Kidney Cancer

Cresswell GD, Apps JR, Chagtai T, et al.
Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.
EBioMedicine. 2016; 9:120-9 [PubMed] Free Access to Full Article Related Publications

The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.

Related:

Chromosome 11

Golabek T, Bukowczan J, Szopinski T, et al.
Obesity and renal cancer incidence and mortality--a systematic review of prospective cohort studies.
Ann Agric Environ Med. 2016; 23(1):37-43 [PubMed] Related Publications

INTRODUCTION AND OBJECTIVE: There have been many studies published recently on obesity and the risk of renal cancer; however, the epidemiological evidence for such an association has not been consistent. Therefore, a systematic review was conducted of the prospective cohort studies to assess the association between obesity and the risk of renal cancer incidence and death.
MATERIALS AND METHODS: A search was conducted of the PubMed database and references to published studies from inception until May 2013. Guidelines for Assessing Quality in Prognostic Studies on the Basis of Framework for Potential Biases were followed for quality assessment of studies included in the systematic review.
RESULTS: Twenty eligible studies were identified and included in the systematic review. Among the 20 selected studies, overall study quality was high. Although the evidence from the prospective cohort studies, linking obesity with renal cancer incidence, has not been entirely consistent, there is a convincing body of data for a positive relationship. Moreover, cumulative data is compelling for a strong positive association between obesity and fatal renal cancer.
CONCLUSIONS: There is a relatively consistent amount of evidence that obesity increases the risk of renal cancer and fatal renal cancer. Further research is needed as better understanding of mechanisms by which obesity may influence renal cancer development and progression will aid the fostering of strategies for prevention and treatment of one of the most lethal human malignancies.

Beaumont JL, Salsman JM, Diaz J, et al.
Quality-adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma.
Cancer. 2016; 122(7):1108-15 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: In a phase 3, randomized, open-label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology.
METHODS: Each patient's overall survival was partitioned into 3 mutually exclusive health states: time with grade 3 or 4 toxicity (TOX), time without symptoms of disease or grade 3/4 toxicity of treatment, and time after tumor progression or relapse (REL). The time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. A threshold utility analysis was used, and utilities were applied across the range of 0 (similar to death) to 1 (perfect health).
RESULTS: A total of 1110 patients were enrolled (557 on pazopanib and 553 on sunitinib). The mean TOX was 31 days (95% confidence interval, 13-48 days) longer for sunitinib versus pazopanib. In the threshold utility analysis, the difference in the Q-TWiST ranged from -11 days (utility for TOX, 1; utility for REL, 0) to 43 days (utility for TOX, 0; utility for REL, 1) in favor of pazopanib across most utility combinations. Differences were significant in less than half of the utility combinations examined, and this typically occurred when the utility for TOX was lower than the utility for REL.
CONCLUSIONS: Patients randomized to pazopanib had a slightly longer Q-TWiST in comparison with sunitinib patients, and this was primarily due to the reduced length of TOX.

Related:

Angiogenesis Inhibitors

Pazopanib (Votrient)

Transitional Cell Cancer of the Renal Pelvis and Ureter

Wragg JW, Finnity JP, Anderson JA, et al.
MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome.
Cancer Res. 2016; 76(8):2314-26 [PubMed] Free Access to Full Article Related Publications

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.

Related:

VEGFA

MCAM

McDermott DF, Sosman JA, 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(8):833-42 [PubMed] Related Publications

PURPOSE: The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes.
PATIENTS AND METHODS: Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non-clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response.
RESULTS: Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell-to-regulatory T-cell gene expression ratio correlated with response to atezolizumab.
CONCLUSION: Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.

Related:

Monoclonal Antibodies

Olsburgh J, Zakri RH, Horsfield C, et al.
TCC in Transplant Ureter--When and When Not to Preserve the Transplant Kidney.
Am J Transplant. 2016; 16(2):704-11 [PubMed] Related Publications

We present four cases of transitional cell carcinoma of the transplant ureter (TCCtu). In three cases, localized tumor resection and a variety of reconstructive techniques were possible. Transplant nephrectomy with cystectomy was performed as a secondary treatment in one locally excised case. Transplant nephroureterectomy was performed as primary treatment in one case. The role of oncogenic viruses and genetic fingerprinting to determine the origin of TCCtu are described. Our cases and a systematic literature review illustrate the surgical, nephrological, and oncological challenges of this uncommon but important condition.

