Where next in kidney cancer?
Authors: T. Powles
Journal: Annals of Oncology (2016)

Kidney cancer has come a long way over the last 10 years with a greater understanding of the molecular biology of the disease, and the development of three new classes of effective treatments for systemic disease [1.Ljungberg B. Bensalah K. Canfield S. et al.EAU guidelines on renal cell carcinoma: 2014 update.Eur Urol. 2015; 67: 913-924Abstract Full Text Full Text PDF PubMed Scopus (1808) Google Scholar, 2.Hakimi A.A. Reznik E. Lee C.H. et al.An integrated metabolic atlas of clear cell renal cell carcinoma.Cancer Cell. 2016; 29: 104-116Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar]. The 12 challenges set out by the International Cancer Symposium group in this edition of Annals of Oncology give a pensive framework for the future [3.Scelo G. Hofmann J.N. Banks R.E. et al.International cancer seminars: a focus on kidney cancer.Ann Oncol. 2016; 27: 1382-1385Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. The question is how realistic are these goals and are they the best way of improving outcomes for cancer patients? These challenges cover a broad spectrum of issues from improving cancer diagnosis to monitoring treatment. Almost all require a better understanding of the molecular biology of the disease to achieve success. There are areas which are perhaps not covered in detail. This includes dynamic changes in surgery and interventional oncology. Simple questions such as the role of nephrectomy in metastatic disease and the safely of surveillance of small renal masses remain uncertain. There are two main strands to this article. The first strand focuses on the cause of disease and the molecular biology responsible for the cancer. This includes not only clear cell renal tumours, but rarer histological subtypes and paediatric Wilm's tumours. A broad spectrum of somatic, genetic and epigenetic factors are covered. It drives towards establishing a molecular screening test which would be massive step forward in the early detection of the disease. A screening programme has never got off the ground in renal cancer. The proportion of patients who present with metastatic disease is relatively high and patients tend to present relatively late; therefore, early diagnosis will improve outcomes. We seem some way from identification and validation of a sensitive and specific screening test. Nevertheless, this is a worthy goal. Von Hippel–Lindeau mutations are established as driving factors in the oncogenic process. However, these mutations cannot be identified in all clear cell renal cancer (CRCC). Intra-tumoural heterogeneity (ITH) may be in part responsible for this [4.Gerlinger M. Rowan A.J. Horswell S. et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med. 2012; 366: 883-892Crossref PubMed Scopus (5729) Google Scholar]. This has been cited as a reason for a lack of established biomarkers in the disease and barriers for future research. ITH was initially described in renal cancer but appears to occur in a spectrum of solid tumours, many of which have successfully developed personalised therapies [5.Lawrence D. Falzon M. Capitanio A. et al.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Science. 2014; 346: 251-256Crossref PubMed Scopus (779) Google Scholar]. Therefore, we are falling behind in kidney cancer and progress is needed. While the argument that vascular endothelial growth factor (VEGF) predominantly targets vessels rather than tumour cells making biomarker research tricky, this should not apply for mammalian target of rapomycin (mTOR) inhibitors. In view of the recent studies questioning the role of mTOR inhibition in CRCC, a biomarker-driven approach is the best way for mTOR inhibitors to remain relevant [6.Choueiri T.K. Escudier B. Powles T. et al.Cabozantinib versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1814-1823Crossref PubMed Scopus (867) Google Scholar, 7.Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (4100) Google Scholar]. Although there is a lack of robust predictive biomarkers, somatic mutations have been identified which are of prognostic significance. Indeed, a molecular signature has been identified which predicts relapse after nephrectomy with some accuracy [8.Lopatin M. Svedman C. Martini J.F. et al.A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies.Lancet Oncol. 2015; 16: 676-685Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar]. Also, promising work on germ line polymorphisms predicting response to targeted therapy in metastatic disease also exists. Nevertheless, we appear some distance from personalised therapy. It is fair to say renal cancer still lags behind other tumours such as breast cancer in terms of understanding the genetic basis of the disease and selecting patients for therapy. Further understanding of the genome and epigenome will help address a number of the goals set out by the Symposium Group. Recent data suggest a lack of ITH in the epigenome and consistent methylation changes are seen with sunitinib [9.Stewart G.D. Powles T. Van Neste C. et al.Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer.Oncotarget. 