Abstract
Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance. Localized RCC can be successfully managed with surgery, whereas metastatic RCC is refractory to conventional chemotherapy. However, over the past decade, marked advances in the treatment of metastatic RCC have been made, with targeted agents including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mechanistic target of rapamycin complex 1 (mTORC1), being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies, such as nivolumab, have also been added to the armamentarium for metastatic RCC. Here, we provide an overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy.
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Introduction
Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells1 and is among the 10 most common cancers worldwide. Key advances in histopathological and molecular characterization of RCC over the past two decades have led to major revisions in its classification2–5. Major subtypes6 with ≥5% incidence are clear cell RCC (ccRCC)7, papillary RCC (pRCC)8 and chromophobe RCC (chRCC)9 (Fig. 1). The remaining subtypes are very rare (each with ≤1% total incidence)5, and in cases in which a tumour does not fit any subtype in the diagnostic criteria, it is designated as unclassified RCC (uRCC; ∼4% total incidence)10. ccRCC is the most common subtype and accounts for the majority of deaths from kidney cancer and is the focus of this Primer11. Indeed, owing to the predominance of clear cell histology in metastatic disease (83–88%)12,13, tumours with non-clear-cell histology have been grouped as ‘nccRCC’ (Table 1) for feasibility in conducting clinical trials14–16. Furthermore, recent cancer genomic studies have revealed an overt complexity of intra-tumour17–19 and inter-tumour7,20 heterogeneity in ccRCC, which could contribute to the heterogeneous clinical outcomes observed21–23.
Approximately 75% of renal cell carcinomas (RCCs) are clear cell RCC (part a). Papillary RCCs make up ∼15% of all kidney cancers and are divided into two types based on staining features: type 1 (basophilic; part b) and type 2 (eosinophilic; part c). Chromophobe RCCs make up ∼5% of kidney tumours (part d). Other minor subtypes include MiT family translocation RCCs (part e) and collecting duct RCCs (part f). Additional minor subtypes include medullary RCC, clear cell papillary RCC, acquired cystic disease-associated RCC, tubulocystic RCC, mucinous tubular and spindle RCC, succinate dehydrogenase-deficient RCC, hereditary leiomyomatosis, RCC-associated RCC and oncocytoma. Tumours not fitting into any of these categories are designated as unclassified RCC.
Localized RCC can be treated with partial or radical nephrectomy (removal of the kidney)24, ablation (destruction of the malignant tissue with heat or cold)25 or active surveillance (monitoring of tumour growth with periodic radiographic studies)26. Despite nephrectomy with curative intent, ∼30% of patients with ccRCC with localized disease eventually develop metastases27–30, which require systemic therapies and are associated with high mortality. Targeted therapies against vascular endothelial growth factor (VEGF) and mechanistic target of rapamycin (mTOR) pathways have been developed, but treatment response is varied and most patients eventually progress31. However, increased genomic and molecular understanding of metastatic ccRCC has contributed to an unprecedented number of drug approvals in the United States and European Union (currently, 12 approved drugs with six different effective mechanisms of action are approved). In this Primer, we discuss these new approvals and the major progress that has made in the biology of ccRCC that led to their development. Furthermore, we present insights into genomic-based risk and treatment stratification and discuss treatment sequencing and combinations that are paving the way for the future design of personalized clinical management plans.
Epidemiology
Incidence and mortality
Kidney cancer accounts for ∼2% of all cancer diagnoses and cancer deaths worldwide, with incidence rates generally higher in developed countries32 (Fig. 2). Annually, ∼295,000 new kidney cancer cases are diagnosed and ∼134,000 deaths are recorded worldwide33,34. Kidney cancer accounts for ∼63,000 new cases and ∼14,000 deaths yearly in the United States35, and for ∼84,000 new cases and ∼35,000 deaths in Europe36. Men are more affected than women (a 2:1 ratio of new diagnoses).
Estimated age-standardized rates of incidence for both sexes (per 100,000 people) in 2012. Rates are generally higher in developed countries, with the highest incidence in the Czech Republic (reasons why are unknown). Reproduced with permission from Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 30/01/2017.
The median age of patients with RCC in the Surveillance, Epidemiology, and End Results (SEER) database in the United States was 64 years with a near-normal distribution37. Accordingly, when RCC is diagnosed at younger ages (≤46 years, which represents the lowest decile of the age distribution)37,38, the possibility of an underlying hereditary kidney cancer syndrome — which accounts for 3–5% of all RCCs5 — should be considered39,40 (Table 2).
The incidence of RCC is highest in the Czech Republic, with age-standardized annual rates of 22.1 and 9.9 new cases per 100,000 men and women, respectively, over the period 2003–2007 (Ref. 41). The incidence is also very high in the Baltic and eastern European countries, although the reasons for this excess are not known. Overall, incidence rates have been increasing over time in most populations, but mortality rates have levelled off or have been decreasing since the 1990s. This divergent pattern of increasing incidence and decreasing mortality is particularly evident in developed countries. For example, analyses within the SEER database indicate that the increase in RCC incidence is confined to small and localized tumours, probably owing, at least in part, to the increasingly frequent incidental detection — from increased use of abdominal imaging — of small renal masses (tumours ≤4 cm in size) that are unlikely to have metastasized42. The global increases in the prevalence of obesity, an established RCC risk factor, might also play a part in increasing incidence, as well as in influencing clinical outcome41,43.
Risk factors
RCC incidence increases markedly with age and is higher for men than for women. In the United States, incidence varies by ethnic group, with rates highest among Native Americans, Indigenous Alaskans and African Americans, and are lowest among Asian Americans and people of Pacific Island descent35. The major established risk factors for RCC include excess body weight, hypertension and cigarette smoking44, which were factors in approximately half of all diagnosed cases in one US study45. Other medical conditions that have been associated with RCC in epidemiological studies include chronic kidney disease, haemodialysis, kidney transplantation, acquired kidney cystic disease, a previous RCC diagnosis and, possibly, diabetes mellitus44.
Many lifestyle, dietary, occupational and environmental factors have also been associated with RCC with varying levels of evidence46. For example, contradictory reports exist on the association between red meat consumption and RCC risk47,48. Moderate alcohol consumption (≥11 g per day) seems to reduce the risk for RCC48,49. In a case–control study on physical activity and the risk of RCC, inverse trends in risk were found, and the authors concluded that 9% of RCC cases could be avoided by increasing physical activity50. However, the inverse association might have involved other confounding factors, such as body mass index (BMI) and social class correlates. Other studies have found no such inverse association51.
