel. They reported drug-induced changes in count of CTC subpopulations, AR expression and AR subcellular localization. Hoving et al. [13] conducted a retrospective pilot study to test the adequacy for targeted imaging of the expression of PSMA, EpCAM, VEGF and GRPR in 17 locally recurrent prostate cancers after brachytherapy or external beam radiotherapy. Staining for PSMA was seen in 100%, EpCAM in 82.3%, VEGF in 82.3% and GRPR in 100% of prostate cancer specimens, whereas only GRPR was seen in specimens’ stromal compartments. Based on the absence of stromal staining of PSMA, EpCAM and VEGF,
future science group
Conference Scene
the authors stated that these markers would be used for targeted imaging of locally recurrent prostate cancer after radiotherapy. Mahon et al. [14] evaluated mGSTP1 as a potential plasma epigenetic marker of prognosis and response to chemotherapy in CRPC. Aberrant DNA methylation is a hallmark of carcinogenesis and GSTP1 hypermethylation is the most common molecular alteration in human prostate cancer. The authors have identified plasma mGSTP1 levels as a potential prognostic marker in men with CRPC as well as a potential marker for cytotoxic chemotherapy. In addition, they validated these findings in an independent Phase II cohort. Another proposed prognostic molecular marker that needs further validation is IL-23, a member of the IL-12 family of cytokines with pro-inflammatory properties. Yousif et al. evaluated prospectively the prognostic importance of circulating IL-23 in 140 men diagnosed with stages I–IV prostate cancer through downstream signaling. They found significant higher systemic IL-23 levels in the metastatic group as compared with non-metastatic patients. Moreover, higher IL-23 levels were associated with shorter OS, suggesting a potential role of IL-23 as an attractive therapeutic target or a biomarker in metastatic prostate cancer [15] . Conclusion Data presented at the 2014 Genitourinary Cancers Symposium are the epitome of a changing landscape in renal and prostate cancers. The introduction of new drugs in recent years in both these malignancies saw a reverse in treatment strategies and outcomes. These transformations led to a need to a wider understanding of these tumors biology and pathways. Numerous data and new findings were presented in 2013. Thus, 2014 data proposed in San Francisco (CA, USA) generated many attractive hypotheses that warrant further investigation. Promising biomarkers of predictive or prognostic potential were presented in both renal and prostate tumors, derived mainly from biological subanalysis of major trials. These markers, although interesting, need to be validated to prove useful in everyday clinical practice, directing clinicians’ therapeutic decisions. The ultimate goal will be to exploit knowledge to diversify our cache of available targets and agents for the treatment of patients with renal and prostate cancer.
www.futuremedicine.com
2105
Conference Scene Bianconi, Santoni, Massari et al. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
References 1
2
3
6
Motzer RJ, Hutson TE, Cella D et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 369, 722–731 (2013). Kattan MW, Sternberg CN, Mehmud F et al. Development and validation of a prognostic nomogram for progression-free and overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib. J. Clin. Oncol. 32(Suppl. 4), Abstract 405 (2014). Choueiri TK, Figueroa DJ, Liu Y et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors: COMPARZ study analysis. J. Clin. Oncol. 32(Suppl. 4), Abstract 416 (2014).
4
Fay AP, Callea M, Gray KP et al. PD-L1 expression in non-clear cell renal cell carcinoma. J. Clin. Oncol. 32(Suppl. 4), Abstract 424 (2014).
5
Yip S, Pavlakis N, Harvie R et al. Circulating biomarkers and outcomes in a single-arm Phase II trial of first-line sunitinib alternating with everolimus for advanced renal cell carcinoma (aRCC): EVERSUN ANZUP trial 0901. J. Clin. Oncol. 32(Suppl. 4), Abstract 428 (2014).
2106
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Escudier BJ, Porta C, Squires M et al. Biomarker analysis from a Phase III trial (GOLD) of dovitinib (Dov) versus sorafenib (Sor) in patients with metastatic renal cell carcinoma after one prior VEGF pathway– targeted therapy and one prior mTOR inhibitor therapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 473 (2014).
