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Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye
EURURO-5664; No. of Pages 2 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye Axel Bex * Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
In this month’s issue of European Urology, Shuch et al. [1] review how renal cell carcinoma (RCC) has changed from being regarded as a single malignant phenotype to a heterogeneous disease that requires a differentiated treatment approach. Establishing the subtype of a renal tumour has been recognised as important for planning systemic treatment options in metastatic disease and has implications for follow-up after local treatment with curative intent. Consequently, pretreatment biopsies in metastatic RCC are now recommended in international guidelines. At present, however, the available systemic treatment strategies are limited. Patients with non–clear cell RCC have inferior outcomes with targeted therapy than patients with the clear cell subtype but often are treated with the same class of drugs in the absence of other therapeutic options [2]. In current clinical practice, knowledge of the subtype is probably more important for prognosis and patient counselling than for tailoring treatment. Often diagnosis of metastatic RCC of the non–clear cell subtype implies less clinical benefit, if any at all, from targeted therapy. In addition, the current uncertainty about the signal transduction pathways involved [1], together with only a few drugs available to specifically inhibit them, largely prevent a personalised approach. The paucity of these variants has precluded larger phase III trials to obtain high-level evidence. Some variants are either extremely malignant, such as collecting duct carcinoma and tumours with sarcomatoid differentiation, which are resistant to almost any therapy, or involve rare hereditary tumours with druggable pathways, which serve as a model approach to this disease. An example is the c-MET pathway in papillary RCC. In a phase II study, patients with germline met
proto-oncogene (MET) mutation had a significantly higher response to foretinib, a tyrosine kinase inhibitor targeting MET [3]. However, the specific germline mutations and pathways unravelled in hereditary RCC are less prominently involved in the relatively more common nonhereditary subtypes. Although activating germline mutations of the MET oncogene at 7q31 have been detected primarily in patients with hereditary papillary renal carcinoma, somatic MET mutations were found in only 5–13% of patients with sporadic papillary RCC [4]. On a broader scale, Shuch et al. [1] touch on a more fundamental issue. In a thorough and robust manner, the authors identified the evidence base regarding the current status of morphologic classification of pathologic variants of RCC. Their work identifies the knowledge gap that suggests we have reached a plateau in the use of morphology-based light microscopy to further subtype RCC. The observation of a plateau has become apparent in other areas related to the management of kidney cancer such as prognostic models and outcome of systemic targeted therapy [2]. There is consensus that further molecular and genomic characterisation is the key to advancing our understanding and treatment of RCC, and the paucity of prognostic and predictive biomarkers has been recognised as an unmet need. Recent advances were made by the Cancer Genome Atlas Research Network, and incorporation of tissue analysis in clinical studies to refine prognosis and prediction of outcome has been initiated [5]. Sequencing of human cancer genomes has confirmed a high degree of genetic heterogeneity among cells of the same tumour [6]. Following the pivotal work on intratumour
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.04.029. * Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 5122553; Fax: +31 20 512 2554. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.05.025 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Bex A. Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.025
EURURO-5664; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
heterogeneity of RCC, it is questionable to what extent tumour biopsies—even when taken from morphologically homogenous tumours—represent the same disease [7]. Trunk driver mutations have been identified as consistently involved but are not yet accessible for treatment. At some point in time, metastatic potential is acquired by branched evolution of various subclonal genetic aberrations that are spatially separated within the same tumour [7]; yet, tumour growth and metastasis is not necessarily driven by cell clones carrying the highest number of cancer-driving mutations. The complex paracrine interdependence of subclones in a tumour microenvironment for cancer progression and maintenance is just coming to light [6]. In addition, tumour cells are not static entities; rather, they are dynamic systems rapidly adapting to intracellular pathway inhibition and changes within their microenvironment, resulting in acquired drug resistance [8]. The attempt to detect these dynamic changes by molecular and genomic analysis of spatially and temporally restricted tumour biopsy material seems elusive. Consequently, investigation of circulating tumour cells may be an interesting approach to circumvent this fundamental problem and augment the diagnostic tools already available [9]. The rapid development of sequencing and molecular techniques that allow detection of genetic and ensuing functional changes make the analysis of circulating genetic material ideal to monitor the development of disease and the effect of therapy almost in real time. However, it remains doubtful that we will have the necessary variety of systemic treatment modalities in the near future to inhibit multiple pathways in sequence or combination as they develop over time. To date, no combination of targeted drugs for RCC has been shown to have a benefit over single-agent therapy, and adverse events often limit this approach. Although the early enthusiasm for vascular endothelial growth factor–targeting drugs is making room for more realistic views, immunotherapy is being revived with the introduction of immune checkpoint inhibitor drugs such us ipilimumab, an antiCTLA-4 checkpoint protein antibody, and nivolumab, an antiPD-1 antibody [10]. Combination of those drugs including other forms of immunotherapy, such as adoptive T-cell transfer, and vaccines are being explored to activate a tumour-specific T-cell reaction through synergism, which may circumvent the limitations of inhibitors of the tyrosine kinome and mammalian target of rapamycin.
