Phase 1 Radioimmunotherapy Study with Lutetium 177–labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Renal Cell Carcinoma

Background

Patients with metastatic clear cell renal cell carcinoma (ccRCC) have a dismal prognosis. Therefore, new and less toxic treatments are needed.

Objective

We determined the maximum tolerated dose (MTD) and potential therapeutic efficacy of multiple infusions of lutetium 177 (¹⁷⁷Lu)-girentuximab (cG250) on various dose levels in a phase 1 trial in patients with progressive metastasized ccRCC.

Design, setting, and participants

In this uncontrolled case series in 23 patients with progressive ccRCC metastases, cG250 accumulation was verified by diagnostic indium 111-cG250 imaging. Patients then received a high-activity dose of ¹⁷⁷Lu-cG250.

Intervention

Groups of three patients received ¹⁷⁷Lu-cG250, starting at a dose level of 1110 MBq/m²¹⁷⁷Lu-cG250, with dose increments of 370 MBq/m² per group. In the absence of persistent toxicity, progressive disease, and accelerated blood clearance, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. Patients could receive a total of three treatment cycles.

Outcome measurements and statistical analysis

Determination of the MTD was the primary and therapeutic efficacy was the secondary outcome measurement of the study.

Results and limitations

The MTD was 2405 MBq/m² because higher doses resulted in dose-limiting myelotoxicity. Some patients received second (13 of 23 [56%]) and third (4 of 23 [17%]) treatment cycles. Most patients (17 of 23 [74%]) demonstrated stable disease 3 mo after the first treatment, and one patient showed a partial response that lasted for 9 mo. Mean growth of target tumor lesions was reduced from 40.4% (95% confidence interval [CI], ±17.0) during the last 3 mo before study entry to 5.5% (95% CI, ±5.3; p < 0.001) at 3 mo after the first treatment cycle. No major nonhematologic side effects were observed.

Conclusions

¹⁷⁷Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m² (MTD). Radioimmunotherapy with ¹⁷⁷Lu-cG250 may stabilize previously progressive metastatic ccRCC.     

Indium-111–labeled Girentuximab ImmunoSPECT as a Diagnostic Tool in Clear Cell Renal Cell Carcinoma

Background

Improved and more frequent radiologic evaluation has resulted in increased identification of renal masses of unknown origin, which frequently pose a diagnostic dilemma for urologists.

Objective

Carbonic anhydrase IX (CAIX) is an antigen ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). The specific and high level of expression in ccRCC makes CAIX an excellent target for imaging ccRCC lesions. We present our experience with immuno–single-photon emission computed tomography (immunoSPECT) imaging with the indium-111 (¹¹¹In)–labeled anti-CAIX antibody girentuximab in patients presenting with either a primary renal tumor or a history of ccRCC and lesions suspect for metastases during follow-up.

Design, setting, and participants

Twenty-nine patients received 100–200 MBq ¹¹¹In-labeled girentuximab. Whole-body and single photon emission computed tomography (SPECT) images were acquired after 4–7 d.

Intervention

Injection with ¹¹¹In-girentuximab and image acquisition after 4–7 d.

Outcome measurements and statistical analysis

Accuracy of ¹¹¹In-girentuximab immunoSPECT.

Results and limitations

Distinct uptake of ¹¹¹In-girentuximab was seen in 16 of 22 patients presenting with a renal mass. All renal masses proven to be ccRCC after resection (n = 15) were detected with ¹¹¹In-girentuximab. Suspect lesions of six patients showed no uptake of ¹¹¹In-girentuximab. In these patients, ccRCC was not found, nor progression occurred. Seven patients with a history of ccRCC and possible metastatic lesions on follow-up computed tomography scans were imaged with ¹¹¹In-girentuximab. In four of these patients, the lesions showed preferential uptake of ¹¹¹In-girentuximab and local or systemic treatment was initiated. In three other cases, no ¹¹¹In-girentuximab targeting was seen. During follow-up of these three patients, one showed progression, for which systemic treatment was started. In the two other patients, no progression occurred, suggesting a benign nature.