Genetic factors also contribute to RCC risk, as evidenced by individuals with a family history of renal cancer having an approximate twofold increased risk52. Investigations into familial RCC have uncovered mutations in at least 11 genes (BAP1, FLCN, FH, MET, PTEN, SDHB, SDHC, SDHD, TSC1, TSC2 and VHL), some of which have also been implicated in sporadic RCC development39. A notable example is VHL (which encodes pVHL), the mutated gene underlying von Hippel–Lindau disease, which is characterized by a high risk of developing ccRCC53; inactivation of pVHL, which leads to the unchecked expression of oncogenic hypoxia-inducible factor 1 (HIF1) and HIF2, is also a hallmark of sporadic ccRCC tumours (see Mechanisms/pathophysiology)39,54. Genome-wide association studies (GWAS) of RCC have identified six susceptibility loci to date, on chromosome regions 2p21, 2q22.3, 8q24.21, 11q13.3, 12p11.23 and 12q24.31 (Refs 55,56,57,58). The 2p21 locus maps to EPAS1, which encodes the HIF2α subunit55, whereas the biological effects underlying the 11q13.3 locus seem to be attributable to changes in the regulation of CCND1 (encoding cyclin D1, which is involved in cell cycle regulation)59. The locus 12p11.23 probably maps to changes in BHLHE41 (encoding basic helix–loop–helix family member e41, which is thought to have a role in the regulation of the circadian rhythm)60. The disease genes underlying the other GWAS susceptibility loci have yet to be identified.
Mechanisms/pathophysiology
Genes and pathways
In ccRCC, the VHL tumour suppressor gene is the most frequently mutated gene7,54, and its complete loss through genetic (point mutations, insertions and deletions (indels) and 3p25 loss) and/or epigenetic (promoter methylation) mechanisms constitute the earliest, truncal oncogenic driving event61,62. VHL is the substrate recognition component of an E3 ligase complex that ubiquitylates HIF1α and HIF2α for proteasome-mediated degradation53,63,64. Thus, loss of VHL leads to the aberrant accumulation of HIF proteins despite an adequately oxygenated tissue microenvironment, which in turn results in uncontrolled activation of HIF target genes that regulate angiogenesis, glycolysis and apoptosis (Fig. 3). Accordingly, human ccRCC tumours are rich in lipids and glycogens, and are highly vascular65,66 — which underlies why agents that primarily inhibit VEGF and its receptor VEGFR are effective treatments for metastatic ccRCC14,15,67. However, VHL loss alone is insufficient to induce ccRCC, as evidenced by the long latency (>30 years) in individuals who harbour VHL germline mutations to develop ccRCC53 and by the observation that Vhl loss in mice is unable to induce ccRCC68. These results suggest that additional genetic and/or epigenetic events are probably needed for ccRCC to develop69.
Loss of VHL (which encodes pVHL) is the most frequent genetic feature of clear cell renal cell carcinoma (ccRCC). Its loss relieves the cell of negative regulation of the hypoxia-inducible factors (HIFs), which results in increased HIF target gene expression and ensuing changes in cellular metabolism and signalling that enhance cell survival. For example, increased vascular endothelial growth factor (VEGF) expression increases angiogenesis in concert with increased growth factor signalling in endothelial cells in the tumour microenvironment (including fibroblast growth factor (FGF) and hepatocyte growth factor (HGF)). Collectively, these changes provide the targets for therapeutic agents to impede tumour growth, as indicated. Dashed inhibitory line indicates indirect inhibition shown in limited reports. EIF4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; FGFR, FGF receptor; HRE, HIF response element; MET, hepatocyte growth factor receptor; mTORC, mechanistic target of rapamycin complex; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue; RHEB, GTP-binding protein Rheb; S6K1, ribosomal protein S6 kinase; TSC, tuberous sclerosis complex; VEGFR, VEGF receptor.
To identify these events, large-scale cancer genomic projects have been undertaken and have revealed several novel prevalent mutations in ccRCC, including PBRM1 (29–41% of tumour samples), SETD2 (8–12%), BAP1 (6–10%), KDM5C (4–7%) and MTOR (5–6%)7,70–73. Interestingly, PBRM1, SETD2 and BAP1 encode chromatin-regulating and histone-regulating proteins, are located at 3p21 and function as tumour suppressors7,70–72. As VHL resides at 3p25, a single copy loss of the short arm of chromosome 3 (3p) would result in haploinsufficiency of these four tumour suppressor genes, corroborating the fact that 3p loss (that is, loss of heterozygosity) is nearly a universal event in ccRCC61 and constitutes an early genetic event69. By contrast, MTOR mutations in ccRCC are generally missense and functionally activating73,74, which could explain the reason why mTOR pathway inhibitors, including everolimus and temsirolimus, are effective75,76.
How individual mutations and their interactions contribute to the pathogenesis and their values as prognostic or predictive biomarkers in ccRCC are largely unknown. Nevertheless, a few studies have demonstrated interesting clinical correlations that warrant future validation. As inactivation of VHL is the founding event of ccRCC, its mutation status has no effect on clinical outcome, whereas mutations involved in disease progression, such as PBRM1, SETD2 and BAP1 as well as KDM5C (which is also involved in chromatin modification), were shown to associate with aggressive clinical features77–79. Small renal masses harbouring PBRM1 mutations were associated with stage III pathological features (that is, extrarenal growth but not extending beyond Gerota's fascia, see below)71, whereas BAP1 mutations were associated with larger tumour sizes, higher Fuhrman nuclear grade (that is, a large nucleus with a prominent nucleolus) and worse cancer-specific survival77,78,80. Interestingly, mutations in BAP1 and PBRM1 (Ref. 70) or KDM5C20 seem to occur mutually exclusively in ccRCC, offering a molecular subclassification of ccRCC. Furthermore, mutations in KDM5C, which is located at Xp11.22, were predominantly detected in male patients and correlated with long-term therapeutic benefit from sunitinib20; mutations in SETD2 were associated with reduced relapse-free survival80.
Tumour heterogeneity and cancer evolution
As Nowell first described 40 years ago81, genetic diversity within tumours is thought to provide the substrate upon which selection can act, to enable tumours to adapt to new microenvironmental pressures and metabolic demands during the natural history of the cancer (Fig. 4a). Such genetic diversity has been studied extensively in ccRCC. For example, in a study of four patients with ccRCC who had multiple tumours and were subjected to multiregion genetic analysis, VHL mutation and 3p loss of heterozygosity were found to be ubiquitous events across all regions sampled17. By contrast, common driver events, such as SETD2, PBRM1, MTOR, PIK3CA, PTEN and KDM5C mutations, were present heterogeneously within the primary tumour and metastatic sites — in some regions but not others. Such genetic characteristics enable the construction of tumour phylogenies, whereby the ‘trunk’ of the evolutionary tree depicts mutations found in the most recent common ancestor (MRCA) that are also present in every tumour cell. ‘Branched’ mutations are found in some subclones but not others; these mutations may be regionally distributed across the tumour, occupying distinct regional niches within the primary tumour or different niches between the primary and metastatic sites of disease.