2016; 27 (in this issue)doi:10.18632/oncotarget.8308Google Scholar]. This epigenetic avenue requires further exploration. A second strand of goals set out by the International Cancer Symposium group covers issues around improving treatments and outcomes. The next steps for targeted therapy, the role of immune therapy and a drive towards personalised therapy are covered within these goals. Large steps have been made over the last decade. This was initiated with the development of VEFG-targeted therapy. The efficacy of VEGF-targeted therapy in advanced CRCC has been the backbone of initial treatment and has changed outcomes for patients [1.Ljungberg B. Bensalah K. Canfield S. et al.EAU guidelines on renal cell carcinoma: 2014 update.Eur Urol. 2015; 67: 913-924Abstract Full Text Full Text PDF PubMed Scopus (1808) Google Scholar]. Survival before these drugs was approximately a year, while today median values can be in the region of 25–30 months. However, we appear to have failed in the two key areas with these agents. First, as described earlier, biomarker discovery has not led to personalised therapy and secondly long-term durable outcomes are elusive, which is reinforced by the recent negative adjuvant study ASSURE with sorafenib and sunitinib [10.Haas N. Manola J. Uzzo R. et al.Initial results from ASSURE (E2805): adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.J Clin Oncol. 2015; 33 (Suppl 7): abstr 403PubMed Google Scholar]. Therefore, these agents are an effective holding measure in advanced disease, but with toxicity and subsequent effects on quality of life. Sequencing these agents follows a law of diminishing returns, which applies to both VEGF inhibitors and mTOR inhibitors [11.Bex A. Haanen J. Tilting the AXIS towards therapeutic limits in renal cancer.Lancet. 2011; 378: 1898-1900Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. So, it has been a big step forward, but we have reached a frustrating plateau. The recent data with the immune checkpoint inhibitor nivolumab open a new chapter in the treatment of the disease [7.Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (4100) Google Scholar]. It is too early to say whether immune oncology drugs (IO) will run into the same problems as VEFG-targeted therapies. While long-term durable remissions occur with immune checkpoint inhibitors in other tumours, these have not yet been characterised accurately in CRCC [12.Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5109) Google Scholar]. This may in part be due to the immaturity of the data and the patient populations in the study. However, it is possible, or perhaps even likely, that combination therapy with different immune agents or immune agents with VEGF-targeted therapy will result in significantly improved outcomes. Also, adjuvant and neoadjuvant immune checkpoint inhibitor studies are underway with the aim of improving survival. The PD-L1 biomarker is an area of significant controversy. Immunohistochemistry is currently used to measure PD-L1 expression, but this is associated with a number of shortcomings. Each IO drug has its own unique companion diagnostic [7.Motzer R.J. Escudier B. McDermott D.F. et al.Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373: 1803-1813Crossref PubMed Scopus (4100) Google Scholar, 13.McDermott D.F. Sosman J.A. Sznol M. et al.Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study.J Clin Oncol. 2016; 34: 833-842Crossref PubMed Scopus (422) Google Scholar]. Therefore, biomarker results for one agent will not apply to another drug in the same setting. PD-L1 expression on tumour cells (with the nivolumab-specific antibody [288]) does not appear to be predictive of outcome, but is prognostic. It is likely that this is just the first short chapter in a long book of biomarker discovery for IO drugs in CRCC. A second generation of biomarker research is moving quickly in this field. The last area to consider is non-CRCC. Papillary tumours dominate this rare subset of the disease. Outcomes for metastatic disease are even worse than those seen in CRCC [1.Ljungberg B. Bensalah K. Canfield S. et al.EAU guidelines on renal cell carcinoma: 2014 update.Eur Urol. 2015; 67: 913-924Abstract Full Text Full Text PDF PubMed Scopus (1808) Google Scholar]. Research and treatment options have fallen behind due in part to the rarity of the disease. A concerted effort from the RCC academic community is required to improve outcomes. Identifying new targets based on the biology of the disease, rather than simply testing drugs (VEGF and mTOR inhibitors) which have worked in CRCC, should be the avenue for future research. Early detection, when employed effectively, is a good way of improving outcomes. It seems unlikely that widespread radiology will be tested in this setting. Research on circulating biomarkers holds much promise and should be pursued enthusiastically. How will we achieve these goals? The emergence of immune therapy has led to biomarker studies, combination studies and adjuvant studies, all of which have tissue and blood collection as mandatory components of the design. It is likely that some of these studies will change practice, but they may also significantly increase our understanding of the disease. The academic community need to work together to develop optimal ways of monitoring treatments and detecting the cancer early to improve cures and prevent the disease. Overall, at the end of the article, the group sets out 12 areas to be prioritised. Some of the treatment-related goals, such as predicting response to immune therapy, are within our reach. Others such as the epigenetic factors predisposing to rarer diseases appear to be more challenging. The more we learn about the molecular biology of the cancer, the sooner we can start thinking of different ways of preventing and curing this difficult group of cancers. TP has received research funding from Astra Zeneca and Roche.