Conclusions

¹¹¹In-girentuximab immunoSPECT can be used to detect ccRCC lesions in patients with a primary renal mass and to clarify the nature of lesions suspect for metastases in patients with a history of ccRCC.     

Effect of tyrosine kinase inhibitor treatment of renal cell carcinoma on the accumulation of carbonic anhydrase IX‐specific chimeric monoclonal antibody cG250

What’s known on the subject? and What does the study add? TKI combined with chemotherapy has shown significant synergistic activity in glioma, colon‐, and breast carcinoma, possibly through improved delivery of therapeutic molecules through vascular normalization and reduced tumour interstitial fluid pressure. Whether this can be achieved with larger molecules such as antibodies is unclear. Possibly, a narrow time window exists in which lowered interstitial fluid pressures precedes tumour vasculature destruction during which enhanced antibody uptake and synergy might be achieved. Here we show that careful timing will be necessary because the TKI‐induced tumour‐vessel destruction is swift and prevents adequate antibody accumulation.

OBJECTIVE

To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC.

MATERIALS AND METHODS

Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 µg ¹²⁵I‐cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250.

RESULTS

While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible.

CONCLUSIONS

Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed.     

Aberrant expression of membranous carbonic anhydrase IX (CAIX) is associated with unfavorable disease course in papillary and clear cell renal cell carcinoma

Objective

Antibodies against carbonic anhydrase IX (CAIX) are often part of immunohistochemical panels used to assist renal cell cancer (RCC) subtyping. This study was undertaken to determine, whether assessing CAIX expression levels could provide additional prognostic information.

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

Background

Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients.

Objectives

We aimed to investigate the prognosis of Japanese patients and their prognostic factors.

Design, setting, and participants

The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002.

Measurements

The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features.

Results and limitations

The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival.

Conclusions

The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.     

External Validation of the Mayo Clinic Stage,Size, Grade,and Necrosis (SSIGN) Score for Clear-Cell Renal Cell Carcinoma in a Single European Centre Applying Routine Pathology

Background

The stage, size, grade, and necrosis (SSIGN) score has been created as an outcome prediction tool for clear-cell renal cell carcinoma (ccRCC) using review pathology.

Objective

We evaluated the prognostic accuracy of the SSIGN score model using routine pathology records.

Design, setting, and participants

We retrospectively evaluated pathology records of 1862 consecutive ccRCC patients with complete data including follow-up who had been operated between 1984 and 2006.

Intervention

Surgical treatment of patients with ccRCC.

Measurements

TNM stage, largest tumour diameter, tumour grade, and presence of histologic tumour necrosis were recorded. ccRCC were categorised according to the SSIGN-score algorithm as 0–15. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method for individual SSIGN-score categories (scores 0–1 and ≥10, respectively, were combined). For evaluation of the prognostic impact of stage, size, grade, and necrosis regarding CSS, a multivariate analysis using a Cox regression model was performed, and for assessment of prognostic accuracy, Harrell's concordance index was performed.

Results and limitations

Median tumour diameter was 5.0 cm (range: 0.6–22 cm). Tumour necrosis was noted in 607 tumours (32.6%). Median follow-up was 72.5 mo (range: 0–281 mo); 359 of 1862 patients (19.3%) died of RCC. Ten-year CSS rates for respective SSIGN scores in our study ranged from 96.5% (scores 0–1) to 19.2% (scores ≥10). pT categories, lymph-node status, distant metastases, high tumour grade (size ≥5 cm), and necrosis were each independent predictors of CSS. The Harrell's concordance index was 0.823. Limitations included smaller sample sizes in higher risk categories and limited numbers of patients at risk after 10 yr.