Although VHL mutation and 3p loss of heterozygosity are early events that are evident in all clear cell renal cell carcinoma (ccRCC) cells regardless of the region of the tumour sampled, common driver mutations (for example, SETD2, MTOR and KDM5C mutations) are present heterogeneously — suggestive of subclonal evolution of the tumour. a | Cancer subclones originate from the most recent common ancestor (MRCA) cell, in which a normal cell acquires all functional capacities to become a cancer cell. b | Genomic heterogeneity can result from the sequential, parallel accumulation of mutations, contributing to the heterogeneity and the evolution of ccRCC. In this example, ‘R’ represents the genomic characteristics of the primary tumour and ‘M’ represents the genomic characteristics of the metastatic sites, numbered accordingly. The major genetic lesions acquired after VHL mutation feature in different samples and are indicated on the branches. c | However, some evidence suggests that tumours can converge by way of parallel evolution. Here, a hypothetical braided river model depicts the sequential convergence of SETD2 and KDM5C mutations through different spatiotemporally distinct genetic events. PreM, before M; PreP, before P. Part a inset is adapted with permission from Ref. 207, Macmillan Publishers Limited.
Furthermore, parallel evolution has been observed, whereby recurrent branch alterations in subclones affect the same gene, the signal transduction pathway or the protein complex (Fig. 4b). In some cases — such as BAP1, PBRM1 and SETD2 mutations — such recurrent but distinct alterations can be readily explained as the ‘second-hit’ event in the evolution of the tumour. In other cases, parallel evolution suggests considerable selection pressures for disruption of the same signalling pathway or protein complex. In addition, convergence of genetic characteristics has been noted in several studies of ccRCC19,23,82, whereby mutations in genes occur at different time points but result in similar overall genomic and phenotypic profiles; a ‘braided river’ model has been conceived to illustrate this phenomenon69 (Fig. 4c). Regardless of the modality, a follow-up study of ccRCC samples from eight patients demonstrated evidence for branched evolution, in which 73–75% of driver alterations were found to be subclonal18.
Multiregion tumour analyses suggest the intriguing possibility that evolutionary trajectories are remarkably constrained in ccRCC, which — as our knowledge of microenvironmental, therapeutic and host selection pressures grows — could render the evolutionary routes predictable and, therefore, therapeutically tractable. For example, it has been shown that patients who responded well to mTOR inhibition harboured recurrent regionally separated aberrations in components of the mTOR pathway75. Furthermore, some subclonal alterations might be involved in the initiation and maintenance of cell-to-cell variation that are necessary for clonal selection. For example, SETD2 loss of function has been shown to impair nucleosome compaction, minichromosome maintenance complex component 7 (MCM7) function and DNA polymerase-δ loading to chromatin, resulting in impaired DNA replication fork progression. In addition, failure to load lens epithelium-derived growth factor p75 splice variant (LEDGF; also known as PSIP1) and DNA repair protein RAD51 homologue 1 (RAD51) — which are involved in DNA break repair — has also been observed upon SETD2 loss, resulting in homologous recombination repair deficiency83. These events are, accordingly, plausible genomic biomarkers in ccRCC that are dispersed within distinct regional niches within each tumour19,84.
Immune infiltration and tumour microenvironment
In addition to genetic alterations, gene expression, metabolic and immunological analyses of ccRCC have also yielded important mechanistic and clinical insights20,85–87. Of these, perhaps the immune infiltration characteristics of ccRCC are of increasing interest, given the rise of immune checkpoint-blocking therapies in this disease (see below, Management). Notably, among 19 cancer types examined by The Cancer Genome Atlas research programme, ccRCC has the highest T cell infiltration score87. Furthermore, higher nuclear grade and stage in ccRCC were correlated with an increase in T helper 2 cell and regulatory T cell infiltration87,88.
Disease models
Although RCC cell lines have been used for mechanistic studies89, ccRCC tumours in patients are highly vascular — a feature that cannot be recapitulated with in vitro cell studies. Furthermore, such cell lines can acquire additional genetic and/or epigenetic changes during passages such that in vitro drug screens do not yield specific, translatable insights90. Nevertheless, when these cell lines were injected subcutaneously into laboratory animals, xenografted tumours largely responded to anti-VEGF therapy91 and can be used to investigate resistance mechanisms92,93.
More recently, patient-derived xenograft models have been established and have been shown to recapitulate the patient's documented clinical response to targeted therapies, which could be used in preclinical drug trials94. At the same time, efforts to develop mouse models that truly reflect human ccRCC genomics and morphology have been hampered by the fact that homozygous inactivation of Vhl in mice does not result in ccRCC68. However, the identification of additional recurrent, prevalent mutations in human ccRCC has rekindled efforts to generate such models. For example, homozygous deletion of Vhl and Pbrm1 in a mouse model resulted in multifocal, lipid-rich, glycogen-rich, transplantable ccRCC (J.J.H., unpublished observation). Interestingly, homozygous deletion of Vhl and Bap1 in a mouse model resulted in early lethality (<1 month), and some mice (within a cohort of seven) carrying homozygous deletion of Vhl and heterozygous deletion of Bap1 developed tumour micronodules (0.25–1.8 mm in size) with unknown tumour incidence and molecular characteristics95. Overall, animal models of RCC are currently limited but are eagerly being pursued.
Diagnosis, screening and prevention
Diagnosis
Historically, patients were diagnosed with RCC after presenting with flank pain, gross haematuria and a palpable abdominal mass. Nowadays, the majority of diagnoses result from incidental findings. This shift is a consequence of the widespread use of non-invasive radiological techniques, such as ultrasonography or abdominal CT imaging, performed for another reason. That being said, paraneoplastic syndromes — symptoms caused by hormones or cytokines excreted by tumour cells or by an immune response against the tumour — are not uncommon in RCC96 and symptoms include hypercalcaemia, fever and erythrocytosis. Most of these symptoms are usually reversed after tumour resection11. Diagnosis is usually strongly suspected by imaging studies; although RCCs can show variable radiographic appearances97. Typical radiological features for ccRCC include exophytic (outward) growth, heterogeneity due to intra-tumoral necrosis or haemorrhage and high uptake of contrast-enhancement agents98.
