Christian Eichelberg

Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability

CONTEXT Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine. OBJECTIVE This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues. EVIDENCE ACQUISITION Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival. Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later. EVIDENCE SYNTHESIS These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel-Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine. CONCLUSIONS Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.

Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer

Purpose: The HER2 oncogene is involved in the biology of many different tumor types and serves as a prognostic marker and a therapeutic target in breast cancer. In contrast to breast cancer, studies on Her2 overexpression and gene amplification in prostate cancer have yielded different results. The purpose of this study was to learn more on the prevalence and clinical significance of HER2 amplification and overexpression in prostate cancer. Experimental Design: A tissue microarray containing >2,000 prostate cancers with follow-up data was used. Tissue microarray sections were analyzed on protein and DNA level using two different antibodies (HercepTest, DAKO; Novocastra NCL-CB11) and fluorescence in situ hybridization. Results: Immunohistochemical analyses showed highly similar results for both antibodies. Detectable Her2 immunostaining was observed in 17.2% for the HercepTest and in 22.5% for the Novocastra antibody with the vast majority of cases showing 1+ or 2+ staining. For both antibodies (HercepTest/Novocastra), significant associations were found between positive staining and high Gleason grade (P < 0.0001, both), advanced pT stage (P < 0.0001/P = 0.0015), rapid tumor cell proliferation (P = 0.0004/P = 0.0071), and tumor recurrence (P < 0.0001, both). HER2 amplification was only found in 1 of 2,525 analyzable cases (0.04%). Conclusions: Low-level Her2 overexpression occurs at relevant frequency in prostate cancer and in the absence of gene amplification. Increased Her2 expression may potentially lead to an aggressive behavior of tumor cells through the stimulation of tumor cell proliferation because Her2 staining was shown to be significantly associated with Ki67 labeling index. These data argue for reconsidering anti-Her2 therapy, possibly with modified approaches. Clin Cancer Res; 16(5); 1553–60

Surgical volume is related to the rate of positive surgical margins at radical prostatectomy in European patients

To assess the association between surgical volume (SV) and the rate of positive surgical margins (PSM) after radical prostatectomy (RP) in a large single‐institution European cohort of patients.

Biochemical recurrence after radical prostatectomy: multiplicative interaction between surgical margin status and pathological stage.

PURPOSE A positive surgical margin after radical prostatectomy is considered an adverse prognostic feature. However, few groups have explored the potential interaction between surgical margin status and other cancer characteristics, specifically pathological stage. We addressed the first degree of interaction between positive surgical margins and other established adverse predictors of biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS We used univariate and multivariate analysis to test the effect of surgical margin status on biochemical recurrence in 4,490 patients treated at a single institution between 1992 and 2008. We systematically tested all first-degree interactions between surgical margin status, and pretreatment prostate specific antigen, pT and pN stage, and radical prostatectomy Gleason sum. If interactions were significant, we quantified the effect on the biochemical recurrence rate. RESULTS Overall 850 patients (18.9%) had positive surgical margins. In those with negative vs positive surgical margins the 5-year biochemical recurrence-free survival rate was 95% vs 83%, 74% vs 62% and 47% vs 29% for pT2, pT3a and pT3b disease, respectively. In multivariate models only the pT stage-surgical margin status interaction achieved independent predictor status (p = 0.003). Negative vs positive surgical margin multivariate HRs were 1 vs 2.9, 2.3 vs 4.3 and 4.1 vs 5.6 in pT2, pT3a and pT3b cases, respectively. CONCLUSIONS Compared to negative surgical margins, positive surgical margins increase the absolute biochemical recurrence 5-year rate by 12% to 18%. More importantly, positive surgical margins may substantially worsen the prognosis beyond that of the original pathological disease stage.

Epidermal growth factor receptor protein expression and genomic alterations in renal cell carcinoma.

Epidermal growth factor receptor (EGFR) is involved in the progression of many cancer types and represents an important therapeutic target.

Epithelial cell adhesion molecule is an independent prognostic marker in clear cell renal carcinoma.