7
Schutz FA1, Pomerantz MM, Gray KP et al. Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study. Lancet Oncol. 14(1), 81–87 (2013).
8
Hakimi AA, Ostrovnaya I, Jacobsen A et al. Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. J. Clin. Oncol. 32(Suppl.4), Abstract 395 (2014).
9
Joseph RW, Kapur P, Serie D et al. Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival. J. Clin. Oncol. 32(Suppl. 4), Abstract 414 (2014).
10 Beer TM, Armstrong AJ, Sternberg CN et al.
Enzalutamide in men with chemotherapynaive metastatic prostate cancer (mCRPC): results of Phase III PREVAIL study. J. Clin. Oncol. 32(Suppl.4), Abstract LBA1^ (2014). 11 Armstrong AJ, Li J, Beaver J et al. Genomic
from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 65 (2014). 12 Ferraldeschi R, Krupa R, Louw J et al.
Sequential monitoring and characterization of circulating tumor cells (CTCs) using the epic sciences platform in metastatic castrationresistant prostate cancer (mCRPC) patients (pts) treated with recently approved therapeutics. J. Clin. Oncol. 32(Suppl. 4), Abstract 78 (2014). 13 Hoving H, Ananias HJK, Rybalov M et al.
PSMA, EpCAM, VEGF, and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 201 (2014). 14 Mahon KL, Qu W, Devaney J et al.
Methylated glutathione s-transferase 1 (mGSTP1) as a potential plasma epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer (CRPC). J. Clin. Oncol. 32(Suppl. 4), Abstract 11 (2014). 15 Yousif NG, Al-Hasani S, Slimani H et al. The
role of IL-23 in regulating metastatic prostate cancer through STAT-3/ROR-gamma signaling. J. Clin. Oncol. 32(Suppl. 4), Abstract 142 (2014).
analysis of circulating tumor cells (CTCs)
Future Oncol. (2014) 10(14)
future science group
Selected news from the 2014 Genitourinary Cancers Symposium: translating novel strategies into clinical practice Maristella Bianconi*,‡,1, Matteo Santoni1, Francesco Massari2, Luca Faloppi1, Michela Del Prete1, Riccardo Giampieri1, Chiara Ciccarese2, Alessandra Modena2, Giampalo Tortora2, Mario Scartozzi‡,1 & Stefano Cascinu1 2014 Genitourinary Cancers Symposium San Francisco, CA, USA, 30 January–1 February 2014 The American Society of Clinical Oncology symposium dedicated to genitourinary tumors represents an unmissable opportunity for the whole oncology community with a special interest in the diagnosis and treatment of genitorurinary tract malignancies, in particular kidney and prostate tumors. The 2014 Genitourinary Cancers Symposium focused attention on the need to find a personalized therapy for metastatic renal cell carcinoma and castration-resistant prostate cancer patients. The development of biomarkers for tumor response and/or resistance will represent a major step in this context and has been the focus of several researches at the symposium. The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium is one of the few key events in which researchers from different countries gather together to show the results of newly acquired knowledge, define and uniform standards of care, debate how recently validated evidences affect clinical practice, and try to identify further research fields to be explored. The 2014 Genitourinary Cancers Symposium, held in San Francisco (CA, USA), has not failed to meet expectations. At present there are two main areas of research: renal cell carcinoma (RCC) issues concern the identification of molecular markers with prognostic and predictive value to guide therapeutic decisions for a foreseeable individualized treatment strategy, reducing ineffective treatments and unnecessary toxicities. Several biomarkers have been identified; none has yet been validated prospectively. The other field of research is to define the appropriate treatment sequence and research for possible biomarkers, as part of a more accurate therapeutic planning strategy in patients with castration-resistant prostate cancer (CRPC); these efforts result from the recent approval of new drugs. The following is a selection of those studies we expect to pave the way towards new therapeutic advances in the near future.