Conclusions

Outcome prediction with the SSIGN score using routine pathology records was comparable to the original data based on review pathology. Combining scores into five categories improved discrimination. Our data support the routine use of the SSIGN score in clinical practice with regard to follow-up decisions and patient selection for adjuvant trials.     

Vimentin over-expression and carbonic anhydrase IX under-expression are independent predictors of recurrence,specific and overall survival in non-metastatic clear-cell renal carcinoma: a validation study

Purpose

Clinical outcomes prognostic markers are awaited in clear-cell renal carcinoma (ccRCC) to improve patient-tailored management and to assess six different markers’ influence on clinical outcomes from ccRCC specimen and their incremental value combined with TNM staging.

Materials and methods

This is a retrospective, multicenter study. One hundred and forty-three patients with pT1b-pT3N0M0 ccRCC were included. Pathology specimens from surgeries were centrally reviewed, mounted on a tissue micro-array and stained with six markers: CAIX, c-MYC, Ki67, p53, vimentin and PTEN. Images were captured through an Ultra Fast Scanner. Tumor expression was measured with Image Pro Plus. Cytoplasmic markers (PTEN, CAIX, vimentin, c-MYC) were expressed as surface percentage of expression. Nuclear markers (Ki67, p53) were expressed as number of cells/mm². Clinical data and markers expression were compared with clinical outcomes. Each variable was included in the Cox proportional multivariate analyses if p < 0.10 on univariate analyses. Discrimination of the new marker was calculated with Harrell’s concordance index.

Results

At median follow-up of 63 months (IQR 35.0–91.8), on multivariate analysis, CAIX under-expression and vimentin over-expression were associated with worse survival (recurrence, specific and overall survival). A categorical marker CAIX-/Vimentin+ with cutoff points for CAIX and vimentin of 30 and 50 %, respectively, was designed. The new CAIX-/Vimentin+ marker presented a good concordance and comparable calibration to the reference model. Limitations are the retrospective design, the need for external validation and the large study period.

Conclusion

Using an automated technique of measurement, CAIX and vimentin are independent predictors of clinical outcomes in ccRCC.

     

Development and characterization of clinically relevant tumor models from patients with renal cell carcinoma

Background

Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo.

Objective

To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy.

Design, setting, and participants

In vivo and in vitro animal experiments.

Measurements

Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC.

Results and limitations

RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC.

Conclusions

We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.     

Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Background

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

Objective

To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.

Design, setting, and participants

Retrospective data from patients with synchronous mRCC (n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.

Outcome measurements and statistical analysis

OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.

Results and limitations

Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.

Conclusions

CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.

Patient summary

We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.     

Higher Expression of Topoisomerase II Alpha Is an Independent Marker of Increased Risk of Cancer-specific Death in Patients with Clear Cell Renal Cell Carcinoma

Background

Tumor-based biomarkers of outcome for patients with clear cell renal cell carcinoma (ccRCC) remain limited, especially for those with low-risk disease. Type IIa topoisomerase (TOPOIIa) is a well-known biomarker of DNA replication and a target for antineoplastic agents, but it has not been evaluated as a biomarker of ccRCC outcome.

Objective

To evaluate the association of TOPOIIa expression in ccRCC and risk of cancer-specific death following surgery.

Design, setting, and participants

Two independent cohort studies were studied in tertiary referral urology practices in the United States. We identified cohorts of 1378 (analytic) and 279 (validation) patients who underwent nephrectomy for clinically localized ccRCC and had paraffin tumor tissue available. TOPOIIa expression was assessed using immunohistochemistry and scored as the number of positive cells per square millimeter.

Outcome measurements and statistical analysis

Our primary end point was cancer-specific survival (CSS). We evaluated TOPOIIa expression as a continuous variable and dichotomized as low versus high. For associations with CSS, we used Kaplan-Meier curves and Cox regression models.