Epithelial cell adhesion molecule (EPCAM) has recently attained a renewed interest as a candidate protein in diagnosis, prognostication and therapy of various tumor entities. The molecular epidemiology and prognostic relevance of EPCAM in renal cell carcinoma (RCC) and amongst the histological subtypes of RCC are unclear. We analyzed the prevalence and prognostic significance of EPCAM in a tumor tissue microarray composed of 1,088 independent RCCs samples by immunohistochemistry (IHC). We found significant variations of EPCAM IHC staining intensities in between the RCC subtypes: in papillary and chromophobe RCC, the majority of tumors (89–93%) showed an at least weak EPCAM protein expression. In the largest subgroup, the clear cell (cc)RCC (n = 767), a negative EPCAM IHC was found in 1/3 of the patients and was associated with high‐grade disease and nodal metastases. Kaplan–Meier analyses demonstrated a significant association between positive EPCAM IHC and prolonged overall survival, even in a subset of low‐risk ccRCC. In multivariable analyses, EPCAM represented an independent risk factor of survival throughout all subgroups. For localized, low‐grade ccRCC, information of EPCAM IHC raised predictive accuracy of a multivariate model by ∼5%, compared to T‐stage and grade alone. Our findings indicate that EPCAM is an independent prognostic molecular marker in ccRCC and, especially in localized ccRCC, might be able to provide auxiliary information for a better prognostication.

PTEN deletions are related to disease progression and unfavourable prognosis in early bladder cancer

This study aimed to determine the prevalence and clinical significance of deletions of the tumour suppressor gene PTEN in bladder cancer.

Effect of autologous blood transfusion on the rate of biochemical recurrence after radical prostatectomy

To test the association between autologous blood transfusion (ABT) and biochemical recurrence (BCR) after radical prostatectomy (RP) in a large group of contemporary patients.

Laparoscopic radical nephrectomy vs laparoscopic or open partial nephrectomy for T1 renal cell carcinoma: comparison of complication rates in elderly patients during the initial phase of adoption.

OBJECTIVE To assess postoperative complication profiles and 30-day mortality (30 dM) in older patients undergoing either laparoscopic radical nephrectomy (LRN) compared with open partial nephrectomy (OPN) or laparoscopic partial nephrectomy (LPN) for early stage renal cell carcinoma. METHODS Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 2277 patients aged>65 years with T1 renal cell carcinoma, who underwent LRN, OPN, or LPN were identified (1992-2005). Surgical and medical complications and 30 dM after nephrectomy were abstracted. Bivariate and multivariate logistic regression analyses were performed. RESULTS Relative to LRN, the rate of surgical complications was higher for OPN (28% vs 20%; P<.001) and LPN (29% vs 20%; P=.01). These differences persisted after multivariate adjustment for patient and tumor characteristics (OPN: odds ratio, 1.6; 95% confidence interval, 1.28-1.91; P<.001; LPN: odds ratio, 1.6; 95% confidence interval, 1.13-2.39; P=.01). Specifically, relative to LRN, OPN was associated with a 7% higher rate of genitourinary complications (13% vs 20%; P<.001). Similarly, relative to LRN, LPN was associated with a 7% higher rate of genitourinary complications (13% vs 20%; P=.001) and with a 4% higher rate of hemorrhagic complications (8% vs 4%; P=.02). No statistically significant differences were recorded for all other surgical and/or medical complication types and 30 dM (all P≥.2). CONCLUSION The complication and 30-dM rates were not different between LRN, OPN, and LPN groups. Exceptions include genitourinary complications that favor LRN relative to OPN and LPN and hemorrhagic complications that favor LRN relative to LPN. It is doubtful that these results should discourage the use of partial nephrectomy relative to LRN in older patients.

Annual prostatectomy volume is related to rectal laceration rate after radical prostatectomy.

OBJECTIVE To examine the effect of annual prostatectomy volume (APV) on contemporary intraoperative rectal laceration (RL) rates after radical prostatectomy. METHODS From 1999 to 2008, 36 699 radical prostatectomy procedures were performed in Florida. First, logistic regression models predicting the RL rate were fitted. Second, other logistic regression models were used to examine the association between RL and 2 other secondary outcomes: prolonged length of stay (>3 days) and increased hospital charges (>