Brian Shuch

Cytogenetic Profile Predicts Prognosis of Patients With Clear Cell Renal Cell Carcinoma

PURPOSE The majority of cytogenetic studies in renal cell carcinoma (RCC) have been impaired by small sample size, retrospective character, and lack of a survival end point. We prospectively studied the prognostic impact of cytogenetic abnormalities on a larger cohort of patients having up to 108 months of follow-up. PATIENTS AND METHODS Tumors of 282 patients who underwent nephrectomy for clear cell RCC were cytogenetically analyzed. Results were correlated with pathological factors and disease-specific survival. RESULTS The most frequently observed cytogenetic abnormalities were loss of 3p (60%), gain of 5q (33%), loss of 14q (28%), trisomy 7 (26%), loss of 8p (20%), loss of 6q (17%), loss of 9p (16%), loss of 4p (13%), and loss of chromosome Y in men (55%). Tumors with loss of 3p presented at lower TNM stages. Loss of 4p, 9p, and 14q were all associated with higher TNM stages, higher grade, and greater tumor size. A deletion of 3p was associated with better prognosis (P = .03), while loss of 4p (P < .001), loss of 9p (P < .01), and loss of 14q (P < .01) were each associated with worse prognosis. Loss of the Y chromosome led to improved progression-free survival in metastatic patients (P = .02). In multivariate analysis, loss of 9p was retained as an independent prognostic factor. CONCLUSION This cytogenetic study serves as a proof of principal that genetic information, such as loss of chromosome 9, can be obtained from widely available technology, and can provide additional prognostic information to standard clinicopathologic variables.

Neoadjuvant targeted therapy and advanced kidney cancer : observations and implications for a new treatment paradigm

To evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise.

Molecular Signatures of Localized Clear Cell Renal Cell Carcinoma to Predict Disease-Free Survival after Nephrectomy

Purpose: To identify the molecular signature of localized (N0M0) clear cell renal cell carcinoma (RCC) and assess its ability to predict outcome. Methods: Clinical characteristics and pathologic records of 170 patients with localized clear cell RCC who underwent nephrectomy were reviewed. Immunohistochemical analysis was done on a tissue microarray of all primary tumors using a kidney cancer–related panel of protein markers, which included CAIX, CAXII, CXCR3, gelsolin, Ki-67, vimentin, EpCAM, p21, p27, p53, pS6, PTEN, HIF-1α, pAkt, VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, and VEGFR-3. Associations with disease-free survival (DFS) were evaluated with Cox models, and a concordance index assessed prognostic accuracy. Results: Median follow-up was 7.1 years. The final multivariate Cox model determined T classification, Eastern Cooperative Oncology Group performance status, and five molecular markers (Ki-67, p53, endothelial VEGFR-1, epithelial VEGFR-1, and epithelial VEGF-D) to be independent prognostic indicators of DFS. The molecular signature based on these markers predicted DFS with an accuracy of 0.838, an improvement over T classification of 0.746, and the University of California-Los Angeles Integrated Staging System of 0.780. A constructed nomogram combined the molecular, clinical, and pathologic factors and approached a concordance index of 0.904. Conclusions: A molecular signature consisting of five molecular markers (Ki-67, p53, endothelial VEGFR-1, epithelial VEGFR-1, and epithelial VEGF-D) can predict DFS for localized clear cell RCC. The prognostic ability of the signature and nomogram may be superior to clinical and pathologic factors alone and may identify a subset of localized patients with aggressive clinical behavior. Independent, external validation of the nomogram is required. (Cancer Epidemiol Biomarkers Prev 2009;18(3):894–900)

Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity.

CONTEXT Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. OBJECTIVE To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. EVIDENCE ACQUISITION A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. EVIDENCE SYNTHESIS The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. CONCLUSIONS Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. PATIENT SUMMARY Kidney cancer can be subdivided into related but different cancers that arise from the kidneys tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtypes clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies.

Cytogenetic and Molecular Tumor Profiling for Type 1 and Type 2 Papillary Renal Cell Carcinoma

Purpose: The goal of this study was to evaluate immunohistochemical and cytogenetic features and their prognostic value in papillary renal cell carcinoma (PRCC) subtypes. Experimental Design: One hundred fifty-eight cases of PRCC were identified and reclassified by subtype. Tumoral expression of 29 molecular markers was determined by immunohistochemistry. Cytogenetic analyses were done on a prospective series of 65 patients. Associations with clinicopathologic information and disease-specific survival were assessed. Results: Fifty-one patients (32%) had type 1 and 107 (68%) type 2 PRCC. Type 2 patients had worse Eastern Cooperative Oncology Group performance status, higher T stages, nodal and distant metastases, higher grades, and a higher frequency of necrosis, collecting system invasion and sarcomatoid features. Type 2 showed greater expression of vascular endothelial growth factor (VEGF)-R2 in the tumor epithelium, and of VEGF-R3 in both tumor epithelium and endothelium. Loss of chromosome 1p, loss of 3p, and gain of 5q were exclusively observed in type 2, whereas type 1 more frequently had trisomy 17. Type 2 PRCC was associated with worse survival than type 1, but type was not retained as an independent prognostic factor. Lower PTEN, lower EpCAM, lower gelsolin, higher CAIX, and higher VEGF-R2 and VEGF-R3 expression, loss of 1p, 3p, or 9p, and absence trisomy 17 were all associated with poorer prognosis. Conclusions: Type 2 PRCC is associated with more aggressive clinicopathologic features and worse outcome. Molecular and chromosomal alterations can distinguish between PRCC subtypes and influence their prognosis. The effect of 3p loss on survival in PRCC is opposite to the relationship seen in clear cell RCC.