Staging. The stage of RCC reflects the tumour size, the extent of invasion outside of the kidney, the involvement of lymph nodes and whether the tumour has metastasized (Fig. 5). CT imaging with contrast enhancement of the chest, abdominal cavity and pelvis is required for optimal staging. Such imaging enables the assessment of the primary tumour (such as the size and whether the tumour is organ-confined or extends to perinephric fat or the renal hilum), regional spread (lymph node involvement) and distant metastases (including lung, bone and distant lymph nodes). MRI can also provide additional information, especially to determine whether the tumour extends into the vasculature (a vena cava tumour thrombus). Bone scan, 18F-fluorodeoxyglucose PET and imaging of the brain are not systematically recommended for initial staging14,15. Prognostic assessment will require further laboratory testing that includes, but is not limited to, haemoglobin levels, leukocyte and platelet counts, serum-corrected calcium levels and lactate dehydrogenase levels99,100.
Staging renal cell carcinoma (RCC) is based on size, position and lymph node involvement15. For example, a stage I or stage II tumour is enclosed wholly in the kidney. Stage III tumours can extend into major veins or adrenal glands within Gerota's fascia (the layer of connective tissue encapsulating the kidneys and adrenal glands) or can involve one regional lymph node. Stage IV tumours can invade beyond Gerota's fascia and/or have distant metastases. *Until the introduction of newer targeted therapies beginning in 2005, the 5-year survival of stage IV RCC was <10%. Treatment is largely guided by stage15,24. For example, those with stage I RCC who are fit for surgery are recommended partial nephrectomy. However, radical nephrectomy is also an option; for elderly patients or those who cannot undergo surgery owing to comorbidities, active surveillance or ablative therapies are recommended. In patients with stage III RCC, radical nephrectomy is recommended with lymph node dissection in those with clinically enlarged lymph nodes, but systemic therapies might be the only available option for those with extensive disease and poor performance status.
Genomic implications. An age of onset of ≤46 years raises the possibility of a hereditary syndrome (Table 2) and, according to the American Society of Clinical Oncology, should trigger consideration for genetic counselling and might serve as a useful cut-off age when establishing genetic testing guidelines37. Indeed, awareness of the non-renal malignancies and non-neoplastic features associated with RCC is of interest to the physician to identify hereditary syndromes40. Furthermore, specific therapeutic options that are driven by the underlying biology are now being developed for these different RCC types related to cancer susceptibility syndromes101. Upon confirmation, patients and their families harbouring mutations are subject to specialized monitoring and treatment plans to minimize morbidity and prevent mortality.
Histopathological confirmation
Histopathological confirmation of malignancy is obtained either with renal core biopsy or on the partial or radical nephrectomy specimen. Initial biopsy is recommended before ablative therapy is undertaken (in those for whom surgery is not an option) or before initiating systemic therapy (in those who have metastatic disease)102. In 2016, the WHO classification of RCC was updated5 from previous (2004) WHO1 and International Society of Urological Pathology (ISUP) Consensus Conference4 (2013) systems. Although most RCCs can be easily classified on the basis of histological criteria, some tumours pose a diagnostic problem because they show a combination of features that are characteristic of different subtypes. For instance, the presence of clear cells is not unique to ccRCC but can be observed in pRCC, chRCC and MiT family translocation RCC66. Similarly, papillary structures, which are a characteristic of pRCC, can be present in other RCC types103. In challenging cases, careful evaluation of cytological features, growth pattern, immunophenotype and genetic alterations usually enables the proper diagnosis. However, a subset of RCCs (∼4%) cannot be assigned to any specific category because they either present with combined morphologies or show unusual features and are, therefore, designated uRCC3,104,105. Nevertheless, a recent molecular characterization of 62 aggressive uRCCs revealed distinct subsets, including NF2 loss (26%), mTOR complex 1 (mTORC1) pathway activation (21%) and mutations in chromatin and DNA damage regulators (21%)10.
At macroscopic examination, the cut surface of the ccRCC tumours is golden yellow in colour with frequent haemorrhagic, necrotic and cystic areas. Microscopically, ccRCC usually consists of tumour cells with clear cytoplasm arranged in nests or tubules surrounded by a rich vascular network. The clear appearance of the cytoplasm is due to the accumulation of glycogen and lipids. A variable proportion of tumour cells with granular eosinophilic cytoplasm can be observed and, in some cases, these cells constitute the entire tumour mass3,104,105. The most widely used grading system for ccRCC is the Fuhrman grading system, which defines four nuclear grades (1–4) in order of increasing nuclear size, irregularity and nucleolar prominence106. The Fuhrman nuclear grade has been shown to have prognostic value in ccRCC30,107,108.
It should be noted that all RCC types can contain foci of high-grade malignant spindle cells (that is, sarcomatoid differentiation). Thus, sarcomatoid RCC is no longer considered as an entity, but rather as a progression of any RCC type109. Of note, recent genomic insights from sequencing-matched sarcomatoid and carcinomatous RCC demonstrated enrichment in TP53 and CDKN2A mutations, which implicate these genetic defects as underlying causes of sarcomatoid differentiation in RCC110–112.
Screening
Owing to the relatively low incidence of RCC, universal screening (such as that for asymptomatic micro-haematuria) has not demonstrated a positive effect on outcomes in RCC113. Furthermore, other biomarkers have not yet been established for screening114,115. Imaging remains the primary tool for the detection and screening of RCC. An ultrasonography screening study in 45,905 participants reported a 10-fold higher RCC incidence than expected for a general population with improved cancer-free survival when compared with symptomatic patients116.
Although most cases are sporadic62, the majority of patients with RCC might have a genetic predisposition38,117. Although, no guideline is available regarding the selection of patients for germline mutation testing, guidelines for monitoring those with confirmed hereditary syndromes that increase the risk of RCC are available37.
Prevention: modifiable risk factors
Smoking, obesity and hypertension are associated with increased risks of developing RCC, whereas exercise and moderate consumption of alcohol and flavonoids reduce the risks of RCC.
Smoking. When compared to never smokers, a relative risk for ever smokers of 1.38 (95% CI: 1.27–1.50) was reported in a meta-analysis including 8,032 cases and 13,800 controls from five cohort studies118. A dose-dependent increase in risk in both men and women was found; individuals who had quit smoking >10 years prior had a lower risk than those who had quit <10 years prior. Another study has confirmed smoking as a risk factor for RCC119.
Obesity. A 5 kg/m2 increase in BMI was found to be strongly associated with RCC120. Similarly, a strong association between weight gain in early and mid-adulthood (18–35 years of age) and RCC was reported121. Moreover, central adiposity (relative risk: 1.8; 95% CI: 1.2–2.5) and the waist-to-hip ratio (range: 0.86–2.88) were positively associated with RCC in women122. The effect of BMI on overall survival was also studied in 1,975 patients treated with targeted agents. The authors reported a median overall survival of 25.6 months (95% CI: 23.2–28.6) in patients with a high BMI versus 17.1 months (95% CI: 15.5–18.5) in patients with a low BMI (adjusted hazard ratio: 0.84; 95% CI: 0.73–0.95)123. Compared with stable weight, neither steady gain in weight nor weight loss was significantly associated with risk of RCC121.