It is the achievement of this current review [1] to point out the limitations of the morphology-based classification system of RCC. Although advances have been made, only a few patients will benefit from a personalised approach based on the currently available therapeutic options. The morphologybased classification system needs augmentation and further subclassification by molecular techniques to take not only diagnostic accuracy but also prognostic models and treatment choices to the next level. Many studies are ongoing that will advance the management of this disease, which continues to resist curative treatment in the metastatic setting. Conflicts of interest: Axel Bex is the principal investigator of the European Organisation for Research and Treatment of Cancer SURTIME trial, which is supported in part by an educational grant from Pfizer to the sponsor.
References [1] Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biological complexity. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2014.04.029. [2] Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a populationbased study. Lancet Oncol 2013;14:141–8. [3] Choueiri T, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31:181–6. [4] Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 1999;155:517–26. [5] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499:43–9. [6] Cleary AS, Leonard TL, Gestl SA, et al. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 2014;508:113–7. [7] Gerlinger M, Horswell S, Larkin J, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 2014;46:225–33. [8] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [9] Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumour cells – biology and biomarkers. Nat Rev Clin Oncol 2014;11:129–44. [10] Ledford H. The killer within. Nature 2014;508:24–6.
Please cite this article in press as: Bex A. Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.025
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye Axel Bex * Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
In this month’s issue of European Urology, Shuch et al. [1] review how renal cell carcinoma (RCC) has changed from being regarded as a single malignant phenotype to a heterogeneous disease that requires a differentiated treatment approach. Establishing the subtype of a renal tumour has been recognised as important for planning systemic treatment options in metastatic disease and has implications for follow-up after local treatment with curative intent. Consequently, pretreatment biopsies in metastatic RCC are now recommended in international guidelines. At present, however, the available systemic treatment strategies are limited. Patients with non–clear cell RCC have inferior outcomes with targeted therapy than patients with the clear cell subtype but often are treated with the same class of drugs in the absence of other therapeutic options [2]. In current clinical practice, knowledge of the subtype is probably more important for prognosis and patient counselling than for tailoring treatment. Often diagnosis of metastatic RCC of the non–clear cell subtype implies less clinical benefit, if any at all, from targeted therapy. In addition, the current uncertainty about the signal transduction pathways involved [1], together with only a few drugs available to specifically inhibit them, largely prevent a personalised approach. The paucity of these variants has precluded larger phase III trials to obtain high-level evidence. Some variants are either extremely malignant, such as collecting duct carcinoma and tumours with sarcomatoid differentiation, which are resistant to almost any therapy, or involve rare hereditary tumours with druggable pathways, which serve as a model approach to this disease. An example is the c-MET pathway in papillary RCC. In a phase II study, patients with germline met
proto-oncogene (MET) mutation had a significantly higher response to foretinib, a tyrosine kinase inhibitor targeting MET [3]. However, the specific germline mutations and pathways unravelled in hereditary RCC are less prominently involved in the relatively more common nonhereditary subtypes. Although activating germline mutations of the MET oncogene at 7q31 have been detected primarily in patients with hereditary papillary renal carcinoma, somatic MET mutations were found in only 5–13% of patients with sporadic papillary RCC [4]. On a broader scale, Shuch et al. [1] touch on a more fundamental issue. In a thorough and robust manner, the authors identified the evidence base regarding the current status of morphologic classification of pathologic variants of RCC. Their work identifies the knowledge gap that suggests we have reached a plateau in the use of morphology-based light microscopy to further subtype RCC. The observation of a plateau has become apparent in other areas related to the management of kidney cancer such as prognostic models and outcome of systemic targeted therapy [2]. There is consensus that further molecular and genomic characterisation is the key to advancing our understanding and treatment of RCC, and the paucity of prognostic and predictive biomarkers has been recognised as an unmet need. Recent advances were made by the Cancer Genome Atlas Research Network, and incorporation of tissue analysis in clinical studies to refine prognosis and prediction of outcome has been initiated [5]. Sequencing of human cancer genomes has confirmed a high degree of genetic heterogeneity among cells of the same tumour [6]. Following the pivotal work on intratumour