Results and limitations

In both cohorts, patients who had high TOPOIIa expression were approximately three times more likely to experience ccRCC death than those with low expression (hazard ratio [HR]: 2.75; 95% confidence interval [CI], 2.12–3.56; p = 1.79E-14 and HR: 3.45; 95% CI, 1.34–8.88; p = 0.0104, respectively). Multivariable adjustment for pathologic features of aggressiveness did not explain these associations, and stratified analysis suggests that the association is more pronounced among patients with low-risk disease as defined by the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score.

Conclusions

Higher TOPOIIa expression is independently associated with increased risk of cancer death among patients undergoing surgery for ccRCC, and the prognostic value is pronounced among patients with low-risk disease. Evaluation of TOPOIIa in ccRCC provides the opportunity to help guide postsurgical surveillance for ccRCC patients as well as inform the design of more targeted clinical trials and novel treatment strategies.     

PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient’s overall survival

Objective

To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression.

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

Clinical, molecular, and genetic correlates of lymphatic spread in clear cell renal cell carcinoma

Background

While it is well known that clear cell renal cell carcinoma (ccRCC) that presents with lymphatic spread is associated with an extremely poor prognosis, its molecular and genetic biology is poorly understood.

Objective

Define the clinicopathologic, molecular, and genetic biological characteristics of these tumors in comparison to nonmetastatic (N0M0) renal cell carcinomas.

Design, setting, and participants

A retrospective study defined clinicopathologic features, expression of 28 molecular markers, and occurrence of chromosomal aberrations for their correlation with lymphatic spread in three cohorts of 502, 196, and 272 patients, respectively.

Measurements

Fisher exact test or the χ² test were used to compare categorical variables; continuous variables were compared with the Mann-Whitney U test or student t test. Cut-off values were calculated based on receiver operating characteristic curves and the Youden Index. Uni- and multivariate regression analyses were used to investigate the correlation with lymphatic spread.

Results and limitations

In clinical analyses, a predictive model consisting of smoking history (p = 0.040), T stage (p < 0.0001), Fuhrman grade (p < 0.0001), Eastern Cooperative Oncology Group performance status (p < 0.0001), and microvascular invasion (p < 0.0001) was independently associated with lymphatic spread. After adjustment with these clinical variables, low carbonic anhydrase IX (CAIX) (p = 0.043) and high epithelial vascular endothelial growth factor receptor 2 (p = 0.033) protein expression were associated with a higher risk of lymphatic spread, and loss of chromosome 3p (p < 0.0001) with a lower risk. The current study is limited by its retrospective design, small sample size, and single-center experience.

Conclusions

The low rates of CAIX expression and loss of chromosome 3p suggest that lymphatic spread in ccRCC occurs independently of von Hippel-Lindau tumor suppressor inactivation.     

Survival and Impact of Clinical Prognostic Factors in Surgically Treated Metastatic Renal Cell Carcinoma

Background

The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era.

Objective

To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC.

Design, setting, and participants

Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25–82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC.

Intervention

Metastasis resection from various anatomic sites with the aim of completely removing detected lesions.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan-Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The α error for statistical significance was set at 0.05.

Results and limitations

Multivariable analysis revealed that primary tumour T stage ≥3 (hazard ratio [HR]: 2.8; p < 0.01), primary tumour Fuhrman grade ≥3 (HR: 2.3; p < 0.03), nonpulmonary metastases (HR: 3.1; p < 0.03), disease-free interval ≤12 mo (HR: 2.3; p < 0.058), and multiorgan metastases (HR: 2.5; p < 0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log-rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% (p < 0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites.

Conclusions

LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC.     

GSTM1 genotype is an independent prognostic factor in clear cell renal cell carcinoma

Purpose

Owing to dual functionality of cytosolic glutathione S-transferases (GSTs), they might affect both the development and the progression of renal cell carcinoma (RCC). However, the data on the prognostic value of GST polymorphism in patients with RCC are scarce. Hence, we evaluated the effect of GST gene variants on both the risk of RCC development and the postoperative prognosis in patients with clear cell RCC (ccRCC).