Related:

van Osch FH, Jochems SH, van Schooten FJ, et al.
Significant Role of Lifetime Cigarette Smoking in Worsening Bladder Cancer and Upper Tract Urothelial Carcinoma Prognosis: A Meta-Analysis.
J Urol. 2016; 195(4 Pt 1):872-9 [PubMed] Related Publications

PURPOSE: Although cigarette smoking is a well established risk factor for urothelial cancer, its role in urothelial cancer prognosis is still undetermined. In this meta-analysis we quantify the role of lifetime smoking history in bladder cancer recurrence, progression and survival by pooling available data on nonmuscle invasive bladder cancer, muscle invasive bladder cancer and upper tract urothelial carcinoma.
MATERIALS AND METHODS: A total of 24 studies, comprising data from 13,114 patients with bladder cancer and 2,259 patients with upper tract urothelial carcinoma, were included in this meta-analysis. Publication bias was addressed through Egger's test, and the heterogeneity among studies was assessed by the I(2) test statistic and subgroup analyses.
RESULTS: Current smokers at diagnosis are at increased risk for local recurrence in nonmuscle invasive bladder cancer (HR 1.27, 95% CI 1.09-1.46) and smokers with muscle invasive bladder cancer have an increased risk of dying of bladder cancer (HR 1.23, 95% CI 1.02-1.44). In the upper tract urothelial carcinoma population smokers have an increased risk of recurrence in the operative bed (HR 1.57, 95% CI 1.19-1.95) and of death from upper tract urothelial carcinoma (HR 1.53, 95% CI 1.13-1.92). We did not identify significant heterogeneity among included studies.
CONCLUSIONS: The body of evidence is limited due to the absence of prospective studies. However, the results from this meta-analysis unambiguously support the hypothesis that lifetime cigarette smokers are at increased risk for a more malignant type of urothelial carcinoma associated with a worse prognosis.

Related:

Transitional Cell Cancer of the Renal Pelvis and Ureter

Bladder Cancer

Bladder Cancer - Molecular Biology

Malec V, Coulson JM, Urbé S, Clague MJ
Combined Analyses of the VHL and Hypoxia Signaling Axes in an Isogenic Pairing of Renal Clear Cell Carcinoma Cells.
J Proteome Res. 2015; 14(12):5263-72 [PubMed] Related Publications

The loss of function of the Von Hippel-Lindau (VHL) tumor suppressor leads to the development of hypervascular tumors, exemplified by clear-cell-type renal cell carcinoma (RCC). VHL governs the adaptive responses to fluctuation of oxygen levels largely through the regulated suppression of hypoxia inducible factors (HIFs). Here, we combine proteome and phospho-proteomic analysis of isogenic 786-O RCC (±VHL) cells to compare signatures that reflect hypoxia and/or loss of VHL. VHL-independent hypoxic responses, notably include up-regulation of phosphorylation at Ser232 on the pyruvate dehydrogenase α subunit that is known to promote glycolysis. Hypoxic responses governed by VHL include up-regulation of known biomarkers of RCC (e.g., GLUT1, NDRG1) and the signaling adaptor molecule IRS-2. Notably, we also observe down-regulation of linked-components associated with the Jacobs-Stewart cycle, including the intracellular carbonic anhydrase II (CA2), which governs cellular response to CO2 fluctuations that often accompany hypoxia in tumors. Further studies indicate an unusual mechanism of control for CA2 expression that, at least in part, reflects enhanced activity of the NFκB pathway, which is associated with loss of VHL.

Related:

Signal Transduction

VHL

Bridgeman VL, Wan E, Foo S, et al.
Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma.
Mol Cancer Ther. 2016; 15(1):172-83 [PubMed] Related Publications

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.