KEYWORDS
• castration resistance • PD-L1 • prostate cancer • renal cell carcinoma
RCC: multiple options for different patients? In 2013, the publication of data from the COMPARZ study, a Phase III trial comparing sunitinib and pazopanib, with the primary end point of progression-free survival (PFS), showed a noninferiority Department of Medical Oncology, AOU Ospedali Riuniti – Polytechnic University of the Marche Region, Ancona, Italy Department of Medical Oncology, University of Verona, Verona, Italy *Author for correspondence: [email protected] ‡ Authors contributed equally 1 2
10.2217/FON.14.185 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2103–2106
part of
ISSN 1479-6694
2103
Conference Scene Bianconi, Santoni, Massari et al. of these two drugs [1] . Thus, biomarkers to separate patients more likely to respond to each of them are strongly needed. Kattan et al. tried to develop and validate prognostic nomograms for predicting the probability of 12-month PFS and 30-month overall survival (OS) for patients who received pazopanib [2] . These predictors included hematological tests (neutrophil count, platelet count, LDH, and alkaline phosphatase, calcium, albumin and hemoglobin) and clinical parameters (Karnofsky score; months from diagnosis to treatment; number of metastatic sites; and presence of lung, liver and bone metastases). This nomogram proved to be able to predict PFS and OS in these patients. Choueiri et al. analyzed the correlation of PD-L1 involved in the apoptotic process, tumor expression and treatment outcomes in the COMPARZ study population [3] . Tumor PD-L1 expression has been associated with poor outcomes in RCC but has not been investigated before as a biomarker of response in RCC patients receiving standard VEGF-targeted therapy. PD-L1 was evaluated through immunohistochemistry expression. In addition, intratumor CD8 - T cells were quantified morphometrically. Increased PD-L1, or increased PD-L1 plus tumor CD8- T cell counts, were associated with shorter OS. PD-L1 was also assessed in non-clear cell (cc) histologies by Fay et al. [4] . PD-L1 expression proved variable in non-ccRCC and depends on histology and tumor versus immune cells scoring. Only PD-L1 positivity in tumor cells was associated with aggressive features. The authors thus suggested that patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway. EVERSUN, a Phase II trial evaluating the alternating administration of sunitinib and everolimus as first-line treatment for advanced RCC patients, was presented at the meeting. This regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. Furthermore, it presented the opportunity to assess circulating biomarkers at baseline in the patients enrolled in this study. Baseline serum was tested for protein biomarkers: bFGF; CAIX; e-selectin; HIF1; IL-8; NGAL; PDGF; PLGF; vCAM; VEGF-A, C and D; and VEGFR1–3. This exploratory study did not find strong statistical evidence for the prognostic value of these circulating baseline biomarkers [5] .
2104
Future Oncol. (2014) 10(14)
Escudier et al. conducted another biomarker analysis on patients included in the GOLD study, a Phase III trial comparing dovitinib and sorafenib as third-line treatment [6] . As previously reported, dovitinib did not improve PFS and OS compared with sorafenib. Plasma samples were obtained longitudinally throughout the study. Baseline plasma biomarker levels were not predictive of dovitinib or sorafenib PFS or OS. However, strong prognostic effects, particularly for OS, were observed. High baseline cKIT and low baseline FGF2, HGF, PlGF, sVEGFR1, VEGFA and VEGFD were associated with better OS for both dovitinib and sorafenib. The authors thus stated that baseline plasma biomarkers are prognostic but not predictive in the third-line. The exonic single nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in ccRCC [7] . Hakimi et al. suggested that the exonic MET variant rs11762213 is an independent predictor of adverse cancer-specific survival and time-to-recurrence in ccRCC and could be integrated into clinical practice for prognostic stratification [8] . Gene-expression analysis showed that inherited variation of MET influences expression of the gene in normal kidney tissue, as well. Another proposed prognostic molecular marker that needs further validation is PBRM1/ BAP1 protein expression. Joseph et al. were able to quantify PBRM1/BAP1 through immunohistochemistry in the vast majority of tumors examined (87%), and found that PRBM1/BAP1 expression strongly associates with both cancerspecific survival and pathologic tumor characteristics, such as tumor size, stage, grade and tumor necrosis [9] . Prostate cancer: beyond castration resistance at last At the 2014 Genitourinary Cancers Symposium, Beer et al. presented the results from the interim analysis of the PREVAIL trial, a large Phase III trial evaluating enzalutamide against placebo in chemotherapy-naive men with metastatic CRPC (mCRPC) progressed on androgen deprivation therapy [10] . Enzalutamide was associated with a 30% risk reduction for death and an 81% risk reduction for radiographic progression or death. The estimated median OS in the enzalutamide arm was 32.4 months compared with 30.2 months in the placebo arm. Median