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.04.029. * Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 5122553; Fax: +31 20 512 2554. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.05.025 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Bex A. Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.025
EURURO-5664; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
heterogeneity of RCC, it is questionable to what extent tumour biopsies—even when taken from morphologically homogenous tumours—represent the same disease [7]. Trunk driver mutations have been identified as consistently involved but are not yet accessible for treatment. At some point in time, metastatic potential is acquired by branched evolution of various subclonal genetic aberrations that are spatially separated within the same tumour [7]; yet, tumour growth and metastasis is not necessarily driven by cell clones carrying the highest number of cancer-driving mutations. The complex paracrine interdependence of subclones in a tumour microenvironment for cancer progression and maintenance is just coming to light [6]. In addition, tumour cells are not static entities; rather, they are dynamic systems rapidly adapting to intracellular pathway inhibition and changes within their microenvironment, resulting in acquired drug resistance [8]. The attempt to detect these dynamic changes by molecular and genomic analysis of spatially and temporally restricted tumour biopsy material seems elusive. Consequently, investigation of circulating tumour cells may be an interesting approach to circumvent this fundamental problem and augment the diagnostic tools already available [9]. The rapid development of sequencing and molecular techniques that allow detection of genetic and ensuing functional changes make the analysis of circulating genetic material ideal to monitor the development of disease and the effect of therapy almost in real time. However, it remains doubtful that we will have the necessary variety of systemic treatment modalities in the near future to inhibit multiple pathways in sequence or combination as they develop over time. To date, no combination of targeted drugs for RCC has been shown to have a benefit over single-agent therapy, and adverse events often limit this approach. Although the early enthusiasm for vascular endothelial growth factor–targeting drugs is making room for more realistic views, immunotherapy is being revived with the introduction of immune checkpoint inhibitor drugs such us ipilimumab, an antiCTLA-4 checkpoint protein antibody, and nivolumab, an antiPD-1 antibody [10]. Combination of those drugs including other forms of immunotherapy, such as adoptive T-cell transfer, and vaccines are being explored to activate a tumour-specific T-cell reaction through synergism, which may circumvent the limitations of inhibitors of the tyrosine kinome and mammalian target of rapamycin.
It is the achievement of this current review [1] to point out the limitations of the morphology-based classification system of RCC. Although advances have been made, only a few patients will benefit from a personalised approach based on the currently available therapeutic options. The morphologybased classification system needs augmentation and further subclassification by molecular techniques to take not only diagnostic accuracy but also prognostic models and treatment choices to the next level. Many studies are ongoing that will advance the management of this disease, which continues to resist curative treatment in the metastatic setting. Conflicts of interest: Axel Bex is the principal investigator of the European Organisation for Research and Treatment of Cancer SURTIME trial, which is supported in part by an educational grant from Pfizer to the sponsor.
References [1] Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biological complexity. Eur Urol. In press. http:// dx.doi.org/10.1016/j.eururo.2014.04.029. [2] Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a populationbased study. Lancet Oncol 2013;14:141–8. [3] Choueiri T, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31:181–6. [4] Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 1999;155:517–26. [5] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499:43–9. [6] Cleary AS, Leonard TL, Gestl SA, et al. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 2014;508:113–7. [7] Gerlinger M, Horswell S, Larkin J, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 2014;46:225–33. [8] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [9] Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumour cells – biology and biomarkers. Nat Rev Clin Oncol 2014;11:129–44. [10] Ledford H. The killer within. Nature 2014;508:24–6.
Please cite this article in press as: Bex A. Classification of Renal Cell Carcinoma Subtypes: There Is More than Meets the Eye. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.025