The regulatory perspective

The development and design of clinical trials varies in the United States. We have a society that is dependent upon knowing how to conduct a clinical trial; yet, we do not train prospective researchers to be trialists. There are, however, resources available. In February of 2014, the Food and Drug Administration (FDA) issued draft guidance for industry that focuses on clinical drug development and trial design issues (FDA, 2014a). This guidance is intended for sponsors involved in the development of medications that are the subject of new drug applications (NDAs) for the management of acute and chronic pain as well as the management of breakthrough pain. The section on peripheral neuropathic pain addresses conditions such as diabetic peripheral neuropathy, post-herpetic neuralgia, HIV-associated neuropathic pain, post-traumatic/post-operative peripheral neuropathy, and chemotherapy associated peripheral neuropathy. The guidance states that two successful trials in any one condition typically will be appropriate for approval of an indication for that particular condition. One additional successful trial in a second condition also may be appropriate for approval of an indication for this second condition. However, for the indication of the treatment of peripheral neuropathic pain, sponsors should conduct one trial in each of at least three separate peripheral neuropathic conditions (for a total of at least three trials) to ensure a reasonable likelihood that efficacy will be generalizable across peripheral neuropathic pain conditions and in at least one indication there should be replicate evidence (thus four trials). Early analgesic development should be consistent with the standard phase 1 and phase 2 development objectives. The typical development program includes non-clinical development utilizing animal data to establish safety and may or may not demonstrate efficacy. Phase I trials involve the initial introduction of the medication to a small number of normal people or a highly defined patient group. The goal is to establish the safe dose range and define the maximally tolerated dose. Care must be taken to assess each dose exposure before moving on to the next. Very careful monitoring is crucial at this stage. These trials are generally simple in design, utilizing a single ascending dose to multiple ascending dose formats. Early pharmacokinetic data may be determined. In their consumer literature, the FDA explains the parameters of a phase I trial as studies that are usually conducted in healthy volunteers. The goal is to determine the drug’s most frequent side effects and how the drug is metabolized (FDA, 2014b). Phase II trials are designed to evaluate the safety and efficacy of the medication in selected populations. Though based on the phase I data, these trials are larger and more closely controlled/monitored to estimate rate of common adverse events. Phase II study parameters should focus on safety and identifying an efficacious dose. The trial design will often differ from later studies. There have been attempts to conduct combined phase II–III controlled trials, in the hope that only one additional phase III trial will be required and approval will be faster. Invariably, these phase II–III trials fail because the optimal dosing strategy has not yet been identified. Phase III studies are open to broader patient populations and designed to assess the effectiveness of therapy and its role in clinical practice. The trial designs are more complicated and continue to look at more “common” adverse events. The desire to observe risk ranging should be between 0.1% and 1%. In conclusion, phase II is the most important stage of development. Completing a successful phase II study enables researchers to begin phase III with an established dose and duration, a solid understanding of the effects, a good safety database, target patient populations, and how to follow them. Establishing these parameters before entering phase III will improve the chances of having better outcomes. Additional information is available from the FDA, including a listing of all the available guidance documents which can be found on their website (FDA, 2014c).

Prolonged oral etoposide in recurrent or advanced non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

OBJECTIVE Previous studies by the Gynecologic Oncology Group have demonstrated a 7% response rate with bolus etoposide as second-line therapy in nonsquamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated increased activity in squamous carcinoma of the cervix compared with bolus administration. To evaluate prolonged oral etoposide in nonsquamous cell carcinoma of the cervix, the current phase II trial was conducted. METHODS Eligibility included nonsquamous cell cancer of the cervix, measurable disease, no more than one prior chemotherapy regimen no prior etoposide, WBC > or = 3000/microl, platelets > or = 100,000/microl, serum creatinine < or = 2 mg%, and adequate hepatic function. The starting dose was 50 mg/m(2)/day (40 mg/m(2)/day for prior radiotherapy) for 21 days, every 28 days. Based on toxicity, dose escalation to a maximum dose of 60 mg/m(2)/day was prescribed. RESULTS Fifty-two patients were entered on this study, with 47 evaluable for toxicity and 42 evaluable for response. A median of three (range: 1-12) courses were given. Thirty-four patients received prior radiation therapy and 15 received prior chemotherapy. Oral etoposide was well tolerated, with grade 4 neutropenia occurring in 29.8% and grade 4 thrombocytopenia occurring in 8.5% of patients. Three complete (7.1%) and two partial (4.8%) responses were observed. All of the responses were seen in chemotherapy-naïve patients (5/27); four of five had disease in nonirradiated sites. CONCLUSION Prior radiation therapy significantly limited our ability to deliver prolonged oral etoposide. At this dose, this regimen is moderately active in chemotherapy-naïve patients with nonsquamous cell carcinoma of the cervix.

Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma

Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death‐ligand 1 (PD‐L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1–20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half‐life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure‐response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3–5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.

Nonsmall Cell Lung Carcinoma With Neuroendocrine Differentiation—An Entity of No Clinical or Prognostic Significance

The existence of non-small cell lung carcinoma with neuroendocrine differentiation as a distinct entity and its relevance for prognostic and treatment purposes is controversial. This study assesses the frequency and biologic and prognostic significance of neuroendocrine (NE) expression of synaptophysin (SNP), chromogranin (Ch), and neural cell adhesion molecule (N-CAM) using tissue microarray (TMA) and immunohistochemistry. Six hundred nine nonsmall cell lung carcinomas (NSCLCs) were reviewed for subclassification. TMA blocks were made using duplicate 0.6-mm-diameter tissue cores and slides stained with SNP, Ch, and N-CAM. Immunoreactivity was considered if 1% or more of tumor cells were positive. Hematoxylin and eosin-stained sections were subclassified as: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (carcinosarcoma, giant cell carcinoma). Positivity for either marker was identified in 13.6% of NSCLC (76/558). NSCLC showed reactivity for Ch in 0.4% of cases (2/524), for SNP in 7.5% of cases (39/521) and for N-CAM in 8.6% of cases (44/511), whereas only 0.2% of cases (1/517) showed coexpression of SNP and Ch and none of all 3 markers. The assessment of NE differentiation in NSCLC is unnecessary and expensive and is of no clinical or prognostic significance. SNP or N-CAM stains a small minority of NSCLC, whereas Ch immunoreactivity is less common. Positivity for any 2 NE markers is rare. SNP is more likely to be expressed in adenocarcinoma (P=0.01) and N-CAM in squamous-cell carcinoma (P=0.008). Otherwise there was no correlation between immunoreactivity and tumor morphology. Disease specific and overall survival is not influenced by NE differentiation and therefore non-small cell lung carcinoma with neuroendocrine differentiation should not be a subclass distinct from the other NSCLC.

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study.

PURPOSE The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety. RESULTS The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0-53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand-foot syndrome, and neuropathy. CONCLUSION Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.

Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: a systematic review and meta‐analysis

Background  Despite the fact that ultraviolet (UV) light exposure is the most important risk factor for cutaneous squamous cell carcinoma (SCC) there is an ongoing debate concerning the relationship between cumulative work‐related UV exposure and SCC occurrence.

Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.

Recent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of three genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into two groups: one group with genomic profiles highly dissimilar to the majority of ccRCC and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL.

Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non–Small Cell Lung Carcinomas

Purpose: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. Experimental Design: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. Results: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non–small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. Conclusion: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.

Proteomic analysis of primary cell lines identifies protein changes present in renal cell carcinoma

New markers/targets for renal cell carcinoma (RCC) are needed to enable earlier detection and monitoring of disease and therapeutic targeting. To identify such molecules, normal and RCC‐derived primary cell lines have been used as a simplified model system for studying changes that accompany tumorigenesis. Short‐term cultures allow enrichment of relevant cell types from tissue samples, which is balanced against the potential for in vitro changes. Examination of 3 proteins with altered expression in RCC tissue showed the maintenance of normal‐tumour differences in culture, although some changes were apparent, including alteration in the isoform of aldolase. Comparative analysis of primary cell lines by 2‐DE found 43 proteins up‐regulated and 29 down‐regulated in at least three out of five tumour cell lines. Many of the observed changes have been previously reported in RCC, including up‐regulation of several glycolytic enzymes, vimentin and heat shock protein 27, validating the approach. Additionally, several novel changes in protein expression were found, including up‐regulation of several proteins involved in actin cytoskeleton organisation such as radixin and moesin, two members of the septin family, and the actin bundling protein, fascin. Validation studies using Western blotting and immunohistochemistry indicate that several of these molecules may be useful as markers for RCC.

Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)

Background: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial. Patients and methods: Patients (n = 1043) received cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point. Results: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64–0.87), P = 0.0003 and 0.85 (0.73–1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78–1.11), P = 0.420 and 1.03 (0.86–1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported. Conclusions: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin–gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.

Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors.

Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma

We have recently developed an allele titration assay (ATA) to assess the sensitivity and influence of normal cell admixture in loss of heterozygosity (LOH) studies based on CA-repeat. The assay showed that these studies are biased by the size-dependent differential sensitivity of allele detection. Based on these data, we have set up new criteria for evaluation of LOH. By combining these new rules with comparative genome hybridization (CGH) we have shown the presence of interstitial deletions in renal cell carcinoma (RCC) biopsies and cell lines. At least three out of 11 analysed RCC cell lines and three out of 37 biopsies contain interstitial deletions on chromosome 3. Our study suggests the presence of several regions on human chromosome 3 that might contribute to tumor development by their loss: (i) 3p25-p26, around the VHL gene (D3S1317); (ii) 3p21.3-p22 (between D3S1260 and D3S1611); (iii) 3p21.2 (around D3S1235 and D3S1289); (iv) 3p13-p14 (around D3S1312 and D3S1285). For the first time, AP20 region (3p21.3-p22) was carefully tested for LOH in RCC. It was found that the AP20 region is the most frequently affected area. Our data also suggest that another tumor suppressor gene is located near the VHL gene in 3p25-p26.

T cells from renal cell carcinoma patients exhibit an abnormal pattern of kappa B-specific DNA-binding activity: a preliminary report.

Recent data suggest that the poor induction of a T-cell response to human renal cell carcinoma (RCC) may be related to alterations in signal transduction pathways. We report that T cells from RCC patients have two alterations in kappa B motif-specific DNA-binding activity. The first alteration involves the constitutive expression of substantial kappa B-binding activity in nuclear extracts, which was observed in the electrophoretic mobility shift assay. The magnitude of kappa B activity in unstimulated patient T cells was similar to that observed in T cells from normal individuals that had been activated in vitro. On the basis of Western blotting experiments using antibodies to kappa B/Rel family proteins, the kappa B-binding activity constitutively expressed in T cells from RCC patients is composed mostly of the NF-kappa B1 (p50) subunit. The second abnormality in kappa B-binding activity in T cells from these patients is that RelA, a member of the Rel homology family which is part of the normal NF-kappa B complex, was not induced in the nucleus following activation. Western blotting analysis did not detect any RelA in nuclear extracts either before or after stimulation of T cells. The altered kappa B-binding activity in T cells from RCC patients may impair their capacity to respond normally to various stimuli.

Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE The efficacy and safety of combining bevacizumab (7.5 and 15 mg/kg) with docetaxel as first-line therapy for human epidermal growth factor receptor 2 (HER2) -negative, locally recurrent or metastatic breast cancer (MBC) was investigated in a three-arm, placebo-controlled, phase III trial. PATIENTS AND METHODS Patients (N = 736) were randomly assigned to docetaxel 100 mg/m(2) plus either placebo or bevacizumab 7.5 or 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS); secondary end points included best overall response, duration of response, time to treatment failure, overall survival, and safety. RESULTS Combination of bevacizumab 15 mg/kg, but not 7.5 mg/kg, with docetaxel showed superior median PFS (mPFS) to placebo plus docetaxel in unstratified analysis (placebo mPFS, 8.2 months; 7.5 mg/kg mPFS, 9.0 months [hazard ratio (HR), 0.86; P = .12]; 15 mg/kg mPFS, 10.1 months [HR, 0.77; P = .006]) and stratified analysis (placebo mPFS, 8.1 months; 7.5 mg/kg mPFS, 9.0 months [HR, 0.80; P = .045]; 15 mg/kg mPFS, 10.0 months [HR, 0.67; P < .001]). Response rates in patients with measurable disease at baseline also increased with bevacizumab 15 mg/kg (46% [placebo] v 55% [7.5 mg/kg; P = .07] and 64% [15 mg/kg; P < .001]). Combination with bevacizumab had limited impact on the known toxicity profile of docetaxel. CONCLUSION Combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased PFS when combined with docetaxel as first-line therapy for MBC compared with docetaxel plus placebo.

EGCG inhibits growth and induces apoptosis in renal cell carcinoma through TFPI-2 overexpression.