future science group
Selected news from the 2014 Genitourinary Cancers Symposium radiographic PFS had not yet been reached at the time of the analysis in the enzalutamide arm but was 3.9 months in the placebo arm. Notably, enzalutamide delayed the median time to chemotherapy initiation by 17 months when compared with placebo. Armstrong et al. [11] performed a genomic analysis on circulating tumor cells (CTCs) from men with mCRPC treated with enzalutamide. They developed a novel method for CTC array comparative genomic hybridization (CGH) that identified genomic alterations, such as androgen receptor (AR) amplification or focal deletions; deletions of CHD1, Rb, PHLLP, FGFR2, FOXA1 and NCOA2; and amplifications of EZH2 and MYC, previously reported in mCRPC. AR amplification was noted in a man with mCRPC who responded to enzalutamide; loss of AR amplification and gain of MYCN and c-MET amplification were present at progression. Whole-exome sequencing demonstratedd acquired PTEN, MAGI1, SMAD4 and RB1 mutations, as well as AR region deletion detected by CGH in a patient who progressed to enzalutamide. Altogether, these data open the door to the employment of CGH and whole-exome sequencing for the identification of previously validated and novel genomic alterations predictive of enzalutamide efficacy and resistance in the clinical practice. The enumeration and molecular characterization of CTCs may allow sequential evaluation of drug-induced changes and mechanisms of drug resistance. Ferraldeschi et al. [12] utilized the Epic Sciences platform to identify and characterize traditional CTCs (CK-CD45 +) and other CTC subpopulations (CK- CD45 - CTCs and small CTCs) in sequential samples obtained from mCRPC patients treated with abiraterone acetate, enzalutamide or cabazitaxel. They reported drug-induced changes in count of CTC subpopulations, AR expression and AR subcellular localization. Hoving et al. [13] conducted a retrospective pilot study to test the adequacy for targeted imaging of the expression of PSMA, EpCAM, VEGF and GRPR in 17 locally recurrent prostate cancers after brachytherapy or external beam radiotherapy. Staining for PSMA was seen in 100%, EpCAM in 82.3%, VEGF in 82.3% and GRPR in 100% of prostate cancer specimens, whereas only GRPR was seen in specimens’ stromal compartments. Based on the absence of stromal staining of PSMA, EpCAM and VEGF,
future science group
Conference Scene
the authors stated that these markers would be used for targeted imaging of locally recurrent prostate cancer after radiotherapy. Mahon et al. [14] evaluated mGSTP1 as a potential plasma epigenetic marker of prognosis and response to chemotherapy in CRPC. Aberrant DNA methylation is a hallmark of carcinogenesis and GSTP1 hypermethylation is the most common molecular alteration in human prostate cancer. The authors have identified plasma mGSTP1 levels as a potential prognostic marker in men with CRPC as well as a potential marker for cytotoxic chemotherapy. In addition, they validated these findings in an independent Phase II cohort. Another proposed prognostic molecular marker that needs further validation is IL-23, a member of the IL-12 family of cytokines with pro-inflammatory properties. Yousif et al. evaluated prospectively the prognostic importance of circulating IL-23 in 140 men diagnosed with stages I–IV prostate cancer through downstream signaling. They found significant higher systemic IL-23 levels in the metastatic group as compared with non-metastatic patients. Moreover, higher IL-23 levels were associated with shorter OS, suggesting a potential role of IL-23 as an attractive therapeutic target or a biomarker in metastatic prostate cancer [15] . Conclusion Data presented at the 2014 Genitourinary Cancers Symposium are the epitome of a changing landscape in renal and prostate cancers. The introduction of new drugs in recent years in both these malignancies saw a reverse in treatment strategies and outcomes. These transformations led to a need to a wider understanding of these tumors biology and pathways. Numerous data and new findings were presented in 2013. Thus, 2014 data proposed in San Francisco (CA, USA) generated many attractive hypotheses that warrant further investigation. Promising biomarkers of predictive or prognostic potential were presented in both renal and prostate tumors, derived mainly from biological subanalysis of major trials. These markers, although interesting, need to be validated to prove useful in everyday clinical practice, directing clinicians’ therapeutic decisions. The ultimate goal will be to exploit knowledge to diversify our cache of available targets and agents for the treatment of patients with renal and prostate cancer.
