The Prognostic Value of DNA Methylation Markers in Renal Cell Cancer: A Systematic Review

Introduction: DNA methylation is an epigenetic event that occurs in normal tissues but changes in both the early and late stages of multiple tumor entities, including renal cell cancer (RCC). Many studies have shown that DNA methylation markers are relevant to RCC prognosis, but none of these markers have entered into clinical routine. Furthermore, because of its potential reversibility, DNA methylation might provide a new target for RCC therapy strategies. Materials and methods: Following PRISMA guidelines, we performed a systematic literature search up to February 2019. After selection for eligibility, a total of 56 studies were identified for analysis. Each study was categorized and the level of evidence assessed. Only articles reporting on DNA methylation markers and their association with survival were included. Descriptive statistical analyses were conducted with R statistical software. Results: We identified promoter methylation of SFRP1, GATA5, NEFH, GREM1, and BCN1 as associated with survival in RCC. Moreover, we found evidence that methylation signatures, i.e., grouping of different potential gene markers, might be of better prognostic value than single gene marker investigations. Nevertheless, because of the heterogeneous features of the studies in terms of design, methodology, patient cohorts, and statistics, the true clinical impact of these methylation markers for prognosis in RCC patients remains uncertain. Conclusion: This systematic review elucidates the potential impact of DNA methylation on survival of patients with RCC. Several promising prognostic markers, especially methylation signatures, were identified, which is encouraging, but prospective validations are necessary to establish their true clinical value.

A Systematic Review of Systemic Treatment Options for Advanced Non-Clear Cell Renal Cell Carcinoma

Introduction: There have been a number of recent advances in the management of advanced clear cell renal cell carcinoma (ccRCC). However, the majority of these studies excluded patients with non-clear cell RCC (nccRCC), and optimal management of nccRCC remains unknown. Materials and Methods: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate systemic treatment options in locally advanced or metastatic nccRCC between 2000-2019. Randomized controlled trials, single-arm phase II–IV trials, and prospective analyses of medication access programs were included. The primary outcome measures were progression free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: A total of 31 studies were included in the final analysis. There was the highest level of evidence to support first-line treatment of nccRCC with sunitinib. Additional single-arm trials support the use of other vascular endothelial growth factor (VEGF) inhibitors with axitinib and pazopanib, as well as mammalian target of rapamycin (mTOR) inhibition with temsirolimus or everolimus +/–bevacizumab. Immune checkpoint inhibition has an emerging role in nccRCC, but optimal sequencing of available options is not clear. Prospective data to support the use of newer immunotherapy combinations are lacking. Treatment for collecting duct carcinoma remains platinum-based chemotherapy. Conclusions: The availability of randomized trials in nccRCC is limited, and most studies include outcomes for nccRCC as a group, making conclusions about efficacy by subtype difficult. This systematic review supports consensus guidelines recommending sunitinib or clinical trial enrollment as preferred first-line treatment options for nccRCC, but also suggests a more nuanced approach to management and new options for therapy such as immune checkpoint inhibition.

Clinical Outcomes by Nephrectomy Status In METEOR, A Randomized Phase 3 Trial of Cabozantinib Versus Everolimus in Patients with Advanced Renal Cell Carcinoma

Background: We investigated outcomes with cabozantinib versus everolimus in patients with advanced renal cell carcinoma (RCC) with or without prior nephrectomy in the phase 3 METEOR trial (NCT01865747). Methods: Patients (N = 658) with advanced clear cell RCC and prior treatment with≥1 VEGFR tyrosine kinase inhibitor (TKI) were randomized to cabozantinib 60 mg/day or everolimus 10 mg/day. Pre-specified subgroup analyses of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were conducted by prior nephrectomy status. Response was assessed by independent radiology committee. Results: Most enrolled patients (85%) had prior nephrectomy. Baseline prognostic factors (e.g. MSKCC risk group) were less favorable for patients without prior nephrectomy. Cabozantinib improved outcomes versus everolimus in the subgroups with and without nephrectomy—hazard ratios (95% CIs) of 0.51 (0.41–0.64) and 0.51 (0.30–0.86), respectively, for PFS, and 0.66 (0.52–0.84) and 0.75 (0.44–1.27), respectively, for OS. Median OS was numerically longer in patients with versus those without prior nephrectomy in both treatment arms. ORR for cabozantinib versus everolimus was 17% versus 4% for the prior nephrectomy subgroup and 21% versus 2% for the subgroup without prior nephrectomy. Among evaluable patients without prior nephrectomy, reductions of renal target lesions occurred in 94% (16/17) of patients in the cabozantinib arm versus 44% (8/18) in the everolimus arm. The safety profiles of both subgroups were generally consistent with that of the overall study population. Conclusion: Cabozantinib improved PFS, ORR, and OS compared with everolimus in patients with advanced RCC irrespective of nephrectomy status.