Related:

Angiogenesis Inhibitors

Angiogenesis and Cancer

VHL

Trpkov K, Hes O, Bonert M, et al.
Eosinophilic, Solid, and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women.
Am J Surg Pathol. 2016; 40(1):60-71 [PubMed] Related Publications

A unique renal neoplasm characterized by eosinophilic cytoplasm and solid and cystic growth was recently reported in patients with tuberous sclerosis complex (TSC). We searched multiple institutional archives and consult files in an attempt to identify a sporadic counterpart. We identified 16 morphologically identical cases, all in women, without clinical features of TSC. The median age was 57 years (range, 31 to 75 y). Macroscopically, tumors were tan and had a solid and macrocystic (12) or only solid appearance (4). Average tumor size was 50 mm (median, 38.5 mm; range, 15 to 135 mm). Microscopically, the tumors showed solid areas admixed with variably sized macrocysts and microcysts that were lined by cells with a pronounced hobnail arrangement. The cells had voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling and round to oval nuclei with prominent nucleoli. Scattered histiocytes and lymphocytes were invariably present. Thirteen of 16 patients were stage pT1; 2 were pT2, and 1 was pT3a. The cells demonstrated a distinct immunoprofile: nuclear PAX8 expression, predominant CK20-positive/CK7-negative phenotype, patchy AMACR staining, but no CD117 reactivity. Thirteen of 14 patients with follow-up were alive and without disease progression after 2 to 138 months (mean: 53 mo; median: 37.5 mo); 1 patient died of other causes. Although similar to a subset of renal cell carcinomas (RCCs) seen in TSC, we propose that sporadic "eosinophilic, solid, and cystic RCC," which occurs predominantly in female individuals and is characterized by distinct morphologic features, predominant CK20-positive/CK7-negative immunophenotype, and indolent behavior, represents a novel subtype of RCC.

Related:

Australia

CGH

Motzer RJ, Escudier B, McDermott DF, et al.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.
N Engl J Med. 2015; 373(19):1803-13 [PubMed] Related Publications

BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
METHODS: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
RESULTS: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
CONCLUSIONS: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

Related:

Monoclonal Antibodies

Everolimus (Afinitor)

Dome JS, Graf N, Geller JI, et al.
Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration.
J Clin Oncol. 2015; 33(27):2999-3007 [PubMed] Free Access to Full Article Related Publications

Clinical trials in Wilms tumor (WT) have resulted in overall survival rates of greater than 90%. This achievement is especially remarkable because improvements in disease-specific survival have occurred concurrently with a reduction of therapy for large patient subgroups. However, the outcomes for certain patient subgroups, including those with unfavorable histologic and molecular features, bilateral disease, and recurrent disease, remain well below the benchmark survival rate of 90%. Therapy for WT has been advanced in part by an increasingly complex risk-stratification system based on patient age; tumor stage, histology, and volume; response to chemotherapy; and loss of heterozygosity at chromosomes 1p and 16q. A consequence of this system has been the apportionment of patients into such small subgroups that only collaboration between large international WT study groups will support clinical trials that are sufficiently powered to answer challenging questions that move the field forward. This article gives an overview of the Children's Oncology Group and International Society of Pediatric Oncology approaches to WT and focuses on four subgroups (stage IV, initially inoperable, bilateral, and relapsed WT) for which international collaboration is pressing. In addition, biologic insights resulting from collaborative laboratory research are discussed. A coordinated expansion of international collaboration in both clinical trials and laboratory science will provide real opportunity to improve the treatment and outcomes for children with renal tumors on a global level.

Related:

Cancer Screening and Early Detection

Kleijnen S, Fathallah M, van der Linden MW, et al.
Can a Joint Assessment Provide Relevant Information for National/Local Relative Effectiveness Assessments? An In-Depth Comparison of Pazopanib Assessments.
Value Health. 2015; 18(5):663-72 [PubMed] Related Publications

BACKGROUND: In many European jurisdictions, relative effectiveness assessments (REAs) of pharmaceuticals are performed during the reimbursement decision-making process. International collaboration in the production of these assessments may prevent the duplication of information in various jurisdictions. A first pilot of a joint REA (pazopanib for the treatment of renal cell carcinoma) was published in 2011.
OBJECTIVE: The objective was to investigate how well the methods used in the joint REA match the methods used in the national/local assessments on the same topic.
METHODS: National/local assessments from European jurisdictions, available in English language, were identified through a literature search and an e-mail request to health technology assessment organizations. Data were abstracted from joint and national/local assessments using a structured data abstraction form. Results were compared for differences and similarities.
RESULTS: In total, five national/local reports were included (Belgium, England/Wales, France, The Netherlands, and Scotland). The general methods (indication, main comparator, main end points, main trial) were similar. The details of the assessment (e.g., exact wording of indication, additional comparators, additional trials included, and method of indirect comparison), however, varied. Despite these differences, the joint REA included nearly all comparators, end points, trials, and methods of analysis that were used in national/local REA reports.
CONCLUSIONS: This study has shown overlap in the methods national/local REA bodies in Europe have chosen for a pazopanib REA for renal cell carcinoma, except for the use and methods of indirect comparisons. Although some additional comparators and outcomes differed between national/local REAs, they can be captured in a comprehensive joint REA.