Hypertension and medications. Higher BMI and hypertension were independently shown to increase the long-term risk of RCC in men, whereas a reduction in blood pressure lowered the risk124. Aspirin use was found to be associated with an increased RCC risk in one out of five studies125; by contrast, paracetamol (also known as acetaminophen) exposure showed no increased risk126. The role of phenacetin (also known as acetophenetidin) exposure has been inconclusive127. Statins were reported to significantly reduce the risk of RCC in a large analysis (n = 483,733), with a 48% risk reduction (adjusted odds ratio: 0.52; 95% CI: 0.45–0.60)128. However, owing to the sporadic and low-frequency nature of RCC, the current guideline does not support the role of empirical treatment for the prevention of RCC in the general population; patients with hereditary syndromes should be monitored more closely and treated accordingly.
Management
For patients with surgically resectable RCC, the standard of care is surgical excision by either partial or radical nephrectomy with a curative intent. By contrast, those with inoperable or metastatic RCC typically undergo systemic treatment with targeted agents and/or immune checkpoint inhibitors. Deciding on which treatment to undertake has been largely guided by various nomograms30. For example, the University of California, Los Angeles (UCLA) Integrated Staging System (UISS) and Stage, Size, Grade and Necrosis (SSIGN) score integrate clinical (1997 TNM stage) and pathological (Fuhrman nuclear grade) information to recommend the length and frequency of clinical follow-up and the selection of high-risk patients for adjuvant studies129–131. Similarly, key prognostic factors have been identified, validated and adopted to guide and stratify patients with metastatic RCC for systemic treatment, including performance status, time from diagnosis to systemic treatment and haemoglobin, calcium and lactate dehydrogenase levels and neutrophil and platelet counts in the blood99,132,133.
Surgery
Surgical treatment of RCC is related to the clinical stage of the disease and to the general condition of the patient (Fig. 5). Although typically reserved for localized disease, both partial and radical nephrectomy can also be used with cytoreductive intent in patients with metastatic disease. Indeed, randomized controlled trials (RCTs) demonstrating the benefit of this approach date from the 1990s, when cytokine-based therapies dominated the systemic therapy landscape. Furthermore, although most patients included in RCTs of targeted therapies also underwent cytoreductive nephrectomy, the current role of excision of the primary tumour in these patients has yet to be validated. However, according to the main international guidelines, many centres offer cytoreductive nephrectomy if there is a substantial disease volume at the primary site but only a low burden of metastatic disease134.
Partial nephrectomy. The goal of partial nephrectomy is to completely remove the primary tumour while preserving the largest possible amount of healthy renal parenchyma. Partial nephrectomy is indicated for patients with a T1 tumour (according to the Union for International Cancer Control TNM staging system) and a normal contralateral kidney (elective indication). Moreover, partial nephrectomy is strongly recommended (imperative absolute indications) in patients with RCC who have only one kidney (anatomically or functionally), in those with bilateral synchronous RCC and in those with von Hippel–Lindau syndrome. Similarly, imperative relative indications include conditions that can impair renal function (for example, kidney stones, hypertension, diabetes mellitus and pyelonephritis). Indeed, partial nephrectomy offers lower renal function impairment135–137 and equivalent oncological survival outcomes compared with radical nephrectomy in those with T1 tumours138,139. More controversial is the favourable effect of partial nephrectomy on overall survival140,141 because conventional wisdom dictates that removal of the whole kidney is better in terms of oncological outcome. In this scenario, surgical feasibility remains the main factor that influences the final decision-making process.
In the past decade, nephrometry scoring systems have been proposed to predict the complexity of the partial nephrectomy procedure and to predict perioperative outcomes according to the anatomical and topographical tumour characteristics142 (Table 3). The R.E.N.A.L. and PADUA nephrometry systems are still the most popular and most used tools to preoperatively classify tumours143. These first-generation systems, along with the Centrality Index system, mainly factor in tumour-related anatomical parameters, including face location (that is, anterior or posterior faces, according to their coverage by the anterior or posterior layers of the renal fascia, respectively), longitudinal polar location, rim location (that is, whether the tumour is located at the lateral or medial rim of the kidney), the degree of tumour extension into the parenchyma, renal sinus involvement, upper urinary collecting system involvement and the clinical maximal diameter of the tumour. Clinical studies demonstrated that such nephrometry systems were able to predict the risk of bleeding and postoperative complications in patients who underwent partial nephrectomy142. Thus, these systems represent valid tools for counselling patients and selecting the ideal candidate for partial nephrectomy according to surgeon experience143. Second-generation nephrometry systems, such as Diameter-Axial-Polar system, Zonal NePhRO scoring system and Arterial Based Complexity system, should be externally validated and tested head-to-head against a first-generation system before being introduced into clinical practice.
Laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN) are the main alternatives to classic open partial nephrectomy (OPN). However, RAPN and OPN are more appropriate in the treatment of more-complex cases (based on expert opinion). Conversely, LPN should be reserved for small tumours (usually ≤4 cm in size) in patients without complex features, as defined according to nephrometry systems (low-risk or intermediate-risk categories). Available meta-analyses have demonstrated that RAPN provides equivalent perioperative outcomes to LPN but a significantly shorter warm ischaemia time144,145. Moreover, RAPN seems to be significantly better than OPN in terms of perioperative complications, estimated blood loss and hospital stay146,147. Conversely, transfusion rate, ischaemia time, change in estimated glomerular filtration rate and early cancer outcomes are similar between the two approaches147. International guidelines recommend the use of both approaches according to the surgeon and patient preferences.
Finally, partial nephrectomy can also involve simple enucleation — entirely sparing the healthy parenchyma around the tumour. Alternatively, classic enucleoresection, in which a thin layer of healthy parenchyma is removed, or polar or wedge resection, in which a wider excision of healthy parenchyma is performed, are also viable options. A minimal tumour-free surgical margin following partial nephrectomy seems appropriate to avoid the increased risk of local recurrence24. Positive surgical margins have been reported in 1–6% of cases, regardless of the type of surgical technique used148. Haematuria, perirenal haematoma and urinary fistulas are the most common complications of partial nephrectomy procedures. Less-frequent postoperative complications can be represented by acute renal impairment and infection149.