Expression of aquaporin 1 in primary renal tumors: a prognostic indicator for clear-cell renal cell carcinoma

Background

Aquaporin 1 (AQP1) is a water channel expressed in many epithelial tissues and endothelium, including the proximal nephron of the kidney.

Objective

We measured AQP1 expression in primary renal cell carcinomas (RCCs) and evaluated its significance and prognostic utility.

Design, setting, and participants

We examined AQP1 expression in 559 sporadic renal tumors as well as in 43 normal kidney tissue samples and collected clinicopathologic and prognostic data.

Measurements

AQP1 expression was measured by using real-time quantitative polymerase chain reaction (PCR).

Results and limitations

All normal kidney samples presented substantial AQP1 expression. Among tumor subtypes, AQP1 expression was significantly higher in clear-cell and papillary RCCs, whereas it was lower in chromophobe RCCs, oncocytomas, and collecting-duct carcinomas. In clear-cell RCC, AQP1 was significantly higher in patients without symptomatic presentation or whose tumors were smaller, lower grade, or either lower stage or lacking in microvascular invasion. Von Hippel-Lindau (VHL) tumor suppressor gene mutational status did not affect expression level. Cox univariate and multivariate analyses strongly associated high AQP1 expression with better prognosis in cancer-specific and cancer-free survival tests in all patient cohorts, as well as in cancer-specific survival in a cohort of patients with advanced metastatic RCC. The time-dependent receiver operation characteristic (ROC) analyses, combined with logistic regression models, revealed that the addition of the AQP1 parameter to the University of California Los Angeles Integrated Staging System (UISS) prognostic score can improve the accuracy of predictions of both cancer death and recurrence for all patient cohorts as well as of cancer death for advanced cases within a 5-yr follow-up period in clear-cell RCC. High AQP1 expression was also associated with better outcome in a univariate cancer-specific survival test in papillary RCCs.

Conclusions

AQP1 shows RCC subtype-specific expression, and its expression level provides useful prognostic information for patients with clear-cell RCC.     

Validation of Serum Amyloid α as an Independent Biomarker for Progression-Free and Overall Survival in Metastatic Renal Cell Cancer Patients

Background

We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model.

Objective

Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs).

Design, setting, and participants

For training we used 114 interferon-treated mRCC patients (inclusion 2001–2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003–2009).

Measurements

Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect.

Results and limitations

Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6–8 wk of TKI treatment had no value in predicting treatment outcome.

Conclusions

SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management.     

Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma

Background

Quinazoline-based α1-adrenoceptor antagonists suppress tumor growth by inducing apoptosis via an α1-adrenoceptor-independent action. Anoikis is a unique mode of apoptosis consequential to insufficient cell-matrix interactions.

Objective

This study investigated the apoptotic effect of novel quinazoline-based compounds on human renal cancer cells.

Design, setting, and participants

Two cell lines were used: renal cell carcinoma (RCC) 786-0, harboring a von Hippel-Lindau (VHL) tumor-suppressor gene mutation with a highly angiogenic phenotype, and Caki cells (no VHL mutation).

Measurements

The lead compound DZ-50 (10 μM) led to significant inhibition of tumor-cell adhesion, migration, and invasion at a lower dose than doxazosin (25 μM) in both RCC lines.

Results and limitations

Doxazosin induced death-receptor-mediated apoptosis, while DZ-50 led to anoikis via targeting of the focal adhesion complex and AKT signaling that subsequently increased RCC susceptibility to caspase-8-mediated apoptosis. Both quinazoline compounds, doxazosin and DZ-50, significantly reduced RCC metastatic potential in vivo.

Conclusions

Quinazoline-based drugs trigger anoikis in RCC by targeting the focal adhesion survival signaling. This potent antitumor action against human RCC suggests a novel quinazoline-based therapy targeting renal cancer.