Related:

Angiogenesis Inhibitors

Pazopanib (Votrient)

Moon A, Rogers A, Talbot D, Rix D
Renal Cell Cancer in a European Regional Renal Transplant Population: Is There a Role for Immediate Native Renal Radiological Surveillance Before and After Transplantation?
Transplant Proc. 2015 Jul-Aug; 47(6):1840-4 [PubMed] Related Publications

BACKGROUND: The risk of the development of renal cell cancer (RCC) in renal transplant recipients is several times higher than the general population. There can often be a delay between initial radiological imaging and patients undergoing renal transplantation. We present and evaluate the prevalence and clinical characteristics of RCC in renal transplant recipients at a single UK transplant center, with particular focus on tumors diagnosed in the immediate post-operative period, that is, likely present before transplantation.
METHODS: This is a retrospective cohort study examining all renal transplant recipients with the diagnosis of RCC of native and/or graft kidneys followed up in a single UK transplant center.
RESULTS: Between January 2002 and April 2014, 1386 patients underwent renal transplantation. 19 of 1386 patients had development of RCC (1.4%): 17 native and 2 graft tumors. The mean interval between pre-operative native renal imaging and transplantation was 3.5 years in 13 of 19 patients (range, 1-10 years). Six patients had no documented renal imaging before their renal transplant. The median time from transplantation to diagnosis of RCC was 5 years (range, 1 month to 30 years). In 5 patients (26.3%), RSS developed within 6 months of undergoing renal transplantation.
CONCLUSIONS: In our study, we identified several patients with RCC diagnosed shortly after surgery, which raised the possibility that this was present before transplantation. With transplant recipients at increased risk of development of RCC and early detection key in the management of RCC, there appears to be a role for native renal radiological screening for patients undergoing renal transplantation.

Related:

Salama R, Masson N, Simpson P, et al.
Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.
PLoS One. 2015; 10(8):e0134645 [PubMed] Free Access to Full Article Related Publications

General activation of hypoxia-inducible factor (HIF) pathways is classically associated with adverse prognosis in cancer and has been proposed to contribute to oncogenic drive. In clear cell renal carcinoma (CCRC) HIF pathways are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor. However HIF-1α and HIF-2α have contrasting effects on experimental tumor progression. To better understand this paradox we examined pan-genomic patterns of HIF DNA binding and associated gene expression in response to manipulation of HIF-1α and HIF-2α and related the findings to CCRC prognosis. Our findings reveal distinct pan-genomic organization of canonical and non-canonical HIF isoform-specific DNA binding at thousands of sites. Overall associations were observed between HIF-1α-specific binding, and genes associated with favorable prognosis and between HIF-2α-specific binding and adverse prognosis. However within each isoform-specific set, individual gene associations were heterogeneous in sign and magnitude, suggesting that activation of each HIF-α isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.

Related:

HIF1A

Signal Transduction

Rothermundt C, Bailey A, Cerbone L, et al.
Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes.
Oncologist. 2015; 20(9):1028-35 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field.
MATERIALS AND METHODS: Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified.
RESULTS: The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria).
CONCLUSION: In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts.
IMPLICATIONS FOR PRACTICE: The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated.

de Vathaire F, Scwhartz B, El-Fayech C, et al.
Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys.
J Urol. 2015; 194(5):1390-5 [PubMed] Related Publications