Radical nephrectomy. Classic radical nephrectomy consists of the removal of the kidney, perirenal fat tissue, adrenal gland and regional lymph nodes. However, in patients with a tumour ≤5 cm in size, located at the inferior pole, the adrenal gland can be spared. Similarly, regional lymph node dissection can be reserved for patients with clinically positive nodes detected by CT or during the surgical procedure150. Radical nephrectomy can be considered in cases with multiple small renal tumours, in cases in which the tumour extends into the vasculature and can be a laparoscopic or open procedure (Fig. 6). In most patients with stage I and stage II tumours, radical nephrectomy is currently performed using a traditional laparoscopic approach; the open approach remains the gold standard for the treatment of more-complex cases. In experienced hands, the robot-assisted approach can represent a potential alternative to open surgery in cases with venous tumour thrombus.
a | Radical nephrectomy could be considered in cases with multiple small renal tumours (circled). b | Conversely, radical nephrectomy and contextual excision of neoplastic thrombus into renal vein or cava vein tumour thrombus is the gold-standard treatment for patients with venous involvement.
Data recently extracted from the US National Cancer Database support the use of cytoreductive nephrectomy in those with metastatic disease even while they receive systemic targeted therapies. Indeed, the median overall survival was 17.1 months in cytoreductive nephrectomy cases versus 7.7 months in the non-cytoreductive nephrectomy group151.
Active surveillance and ablative therapies
Active surveillance and ablative techniques, such as cryotherapy or radiofrequency ablation, are alternative strategies for elderly patients and/or those with competing health risks and limited life expectancy that render them unsuitable for surgery15,24.
A definite protocol for active surveillance has yet to be defined. The most common approach consists of alternating between ultrasonography imaging and CT or MRI every 3 months in the first year, every 6 months in the second year and annually thereafter. Intervention should be considered for growth to >3–4 cm or by >0.4–0.5 cm per year152. Data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry in the United States showed that, in a well-selected cohort of patients with up to 5 years of prospective follow-up, active surveillance was not inferior to primary intervention in terms of both overall survival and cancer-specific survival26.
Ablative technology must be able to completely destroy all viable tumour tissue with no area of viable tumour left. Both cryotherapy and radiofrequency ablation can be performed using a laparoscopic or percutaneous approach under CT or ultrasound guidance. A meta-analysis of case series showed 89% and 90% of efficacy for cryoablation and radiofrequency ablation, respectively25; complication rates were 20% and 19%, respectively. Available low-quality studies suggest a higher local recurrence rate for ablative therapies than for partial nephrectomy153.
Medical management
The past 10 years have seen the approval of several targeted therapeutic agents and one immunotherapy agent for the treatment of metastatic RCC (Fig. 7). However, in the adjuvant setting after surgery, the situation is less clear and a randomized trial (ASSURE) of sunitinib versus sorafenib versus placebo showed no benefit for either drug therapy in terms of disease-free survival131. Notably, a recent study in the adjuvant setting reported a disease-free survival benefit for 1 year of sunitinib therapy in comparison with observation in the S-TRAC trial130. Several other trials of adjuvant targeted therapies (such as PROTECT and SORCE) have completed accrual and will report outcomes in the next 12 months.
a | Before 2005, two drugs were available to treat renal cell carcinoma (RCC; with a median survival of ∼15 months). This so-called dark age of treatments was followed by the modern age (2005–2014), which saw seven additional regimens gain approval (increasing the median survival to ∼30 months). Currently, the golden age has already witnessed the introduction of three drugs, with more anticipated over the next decade. b | These advances promise to be translated to a significant number of patients (∼50%), achieving durable remissions under active surveillance by 2025 with a median survival of ∼5 years. The ultimate goal of the future diamond age of drug approvals is >80% of patients with metastatic clear cell RCC achieving long-term survival. Dashed lines represent predicted survival.
Targeted therapies. Given the highly vascular nature of RCCs, it is unsurprising that several therapies are available to exploit this feature. Indeed, tyrosine kinase inhibitors targeting the VEGF signalling axis that are approved in the first-line and second-line settings for the treatment of metastatic RCC in the United States and the European Union are sorafenib, sunitinib, pazopanib, axitinib, lenvatinib and cabozantinib154–159. All approvals have been as single agents, except the combination of lenvatinib with everolimus; in addition, the anti-VEGF monoclonal antibody bevacizumab is approved for use with interferon-α160,161. Broadly speaking, sunitinib, pazopanib and the combination of bevacizumab and interferon-α are approved as first-line options, whereas axitinib and cabozantinib are approved as second-line options. The mTOR inhibitors everolimus and temsirolimus are approved as single agents in the second-line setting and in the first-line setting in patients with poor risk status162,163. Indeed, arguably the landmark trial of first-line systemic therapy of metastatic RCC was the phase III study of sunitinib versus interferon-α reported in 2007, in which the superiority of sunitinib in terms of response rate, progression-free survival and overall survival was reported155. This trial established sunitinib as the standard of care and the drug remains the comparator for all currently recruiting phase III studies of new drugs.
No clinically usable markers are available to select patients for particular therapies, despite intensive efforts. As such, the average duration of disease control with these drugs is 8–9 months in the first-line setting and 5–6 months in the second-line setting. Most of the phase III RCTs leading to the approval of these agents have excluded patients with nccRCC (Box 1) and, as such, this evidence base relates largely to ccRCC. Furthermore, all of these agents are given continuously until disease progression in the absence of major toxicity. In addition, alternative schedules, such as those electively interrupting therapy for prolonged periods, have not been reported from RCTs.
Immunotherapy. Cytokines such as interferon-α and high-dose IL-2 that enhance antitumour immune activity have been used since the 1990s to treat metastatic RCC and were standards of care before the introduction of sunitinib164. Both drugs typically benefit only a small subset of patients (generally those with intrinsically favourable disease biology) and are associated with substantial toxicity, particularly in the case of high-dose IL-2. Many studies are currently investigating combinations of anti-VEGF therapy with a new generation of immunotherapy agents in the form of T cell immune checkpoint inhibitors, such as antibodies against programmed cell death protein 1 ligand 1 (PDL1), which include avelumab and atezolizumab, and antibodies against programmed cell death protein 1 (PD1), which include nivolumab and pembrolizumab. PD1 negatively regulates T cell function and its ligand PDL1 is highly expressed by cancer cells; accordingly, blockade of the PD1–PDL1 axis promotes T cell activation and immune killing of the cancer. Another combination under investigation (CheckMate 214; NCT02231749) is nivolumab with ipilimumab, an inhibitor of the T cell checkpoint cytotoxic T lymphocyte-associated protein 4 (CTLA4). CTLA4 also downregulates T cell function; its inhibition by these antibodies promotes T cell activation.