Contemporary Management of Renal Tumors With Venous Tumor Thrombus

PURPOSE Renal cell carcinoma with intravenous tumor thrombus remains one of the most intriguing and challenging topics in urological oncology. With better understanding of the biology of intravascular tumor invasion and improvements in overall survival, the surgical and medical treatment of these patients is being completely redefined. MATERIALS AND METHODS We performed a MEDLINE(R) search for relevant articles on renal cell carcinoma with intravenous tumor thrombus. RESULTS We describe the staging systems, prognostic factors and surgical techniques involved in the management of renal cell carcinoma with intravenous tumor thrombus. We also review long-term survival of local, advanced and metastatic renal cell carcinoma with tumor thrombus invasion. Finally, we propose a clinical algorithm for the treatment of patients with renal cell carcinoma invading the venous system. CONCLUSIONS Management of a kidney cancer tumor invading the venous system should now consider the primary biology and natural behavior of a given tumor in that specific patient rather than only focusing on the level and extent of venous invasion. Treatment must be individualized for every patient based on performance status, tumor biology and risk of surgery.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

PD-L1 Expression in Clear Cell Renal Cell Carcinoma: An Analysis of Nephrectomy and Sites of Metastases.

Background: Expression of programmed death ligand (PD-L1/B7-H1/CD274) represents a mechanism of immune escape for renal cell carcinoma (RCC) cells. Drugs blocking PD-L1 or its receptor are in clinical development and early data suggests that tumor PD-L1 expression may predict response. Patients and Methods: A tissue microarray (TMA) consisting of four biopsy cores from 34 matched pairs of nephrectomy and metastatic sites of clear cell RCC was used to assess PD-L1 expression by quantitative immunofluorescence. Assessment of intra- and inter-tumor heterogeneity and primary and metastatic tumor expression was performed using a method of Automated Quantitative Analysis (AQUA). Results: The median AQUA scores were higher in metastatic than primary specimens (P < 0.0001). The correlation between PD-L1 expression in matched primary and metastatic specimens was weak (R= 0.24). Within a given tumor, variable PD-L1 staining heterogeneity was seen, however the degree of heterogeneity was similar in primary and metastatic sites (P = 0.482). Conclusions: The weak correlation between PD-L1 expression in primary and metastatic sites for a given patient suggests that expression in nephrectomy specimens cannot be used to select metastatic RCC patients for PD-L1 and PD-1 inhibitors. The intra-tumor heterogeneity seen in both primary and metastatic specimens indicates that a single core biopsy might not be sufficient to determine PD-L1 expression.

Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate Cancer

PURPOSE The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors. PATIENTS AND METHODS We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically. RESULTS EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.

Cytoreductive Nephrectomy for Kidney Cancer With Sarcomatoid Histology—Is Up-Front Resection Indicated and, if Not, is it Avoidable?

PURPOSE Cytoreductive nephrectomy has a survival advantage in select patients. Patients with sarcomatoid features are known to have poor outcomes. We reviewed the role of surgery in this population to see if these patients could be identified preoperatively. MATERIALS AND METHODS Cytoreductive nephrectomy cases identified as having sarcomatoid features or spindle cells were reviewed. The histology, grade, and the presence and percentage of sarcomatoid elements were recorded. Clinicopathological characteristics, survival and systemic therapy were compared to cases without sarcomatoid histology. RESULTS A total of 62 tumors with sarcomatoid histology were identified, accounting for 14.9% of the 417 patients undergoing cytoreductive nephrectomy. The percentage of sarcomatoid transformation widely varied with a range of 2% to 100% and a mean/median of 49.8%/50%. An increased percentage of sarcomatoid features is associated with a worse prognosis. Patients with and those without sarcomatoid features had similar clinical characteristics. In the sarcomatoid group a higher T stage (p <0.001) and increased incidence of nonclear cell histology (p <0.001) were noted. Median survival of patients with sarcomatoid features was 4.9 vs 17.7 months for nonsarcomatoid histology (p <0.001). Use of postoperative therapy was significantly worse for patients with sarcomatoid histology. CONCLUSIONS Patients with sarcomatoid histology undergoing cytoreductive nephrectomy have a dire prognosis despite aggressive surgery and postoperative therapy. The variability in the sarcomatoid component and the lack of specific clinical features make preoperative identification challenging. Research should focus on identifying biomarkers for this subset of tumors that may allow up-front systemic therapy with surgery reserved for responding patients.