Joshua E. Logan

Gain of Chromosome 8q Is Associated With Metastases and Poor Survival of Patients With Clear Cell Renal Cell Carcinoma

The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease‐specific survival (DSS).

Non–clear cell histology in patients with metastatic RCC as a prognostic indicator in the targeted therapy era.

454 Background: The role of targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) having non-clear cell histology (non-ccRCC) is still being defined. We sought to examine the factors associated with survival outcomes in patients presenting with various histological subtypes in the TT era. METHODS The UCLA Kidney Cancer Program database containing records of over 2000 patients was queried. The clinicopathologic factors between patients with clear cell subtype (ccRCC) and those with non-clear cell histology were compared using the Students T-test and the chi-square test for continuous and categorical variables, where appropriate. Survival outcomes were estimated using Kaplan-Meier (log rank). Univariate and multivariate Cox regression models were used to identify independent associations with survival. RESULTS Of 157 patients treated with FDA-approved TT, 132 (84%) had ccRCC while 25 (16%) had non-ccRCC. The two groups were balanced for baseline demographic variables, including gender, race, BMI, pack-years of smoking, T-stage, Fuhrman grade, performance status and UCLA Integrated Staging System (UISS) risk category. Median survival of patients with ccRCC and non-ccRCC was 41.6 and 18.1 months (p<0.001). In univariate analysis, non-ccRCC was associated with a 2.7-fold risk of cancer specific death compared to ccRCC patients. Among patients receiving TT-only, median survival of patients with ccRCC and non-ccRCC was 35 and 15.4 months (p=0.007). A subset of ccRCC patients treated sequentially with IMT followed by TT had a median survival of 73 months. Worsening UISS risk class and non-ccRCC histology, but not age, gender, race, tobacco exposure history, or tumor size, were independently associated with the risk of cancer death. CONCLUSIONS Non-clear cell histology remains a significant and independent risk factor for cancer specific death for mRCC patients treated by TT even after controlling for UISS risk category. [Table: see text].

Effect of PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, on proliferation in renal cell carcinoma at nanomolar concentrations and prediction of sensitivity by molecular markers.

413 Background: Cell cycle dysregulation is prevalent in renal cell carcinoma (RCC). PD-0332991 is an orally active, potent, and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, blocking retinoblastoma (Rb) phosphorylation at nanomolar concentrations. METHODS 28 RCC and immortalized kidney cell lines were used to examine the effects of PD-0332991 on proliferation to determine the half maximal inhibitory concentration (IC50). Effects of PD-0332991 on cell-cycle, apoptosis, and Rb phosphorylation were assessed with flow cytometry and western blot analysis for five of the cell lines: RCC-HB and SW 156 (sensitive/malignant), R444 and Hs 891.T (resistant/malignant), and CCD 1103 (resistant/immortalized non-malignant). Molecular markers for response prediction were studied using array CGH and gene expression profiling. RESULTS Concentration-dependent inhibition of proliferation was identified in response to PD-0332991, with IC50values ranging from 25.0nM up to 700nM; five cell lines were identified as completely resistant at 1000nM. PD-0332991 induced G0/G1 cell cycle arrest, as well as induction of late apoptosis in SW 156, and Rb phosphorylation was blocked in a time-dependent fashion in both sensitive cell lines, while resistant lines were unaffected. Genotype and expression data of CDKN2A and CDKN2B were combined and a consensus was made regarding p16 and p15 status; significant association between loss and sensitivity to PD-0332991 was identified for p16 (p = 0.027). For CCND1, CCNE1, E2F1, Rb, CDK4, and CDK6 no amplifications or homozygous deletions were identified by array CGH; cell lines were then classified as having high or low expression for each of these markers. E2F1 had low expression levels significantly associated with response to PD-0332991 (p = 0.041). CONCLUSIONS PD-0332991 shows anti-proliferative activity in RCC through blockade of the cell cycle. The decreased expression of molecular markers p16 and E2F1 predict for sensitivity to PD-0332991 in RCC.