Thickness of Perirenal Fat Predicts the Growth Pattern of Renal Cell Carcinoma

Background: Partial nephrectomy is the standard treatment for T1a and select T1b tumors. Tumor location is very important because it may predict surgical complications and malignant potential. The aim of this study was to investigate the association between adipose tissue, especially around the kidney, and the growth pattern of RCC. Methods: We retrospectively reviewed computed tomography scans of 153 patients with stage 1 renal cell carcinoma who underwent radical or partial nephrectomy at our hospital between January 2013 and July 2016. We calculated visceral/subcutaneous/perirenal fat volumes using SYNAPSE VINCENT®. In 60 patients, perirenal fat was immunohistochemically stained for leptin, adiponectin, COX-2 and UCP1, and the association with outward tumor protrusion was evaluated. Results: Among the 153 cases, 88 had confirmed outward expansion (57.5%), 110 were classed as pT1a (52 and 58 with outer and inner expansion, respectively), and 43 were classed as pT1b (36 and seven with outer and inner expansion, respectively; pT1a vs. pT1b, P < 0.0001). A multivariate logistic regression model showed a trend towards significance in pT1b (vs. pT1a; odds ratio [OR] 6.033; 95% confidence interval [CI] = 2.409– 15.108; P = 0.0001) and perirenal fat percentage >1.0 (vs. ≤1.0; [OR] 2.596; 95% CI = 1.205– 5.591; P = 0.014) as independent predictors for outer protrusion. Immunohistochemical staining was positive for UCP1 expression in 31 out of 41 outgrowth types (75.6%) and in all 19 endogenous types (100%; P = 0.003). Conclusions: Renal cell carcinoma with thick perirenal fat correlates with an increased likelihood of developing outward tumor protrusion; therefore, fat distribution may affect the development of renal cell carcinoma.

Prognostic Value of Histologic Subtype and Treatment Modality for T1a Kidney Cancers

Introduction: To evaluate overall survival (OS) of T1a kidney cancers stratified by histologic subtype and curative treatment including partial nephrectomy (PN), percutaneous ablation (PA), and radical nephrectomy (RN). Materials and Methods: We queried the National Cancer Data Base (2004–2015) for patients with T1a kidney cancers who were treated surgically. OS was estimated by Kaplan-Meier curves based on histologic subtype and management. Cox proportional regression models were used to determine whether histologic subtypes and management procedure predicted OS. Results: 46,014 T1a kidney cancers met inclusion criteria. Kaplan Meier curves demonstrated differences in OS by treatment for clear cell, papillary, chromophobe, and cystic histologic subtypes (all p < 0.001), but no differences for sarcomatoid (p = 0.110) or collecting duct (p = 0.392) were observed. Adjusted Cox regression showed worse OS for PA than PN among patients with clear cell (HR 1.58, 95% CI [1.44–1.73], papillary RCC (1.53 [1.34–1.75]), and chromophobe RCC (2.19 [1.64–2.91]). OS was worse for RN than PN for clear cell (HR 1.38 [1.28–1.50]) papillary (1.34 [1.16–1.56]) and chromophobe RCC (1.92 [1.43–2.58]). Predictive models using Cox proportional hazards incorporating histology and surgical procedure alone were limited (c-index 0.63) while adding demographics demonstrated fair predictive power for OS (c-index 0.73). Conclusions: In patients with pathologic T1a RCC, patterns of OS differed by surgery and histologic subtype. Patients receiving PN appears to have better prognosis than both PA and RN. However, the incorporation of histologic subtype and treatment modality into a risk stratification model to predict OS had limited utility compared with variables representing competing risks.