Nivolumab was approved in the United States and the European Union after the CheckMate 025 RCT showed an overall survival benefit compared with everolimus in patients who had failed prior therapy with sunitinib and pazopanib165. However, the response rate to nivolumab was only 25% (5% for everolimus) and most patients treated did not experience significant tumour shrinkage. Although these checkpoint inhibitors show promise, predicting response is difficult. For example, in the CheckMate 025 trial, PDL1 expression did not correlate with response, as had been reported in other trials in other cancer types165. The reason for this observation is unknown, but PDL1 expression is dynamic in space and time, and archival (paraffin-embedded) material from the primary tumour used in the CheckMate 025 trial might not have been representative of PDL1 expression at metastatic tumour sites.
Finally, nivolumab is well tolerated compared with everolimus. Furthermore, it has been possible to combine nivolumab (and other anti-PD1 or anti-PDL1 therapies) with ‘clean’ (that is, more-specific, less-toxic and easier to combine) anti-VEGF therapies, such as axitinib and bevacizumab, leading to several phase III studies of such combinations in metastatic RCC.
Quality of life
Quality of life and patient-reported outcomes have become an important way to assess therapeutic strategies in the treatment of patients with RCC. Adverse events are important to consider and these are summarized in Table 4. Although oncological outcomes such as survival are more objective, validated measures of quality of life have been developed to help assess the patient experience.
For localized RCC, a systematic review was performed, which included data from 29 studies that included randomized and non-randomized studies149. This review noted that quality-of-life outcomes after partial nephrectomy were superior to those of radical nephrectomy regardless of approach or technique. Interestingly, no good evidence suggested that cryotherapy or radiofrequency ablation had better quality-of-life outcomes than nephrectomy.
For metastatic RCC, measures of quality of life become more important as treatment is usually palliative and patients continually balance quality versus quantity of life. A validated 15-question tool called the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI) is the most specific to kidney cancer166. A subscale of this, the FKSI-DRS (disease-related symptoms) has nine kidney cancer-specific questions on the topics of lack of energy, pain, weight loss, bone pain, fatigue, shortness of breath, cough, fever and haematuria. Other more-general questionnaires exist and have been used in RCC clinical trials, including the Functional Assessment of Cancer Therapy General (FACT-G), the EuroQOL EQ-5D and Visual Analogue Scale (VAS)167. These tools enable investigators to assess quality of life; however, limitations, including questionnaire burden, incomplete answering and defining a truly clinically significant minimal difference in quality-of-life scores, remain.
In the phase III registration trial of first-line sunitinib versus interferon-α in the metastatic setting, the FKSI, FKSI-DRS, FACT-G, EQ-5D and EQ-VAS demonstrated a consistent favourable difference in quality of life for sunitinib155. This finding can probably be attributed to the favourable adverse-effect profile of sunitinib, which is associated with less fatigue than interferon-α, and higher efficacy of sunitinib (31% response rate) than interferon-α (6% response rate).
Quality of life was assessed with FKSI-19, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Cancer Therapy Satisfaction Questionnaire (CTSQ) and the Seville Quality of Life Questionnaire (SQLQ) in the COMPARZ clinical trial, which compared first-line sunitinib versus pazopanib156. Measurements were taken at baseline and at day 28 of each treatment cycle, which is typically the point of highest sunitinib toxicity (including soreness in the mouth, throat, hands and feet). Improved quality-of-life scores were observed in those patients taking pazopanib versus those taking sunitinib.
The immune checkpoint inhibitors have also had quality-of-life analyses reported167. The CheckMate 025 study of nivolumab used the FKSI-DRS score, which was performed at baseline and every 4 weeks up to study week 104, after which assessments were reduced. Median time to improvement in health-related quality of life was shorter in patients given nivolumab (4.7 months; 95% CI: 3.7–7.5) than in patients given everolimus (median not reached). The overall survival of patients was longer in those who had high baseline health-related quality-of-life scores who then improved than in those with similar baseline scores whose scores then deteriorated. The shortest overall survival was observed in patients with low baseline scores who then deteriorated.
Outlook
With the considerable advances in the molecular biology and management of RCC over the past several decades, it is not without reason that one could describe the current era of knowledge and available treatments as the ‘golden age’ of research. If we are to progress further, advances in diagnosis, local management and systemic therapy are needed to achieve >80% long-term survival that might define the future ‘diamond age’ of kidney cancer research and therapy (Fig. 7). Areas that currently show promise include developing strategies for treating high-risk patients, biomarkers to guide treatment and preventing and overcoming drug resistance.
Biomarkers to guide treatment
Although wide ranging clinical outcomes can be attributed to tumour heterogeneity in RCC, opportunities to further improve clinical outcomes on the basis of individual tumour characteristics (so-called precision medicine) are an emerging field. Given that nivolumab, cabozantinib and lenvatinib were only recently approved, and few correlative studies have been reported, potential biomarkers for VEGF and mTOR inhibitors currently have the most promise.
Biomarkers can range from clinical parameters (such as blood pressure) and endogenous substances (such as plasma proteins) to pathobiological features that are specific to individual tumours (such as mutations). For example, as an on-target clinical biomarker, hypertension (a systolic blood pressure of ≥140 mmHg) in patients receiving VEGF inhibitors has been shown to be associated with improved progression-free survival and overall survival168. In addition, many studies have looked into circulating biomarkers169, among which high levels of IL-6, IL-8, hepatocyte growth factor and osteopontin were associated with shorter progression-free survival in patients receiving pazopanib and sunitinib170,171, whereas high levels of lactate dehydrogenase were associated with better overall survival in those receiving temsirolimus but not interferon-α172.
Genetic biomarkers are also beginning to be studied for associations with treatment outcome in various metastatic settings173–175. For example, RECORD-3, a large randomized phase II trial (n = 471), demonstrated the better first-line efficacy of sunitinib (a progression-free survival of 10.7 months) over first-line everolimus (a progression-free survival of 7.9 months)22. Interestingly, genomic biomarker analysis of patients enrolled in RECORD-3 showed that BAP1 mutations were associated with a progression-free survival of 8.1 months with first-line sunitinib but 5.5 months with first-line everolimus — a significant difference. By contrast, PBRM1 mutations showed no such association20, which is consistent with a VEGF inhibitor outlier study173 and warrants further validation. That BAP1 mutations were associated with inferior outcomes on everolimus20 is surprising given their reported higher mTORC1 activity than PBMR1-mutant tumours70. Furthermore, patients with KDM5C mutations were associated with a much longer first-line progression-free survival with sunitinib (20.6 months) than with everolimus (9.8 months)20. As mutual exclusivity was detected between mutations in BAP1 and PBRM1 or KDM5C20, molecular subgrouping of metastatic ccRCC based on these three genes could be of clinical value in the future. In addition, case-based mTOR inhibitor outlier studies recognized activation mutations of MTOR and biallelic inactivation of TSC1 or TSC2 as potential biomarkers for long-term responders69,73,75,76.
