Essential Peer-Reviewed Reading in Kidney Cancer


Essential Peer-Reviewed Reading in Kidney Cancer

The peer-reviewed articles summarized in this section were selected by the Guest Editor, James Brugarolas, MD, PhD, for their timeliness, importance, relevance, and potential impact on clinical practice or translational research.

Adjuvant therapy in renal cell carcinoma: does higher risk for recurrence improve the chance for success? Figlin RA, Leibovich BC, Stewart GD, et al. Ann Oncol. 2017 Nov 24; doi: 10.1093/annonc/mdx743.   Summary: The success of targeted therapies, including inhibitors of the vascular endothelial growth factor pathway or the mammalian target of rapamycin, in the treatment of metastatic renal cell carcinoma (RCC) led to interest in testing their efficacy in the adjuvant setting. Results from the first trials are now available with other studies due to report imminently. This review provides an overview of adjuvant targeted therapy in RCC, including interpretation of currently available conflicting data and future direction of research. It discusses the key differences between the completed targeted therapy adjuvant trials, and highlight the importance of accurately identifying patients who are likely to benefit from adjuvant treatment. Also considered are reasons why blinded independent radiology review and treatment dose may prove critical for adjuvant treatment success. The implications of using disease free survival as a surrogate endpoint for overall survival from the patient perspective and measurement of health benefit have recently been brought into focus and are discussed. Finally, the paper discusses how the ongoing adjuvant trials with targeted therapies and checkpoint inhibitors may improve our understanding and ability to prevent tumor recurrence after nephrectomy in the future.

Insights into Epigenetic Remodeling in VHL-Deficient Clear Cell Renal Cell Carcinoma. Ricketts CJ, Linehan WM. Cancer Discov. 2017 Nov; 7(11):1221-1223. doi: 10.1158/2159-8290.

Summary: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel-Lindau tumor suppressor gene (VHL), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how VHL loss contributes to chromatin alteration at both gene promoters and enhancers/superenhancers, in both an HIF-dependent as well as independent manner, and how this may provide additional targets for therapeutic intervention in advanced ccRCC.

HIF2 targeted RNAi therapeutic inhibits clear cell renal cell carcinoma. Wong SC, Cheng W, Hamilton H, et al. Mol Cancer Ther. 2017 Oct 27; pii: molcanther. 0471.2017. doi: 10.1158/1535-7163.

Summary: Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2 (HIF2) and that an over-abundance of HIF2 functions as a tumorigenic driver of ccRCC.

Conclusion: In this report, we describe an RNAi therapeutic for HIF2 that utilizes a targeting ligand that selectively binds to integrins v3 and v5 frequently over-expressed in ccRCC. We demonstrate that functional delivery of a HIF2 specific RNAi trigger resulted in HIF2 gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805. Jilaveanu LB, Puligandla MA, Weiss SA, et al. Clin Cancer Res. 2017 Oct 24; doi: 10.1158/1078-0432.

Summary: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumorangiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34- expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables. High MVD (above the median) was associated with prolonged OS for the entire cohort (P = 0.021) and for patients treated with placebo (P = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (P = 0.060). MVD was not associated with DFS (P = 1.00). On multivariable analysis, MVD remained independently associated with improved OS (P = 0.013). High MVD correlated with Fuhrman grade 1-2 (P < 0.001), clear cell histology (P < 0.001), and absence of necrosis (P < 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size.

Conclusion: High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials.

Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma. Ho TH, Kapur P, Eckel-Passow JE, et al. J Clin Oncol. 2017 Nov 10; 35(32):3706-3713. doi: 10.1200/JCO.2017.73.3238.

Summary: Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. Methods We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Results Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001).

Conclusion: EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Motzer RJ, Ravaud A, Patard JJ, et al. Eur Urol. 2017 Sep 26. Pii: S0302-2838(17)30772-8. Doi: 10.1016/j.eururo.2017.09.008.

Summary: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; P=0.03). To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial. Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophilto-lymphocyte ratio (NLR), and Fuhrman grade. Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; P=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; P=0.02), and Fuhrman grade ¾ (HR 0.73, 95% CI 0.55-0.98; P=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; P=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively.

Conclusion: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy. Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib. KCJ

Conclusion: OS was similar between axitinib andsorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged.

Inhibiting Histone Deacetylase as Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies. Aggarwal R, Thomas S, Pawlowska N,  et al. J Clin Oncol. 2017 Feb 21:JCO2016705350. doi: 10.1200/JCO.2016.70.5350.

Summary: This phase 1 trial evaluated epigenetic modula- tion of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Pazopanib was adminis- tered once a day on days 1 to 28 and abexinostat was ad- ministered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Fifty-one patients with RCC were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ³ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase 2 dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d.

Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regres- sions were observed in seven (70%) of 10 patients with pazopanibrefractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment.

Conclusion: Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promis- ing durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance. KCJ