www.futuremedicine.com
2105
Conference Scene Bianconi, Santoni, Massari et al. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
References 1
2
3
6
Motzer RJ, Hutson TE, Cella D et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 369, 722–731 (2013). Kattan MW, Sternberg CN, Mehmud F et al. Development and validation of a prognostic nomogram for progression-free and overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib. J. Clin. Oncol. 32(Suppl. 4), Abstract 405 (2014). Choueiri TK, Figueroa DJ, Liu Y et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors: COMPARZ study analysis. J. Clin. Oncol. 32(Suppl. 4), Abstract 416 (2014).
4
Fay AP, Callea M, Gray KP et al. PD-L1 expression in non-clear cell renal cell carcinoma. J. Clin. Oncol. 32(Suppl. 4), Abstract 424 (2014).
5
Yip S, Pavlakis N, Harvie R et al. Circulating biomarkers and outcomes in a single-arm Phase II trial of first-line sunitinib alternating with everolimus for advanced renal cell carcinoma (aRCC): EVERSUN ANZUP trial 0901. J. Clin. Oncol. 32(Suppl. 4), Abstract 428 (2014).
2106
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Escudier BJ, Porta C, Squires M et al. Biomarker analysis from a Phase III trial (GOLD) of dovitinib (Dov) versus sorafenib (Sor) in patients with metastatic renal cell carcinoma after one prior VEGF pathway– targeted therapy and one prior mTOR inhibitor therapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 473 (2014).
7
Schutz FA1, Pomerantz MM, Gray KP et al. Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study. Lancet Oncol. 14(1), 81–87 (2013).
8
Hakimi AA, Ostrovnaya I, Jacobsen A et al. Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. J. Clin. Oncol. 32(Suppl.4), Abstract 395 (2014).
9
Joseph RW, Kapur P, Serie D et al. Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival. J. Clin. Oncol. 32(Suppl. 4), Abstract 414 (2014).
10 Beer TM, Armstrong AJ, Sternberg CN et al.
Enzalutamide in men with chemotherapynaive metastatic prostate cancer (mCRPC): results of Phase III PREVAIL study. J. Clin. Oncol. 32(Suppl.4), Abstract LBA1^ (2014). 11 Armstrong AJ, Li J, Beaver J et al. Genomic
from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 65 (2014). 12 Ferraldeschi R, Krupa R, Louw J et al.
Sequential monitoring and characterization of circulating tumor cells (CTCs) using the epic sciences platform in metastatic castrationresistant prostate cancer (mCRPC) patients (pts) treated with recently approved therapeutics. J. Clin. Oncol. 32(Suppl. 4), Abstract 78 (2014). 13 Hoving H, Ananias HJK, Rybalov M et al.
PSMA, EpCAM, VEGF, and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy. J. Clin. Oncol. 32(Suppl. 4), Abstract 201 (2014). 14 Mahon KL, Qu W, Devaney J et al.
Methylated glutathione s-transferase 1 (mGSTP1) as a potential plasma epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer (CRPC). J. Clin. Oncol. 32(Suppl. 4), Abstract 11 (2014). 15 Yousif NG, Al-Hasani S, Slimani H et al. The
role of IL-23 in regulating metastatic prostate cancer through STAT-3/ROR-gamma signaling. J. Clin. Oncol. 32(Suppl. 4), Abstract 142 (2014).
analysis of circulating tumor cells (CTCs)
Future Oncol. (2014) 10(14)
future science group