Managing high-risk patients
A significant number (∼30%) of patients with non-metastatic disease (based on clinical and pathological evaluation at the initial diagnosis) have occult metastases that will eventually become clinically evident. How to identify and better manage these high-risk patients presents a major challenge for operating urologists. As we begin to appreciate the effect that prevalent RCC mutations (in PBRM1, SETD2, BAP1, KDM5C, PTEN and TP53) have on clinical outcomes, incorporating specific mutational information into prognostic nomograms will become increasingly useful. For example, transcription signatures, such as ClearCode34 (Ref. 86), and other biomarkers in the blood and urine might be incorporated into validated predictive biomarkers for RCC recurrence after surgery. Similarly, predicting treatment response to systemic therapy might be plausible and will reduce cost and improve care for patients with RCC. Our improving ability to identify high-risk patients with RCC and formulate personalized treatment and follow-up plans based on multi-omics holds the promise to quickly reduce the incidence of patients developing overt metastatic disease and render long-term survival.
Emerging therapies and changes to treatment
Several promising new drugs with novel mechanisms of action are in various stages of clinical trials. For immunotherapeutics, ipilimumab, an anti-CTLA4 antibody, in combination with nivolumab has shown a remarkable response rate of ∼40% in the CheckMate 016 trial176. In addition, the efficacy of autologous dendritic cell-based immunotherapy, which consists of expanding the patient's own dendritic cell numbers in vitro followed by the introduction of tumour RNA before re-infusion back into the patient, in combination with sunitinib has been examined and has shown early promise177.
In the realm of targeted therapeutics, inhibitors specifically targeting HIF2 have been developed178,179. As kidney cancer is characterized by aberrant glycolysis (with aberrant glutamine and tryptophan metabolism65,180,181), it is of interest to learn whether the glutaminase inhibitor CB-839 (Ref. 182) and the indoleamine-2,3-dioxygenase inhibitor INCB024360 (Ref. 183) could yield additional clinical benefits when added to existing therapies. Finally, as many of these novel therapeutic agents act on modulating the anticancer response in patients, further understanding of the intricate relationship between an individual kidney cancer cell and its respective immune microenvironment would be crucial for the future success in designing combination treatments to improve survival87,184–187.
Given the increasing understanding of tumour biology and the increasing number of treatment options, how treatments are selected in the future will undoubtedly change (Fig. 8). In addition to those already discussed, potential treatments of high value might include personalized vaccination188, targeted radiotherapy to enhance antitumour immune response189 and selective cytoreductive nephrectomy in patients who were initially inoperable but later showed marked shrinkage of tumours after systemic treatments. Furthermore, neoadjuvant or adjuvant190 immunotherapy or targeted therapy could become integrated into the current treatment algorithms.
Given the advances in renal cell carcinoma (RCC) research, how patients are treated — based on their individual tumour characteristics — will probably change in the future.
Preventing and overcoming drug resistance
Model systems and clinical experience have shown that inhibiting RCC activity with multiple drugs specific to different targets is superior to single-agent approaches23,191,192. However, such approaches tend to produce more toxicities — on-target and off-target. For example, the combination of sunitinib and everolimus in treating metastatic RCC subjected patients to severe toxicity193. Nevertheless, bevacizumab, a more tolerable VEGF pathway inhibitor than sunitinib, plus everolimus is well tolerated and has been shown to be efficacious in treating nccRCC with papillary features194. The success of polypharmacy relies on efficient and correct targeting of both primary and secondary (bypass) pathways69,195. In ccRCC, VEGF is the primary pathway due to the universal VHL loss; secondary targets can include mTORC1, MET and IL-8, but not epidermal growth factor receptor or phosphoinositide 3-kinase pathways, when one takes into consideration the available clinical158,159,169,196,197 and preclinical studies92,198–200.
Given the availability of targeted therapies (Fig. 7), the immediate challenge is to design the most effective and specific regimen through combining or sequencing drugs to prevent resistance in individual patients201. Interestingly, a recent study in patients with melanoma who relapsed after initial treatment response on PD1 blockade revealed invaluable insights on how tumour cells might develop resistance to immunotherapies, including defects in interferon signalling and in antigen presentation202. As immune checkpoint inhibitors function independently of specific oncogenic pathways and incur distinct resistance mechanisms202, the combination of these drugs with targeted therapies is of great clinical interest203 and theoretically can prevent the emergence of escape mechanisms from either agent.
Additional information
How to cite this article: Hsieh, J. J. et al. Renal cell carcinoma. Nat. Rev. Dis. Primers 3, 17009 (2017).
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Acknowledgements
J.J.H. is supported by the J. Randall & Kathleen L. MacDonald Family Research Fund, the Tom and Mila Tuttle Family Research Fund, the Jill and Rafic Dahan Family Research Fund, and the Jill and Jeffrey Weiss Family Research Fund for the cure of metastatic kidney cancer. J.L. is supported by the National Institute of Health Research (NIHR) Royal Marsden/Institute of Cancer Research Biomedical Research Centre for Cancer. M.P.P. is supported by the Intramural Research Program of the National Cancer Institute, US National Institutes of Health.
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Introduction (J.J.H.); Epidemiology (M.P.P.); Mechanisms/pathophysiology (S.S., J.J.H. and C.S.); Diagnosis screening and prevention (L.A. and M.S.); Management (V.F. and J.L.); Quality of life (D.Y.H.); Outlook (J.J.H.); Overview of Primer (J.J.H.).
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Competing interests
J.J.H. is a consultant for Novartis, Eisai and Chugai and has received research funding from Pfizer, Novartis, Eisai and Cancer Genomics Inc. C.S. is a consultant for Roche, Pfizer, Boehringer Ingelheim, Novartis, Celgene, Servler, Eli Lilly and GlaxoSmithKline, and owns stock options from Achilles Therapeutics, Epic Biosciences, Grail and ApoGen Biotech. L.A. is a consultant for Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer and Cerulean, and has received research funding from Pfizer and Novartis. M.S. is a consultant for Pfizer, Bristol-Myers Squibb, Ipsen, Exelixis, Eisai, Roche, Novartis and Astellas. D.Y.H. is a consultant for Pfizer, Novartis and Bristol-Myers Squibb. J.L. has received research funding from Novartis, Pfizer, Bristol-Myers Squibb and Merck Sharp & Dohme. M.P.P., S.S. and V.F. declare no competing interests.
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Hsieh, J., Purdue, M., Signoretti, S. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017). https://doi.org/10.1038/nrdp.2017.9
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DOI: https://doi.org/10.1038/nrdp.2017.9
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