PURPOSE: Kidney carcinoma is a rare second malignancy following childhood cancer.
MATERIALS AND METHODS: We sought to quantify risk and assess risk factors for kidney carcinoma following treatment for childhood cancer. We evaluated a cohort of 4,350 patients who were 5-year cancer survivors and had been treated for cancer as children in France and the United Kingdom. Patients were treated between 1943 and 1985, and were followed for an average of 27 years. Radiation dose to the kidneys during treatment was estimated with dedicated software, regardless of the site of childhood cancer.
RESULTS: Kidney carcinoma developed in 13 patients. The cumulative incidence of kidney carcinoma was 0.62% (95% CI 0.27%-1.45%) at 40 years after diagnosis, which was 13.3-fold higher (95% CI 7.1-22.3) than in the general population. The absolute excess risk strongly increased with longer duration of followup (p <0.0001). Compared to the general population, the incidence of kidney carcinoma was 5.7-fold higher (95% CI 1.4-14.7) if radiotherapy was not performed or less than 1 Gy had been absorbed by the kidney but 66.3-fold higher (95% CI 23.8-142.5) if the radiation dose to the kidneys was 10 to 19 Gy and 14.5-fold higher (95% CI 0.8-63.9) for larger radiation doses to the kidney. Treatment with chemotherapy increased the risk of kidney carcinoma (RR 5.1, 95% CI 1.1-22.7) but we were unable to identify a specific drug or drug category responsible for this effect.
CONCLUSIONS: Moderate radiation dose to the kidneys during childhood cancer treatment increases the risk of a second kidney carcinoma. This incidence will be further increased when childhood cancer survivors reach old age.

Related:

France

Gatto F, Miess H, Schulze A, Nielsen J
Flux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism.
Sci Rep. 2015; 5:10738 [PubMed] Free Access to Full Article Related Publications

Flux balance analysis is the only modelling approach that is capable of producing genome-wide predictions of gene essentiality that may aid to unveil metabolic liabilities in cancer. Nevertheless, a systemic validation of gene essentiality predictions by flux balance analysis is currently missing. Here, we critically evaluated the accuracy of flux balance analysis in two cancer types, clear cell renal cell carcinoma (ccRCC) and prostate adenocarcinoma, by comparison with large-scale experiments of gene essentiality in vitro. We found that in ccRCC, but not in prostate adenocarcinoma, flux balance analysis could predict essential metabolic genes beyond random expectation. Five of the identified metabolic genes, AGPAT6, GALT, GCLC, GSS, and RRM2B, were predicted to be dispensable in normal cell metabolism. Hence, targeting these genes may selectively prevent ccRCC growth. Based on our analysis, we discuss the benefits and limitations of flux balance analysis for gene essentiality predictions in cancer metabolism, and its use for exposing metabolic liabilities in ccRCC, whose emergent metabolic network enforces outstanding anabolic requirements for cellular proliferation.

Related:

Prostate Cancer

Sim J, Johnson RS
Through a Clear Cell, Darkly: HIF2α/PLIN2-Maintained Fat Droplets Protect ccRCCs from ER Stress.
Cancer Discov. 2015; 5(6):584-5 [PubMed] Related Publications

Qiu and colleagues describe how a structural component of lipid droplets is markedly induced in pseudohypoxic renal tumors, where it maintains endoplasmic reticulum (ER) homeostasis. This adaptation is indispensable in tumor cells-where growth demands and a fluctuating blood supply place unnatural stresses on ER function-and is therefore an attractive therapeutic target.

Stewart GD, O'Mahony FC, Laird A, et al.
Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer.
Clin Cancer Res. 2015; 21(18):4212-23 [PubMed] Related Publications

PURPOSE: The aim of this study was to investigate the effect of VEGF-targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC).
EXPERIMENTAL DESIGN: Multiple tumor samples (n = 187 samples) were taken from the primary renal tumors of patients with mccRCC who were sunitinib treated (n = 23, SuMR clinical trial) or untreated (n = 23, SCOTRRCC study). ITH of pathologic grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia, and stromal-related genes). ITH was analyzed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene-expression clustering.
RESULTS: Tumor grade heterogeneity was greater in treated compared with untreated tumors (P = 0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (P < 0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1, and CAIX, occurred in the treated samples.
CONCLUSIONS: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.