EGCG (epigallocatechin gallate), the major catechin found in green tea, has been shown to inhibit proliferation and induce apoptosis in many tumors. EGCG can inhibit DNMT (DNA methyltransferase) activity, and cause CpG demethylation and reactivation of methylation-silenced genes. Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type serine proteinase inhibitor family, is inversely related to an increasing degree of malignancy. Our previous study showed that the expression of TFPI-2 and invasiveness of renal cell carcinoma had a negative correlation. Overexpression of TFPI-2 may induce tumor cell apoptosis in renal cell carcinoma. Lower expression of TFPI-2 in renal cell carcinoma was partly due to hypermethylation of the gene promoter. Herein, using MTT and flow cytometry, we demonstrated that EGCG can inhibit growth and induces apoptosis in renal cell carcinoma cell line 786-0. In addition, Western blotting and real-time RT-PCR showed that EGCG can upregulate expression of TFPI-2. Before and after EGCG treatment, real-time methylation specific PCR could not detect methylation status of TFPI-2 gene promoter in cell line 786-0. In vivo invasiveness and metastasis test did not indicate any significant differences between control and treatment group. Our results suggest that EGCG inhibits growth and induces apoptosis in renal cell carcinoma through TFPI-2 overexpression. This is the first report showing that EGCG is likely to be an effective agent for renal cell carcinoma.

Genetic Basis of Cancer of the Kidney

Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2α for ubiquitin-mediated degradation. VHL−/− clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor α. Both hypoxia-inducible factor 1α and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dubé syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene.

Imaging , Diagnosis , Prognosis Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma : Results from the International Kidney Cancer Working Group

Purpose: To develop a single validated model for survival in metastatic renal cell carcinoma (mRCC) using a comprehensive international database. Experimental Design: A comprehensive database of 3,748 patients including previously reported clinical prognostic factors was established by pooling patient-level data from clinical trials. Following quality control and standardization, descriptive statistics were generated. Univariate analyses were conducted using proportional hazards models. Multivariable analysis using a log–logistic model stratified by center and multivariable fractional polynomials was conducted to identify independent predictors of survival. Missing data were handled using multiple imputation methods. Three risk groups were formed using the 25th and 75th percentiles of the resulting prognostic index. The model was validated using an independent data set of 645 patients treated with tyrosine kinase inhibitor (TKI) therapy. Results: Median survival in the favorable, intermediate and poor risk groups was 26.9 months, 11.5 months, and 4.2 months, respectively. Factors contributing to the prognostic index included treatment, performance status, number of metastatic sites, time from diagnosis to treatment, and pretreatment hemoglobin, white blood count, lactate dehydrogenase, alkaline phosphatase, and serum calcium. The model showed good concordance when tested among patients treated with TKI therapy (C statistic = 0.741, 95% CI: 0.714–0.768). Conclusions: Nine clinical factors can be used to model survival in mRCC and form distinct prognostic groups. The model shows utility among patients treated in the TKI era. Clin Cancer Res; 17(16); 5443–50. ©2011 AACR.

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8.

The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma. Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene (FHIT) in its 5' noncoding region. However, evidence that FHIT is causally related to renal or other malignancies is controversial. We now show that the 8q24.1 breakpoint region encodes a 664-aa multiple membrane spanning protein, TRC8, with similarity to the hereditary basal cell carcinoma/segment polarity gene, patched. This similarity involves two regions of patched, the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog. In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched, TRC8 might function as a signaling receptor and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

SUMMARY Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score.

PURPOSE Currently outcome prediction in renal cell carcinoma is largely based on pathological stage and tumor grade. We developed an outcome prediction model for patients treated with radical nephrectomy for clear cell renal cell carcinoma, which was based on all available clinical and pathological features significantly associated with death from renal cell carcinoma. MATERIALS AND METHODS We identified 1,801 adult patients with unilateral clear cell renal cell carcinoma treated with radical nephrectomy between 1970 and 1998. Clinical features examined included age, sex, smoking history, and signs and symptoms at presentation. Pathological features examined included 1997 TNM stage, tumor size, nuclear grade, histological tumor necrosis, sarcomatoid component, cystic architecture, multifocality and surgical margin status. Cancer specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to test associations between features studied and outcome. The selection of features included in the multivariate model was validated using bootstrap methodology. RESULTS Mean followup was 9.7 years (range 0.1 to 31). Estimated cancer specific survival rates at 1, 3, 5, 7 and 10 years were 86.6%, 74.0%, 68.7%, 63.8% and 60.0%, respectively. Several features were multivariately associated with death from clear cell renal cell carcinoma, including 1997 TNM stage (p <0.001), tumor size 5 cm. or greater (p <0.001), nuclear grade (p <0.001) and histological tumor necrosis (p <0.001). CONCLUSIONS In patients with clear cell renal cell carcinoma 1997 TNM stage, tumor size, nuclear grade and histological tumor necrosis were significantly associated with cancer specific survival. We present a scoring system based on these features that can be used to predict outcome.