Related:

CGH

VHL

Bex A, Larkin J, Voss M
Challenging the treatment paradigm for advanced renal cell carcinoma: a review of systemic and localized therapies.
Am Soc Clin Oncol Educ Book. 2015; :e239-47 [PubMed] Related Publications

The current standard of care for the management of advanced renal cell carcinoma (RCC) revolves around systemic therapy with molecularly targeted agents. Over the last decade, a total of seven targeted drugs have been approved but, altogether, only exploit two molecular targets in this disease: the vascular endothelial growth factor (VEGF) axis and the mammalian target of rapamycin (mTOR). Introduction of these agents has markedly improved outcomes compared with those in the cytokine era, yet comparatively little progress has been made since registration of the first targeted therapeutics occurred 10 years ago. In this article, we review efforts to improve on this current treatment paradigm. We discuss novel targets in this disease and corresponding new agents under investigation. The article dedicates particular attention to targeted immunotherapeutics, which are rapidly emerging as a new category of interest in this disease. Last, we review current data supporting the use of surgical interventions to improve outcomes in patients with metastatic disease.

Laitinen M, Parry M, Ratasvuori M, et al.
Survival and complications of skeletal reconstructions after surgical treatment of bony metastatic renal cell carcinoma.
Eur J Surg Oncol. 2015; 41(7):886-92 [PubMed] Related Publications

Improvements in survival for patients with renal cell carcinoma have resulted in an increase in the burden of disease due to skeletal metastases, which are often solitary and resistant to radiotherapy. Surgical intervention remains a valid treatment to improve function and relieve pain, and replacement is able to achieve this and improve disease free implant survival. The aim of this study was identify prognostic factors for reconstruction survival of skeletal metastases in renal cell carcinoma and to characterise the nature of the reconstruction related complications. A retrospective analysis of all patients treated for metastatic renal cell carcinoma in three international bone tumour units between 2000 and 2014 identified 268 surgical interventions suitable for inclusion. Reconstruction survivorship was calculated using the Kaplan-Meier method whilst factors affecting reconstruction survival were assessed using Cox-regression multivariate analysis. Differences in proportions were assessed using Fisher's exact test. The overall rate of complications was 17%, which were classified as structural failure (7.1%), infection (4.9%) and tumour progression (3.7%). Endoprosthetic replacement when performed as the primary procedure demonstrate the best survivorship whilst factors associated with compromised reconstruction survival included previous surgical intervention and pre operative radiotherapy, and intralesional resection margins. We conclude that endoprosthetic replacement be considered as the index surgical intervention for skeletal metastases from renal cell carcinoma in certain locations as this carries the lowest incidence of complications. Revision of previous skeletal stabilisation, especially when combined with radiotherapy carries a high risk of complication, including infection, which often necessitates amputation.

Russell B, Johnston JJ, Biesecker LG, et al.
Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
Am J Med Genet A. 2015; 167A(9):2122-31 [PubMed] Free Access to Full Article Related Publications

Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.

Related:

ASXL1

Jafri M, Wake NC, Ascher DB, et al.
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.
Cancer Discov. 2015; 5(7):723-9 [PubMed] Related Publications

UNLABELLED: Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.
SIGNIFICANCE: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.

Related:

CDK4

CDK6

Wozniak MB, Brennan P, Brenner DR, et al.
Alcohol consumption and the risk of renal cancers in the European prospective investigation into cancer and nutrition (EPIC).
Int J Cancer. 2015; 137(8):1953-66 [PubMed] Related Publications

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 through to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n = 931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment versus the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), 0.91 (0.63-1.30), respectively, (ptrend = 0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer.

Henrion MY, Purdue MP, Scelo G, et al.
Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer.
PLoS One. 2015; 10(3):e0122589 [PubMed] Free Access to Full Article Related Publications

So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.

Related:

Chromosome 1

Schuller AG, Barry ER, Jones RD, et al.
The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient-Derived Xenograft Models.
Clin Cancer Res. 2015; 21(12):2811-9 [PubMed] Related Publications

PURPOSE: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.
EXPERIMENTAL DESIGN: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).
RESULTS: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death.
CONCLUSIONS: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

Related:

MET

Crizotinib (Xalkori)

Hohenstein P, Pritchard-Jones K, Charlton J
The yin and yang of kidney development and Wilms' tumors.
Genes Dev. 2015; 29(5):467-82 [PubMed] Free Access to Full Article Related Publications

Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general-and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

Related:

MicroRNAs

Tzogani K, Skibeli V, Westgaard I, et al.
The European Medicines Agency approval of axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine: summary of the scientific assessment of the committee for medicinal products for human use.
Oncologist. 2015; 20(2):196-201 [PubMed] Free Access to Full Article Related Publications

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544-0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375-0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578-0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556-1.191) or sunitinib (HR: 0.997; 95% CI: 0.782-1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Related: