Gurudatta Naik

Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors

A trial-level meta-analysis was conducted to determine the relative risk (RR) of pancreatitis associated with multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized phase 2 and 3 trials comparing arms with and without an FDA-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Statistical analyses calculated the RR and 95% confidence intervals (CI). A total of 10,578 patients from 16 phase III trials and 6 phase II trials were selected. The RR for all grade and high-grade pancreatitis for the TKI vs. no TKI- arms was 1.95 (p=0.042, 95% CI: 1.02 to 3.70) and 1.89 (p=0.069, 95% CI: 0.95 to 373), respectively. No differential impact of malignancy type or specific TKI agent was seen on RR of all grade of high grade pancreatitis. Better patient selection and monitoring may mitigate the risk of severe pancreatitis.

High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM’s and MAPKAPK’s in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Impact of prednisone on toxicities and survival in metastatic castration- resistant prostate cancer: A systematic review and meta-analysis of randomized clinical trials.

We conducted a meta-analysis of randomized trials comparing regimens that included daily oral prednisone (P) in only one arm to investigate its impact on toxicities and outcomes in metastatic castration-resistant prostate cancer (mCRPC). Five trials were identified totaling 2939 patients, of whom 1471 were randomized to an arm not containing P and 1468 received therapy containing P. There was no difference between the non-P and P groups for severe toxicities (incidence rate ratio [IRR]=0.82, p=0.712, I(2)=97.9%). When examining toxicities as a reason for discontinuing therapy, the non-P groups were not different from the P groups (relative risk [RR]=1.24, p=0.413, I(2)=86.8%). The non-P groups demonstrated no difference in OS compared to the P groups (HR=1.09, p=0.531, I(2)=79.7%). The meta-analysis is limited by the trial level design and small number of trials.

Prognostic Impact of C-Reactive Protein in Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis

Background: Serum C-reactive protein (CRP) demonstrates a prognostic impact in small studies of metastatic prostate cancer (MPC). Methods: A systematic review was conducted to identify publications and presentations exploring the association of serum CRP and overall survival (OS) in MPC, both castration-sensitive and castration-resistant. Heterogeneity among trials was assessed using Cochranes Q statistic, and the I2 statistic was used to quantify inconsistency. The assumption of homogeneity was considered invalid if p < 0.1. All statistical tests were 2-sided, and p < 0.05 was considered significant. Results: 6 studies were eligible, totaling 659 evaluable patients. 2 studies evaluated castration-sensitive men receiving androgen deprivation, while the remaining 4 studies evaluated castration-resistant men receiving docetaxel-based chemotherapy. Men with higher CRP had significantly worse OS than those with lower CRP (hazard ratio (HR) = 1.42, p < 0.001, 95% confidence interval (CI) 1.17-1.73). In trials of castration-sensitive men, high CRP yielded a HR = 1.92 (p = 0.005, 95% CI 1.22-3.03; I2 = 0). In castration-resistant men, high CRP yielded HR = 1.35 (p = 0.003, 95% CI 1.11-1.65; I2 = 78.6%). Conclusion: This meta-analysis suggests a detrimental impact for CRP on OS in MPC. Prospective validation is justified to enhance prognostication and trial design, given the affordability, ready availability, and large dynamic range of CRP.

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6–12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment. Materials and methods: We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models. Results: Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6–39.7%) and median OS and PFS were 20 (95% CI = 20–21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20–40) weeks and 1-year (95% CI) OS of 13.7% (4.4–42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16–20) weeks and 1-year (95% CI) OS of 6.7% (1.8–24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84–30.37, p = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size. Conclusion: This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Biomarker‐guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Gene Expression Profiling of Advanced Penile Squamous Cell Carcinoma Receiving Cisplatin-based Chemotherapy Improves Prognostication and Identifies Potential Therapeutic Targets

In men with advanced penile squamous cell carcinoma receiving first-line chemotherapy, visceral metastases (VM) and Eastern Cooperative Oncology Group performance status ≥1 are poor prognostic factors for overall survival (OS). We hypothesized that tumor gene expression profiling may enhance prognostic stratification and identify potential therapeutic targets. In this retrospective study, RNA extracted from macrodissected tumors underwent profiling for the expression of 738 genes using NanoString. Univariate and multivariate analyses assessed the association of genes, VM, and performance status with OS. Tumors were available from 25 men who received first-line cisplatin-based chemotherapy. In univariate analysis, upregulated MAML2 (p=0.004), KITLG (p≤0.0001), and JAK1 (p=0.029) genes were associated with poor OS, and upregulated FANCA was associated with better OS (p=0.024). In stepwise multivariate analyses, VM (hazard ratio=12.75, p=0.0001) and MAML2 (hazard ratio=10.411, p=0.003) were associated with poor OS. The presence of none, one, and both of these poor risk factors was associated with significantly different median OS of 18.4 mo, 7.2 mo, and 2.1 mo, respectively. Unsupervised clustering demonstrated two major molecular subtypes with trend for different survivals (p=0.052). Validation of results is necessary. PATIENT SUMMARY: The expression of the MAML2 gene in penile cancers from men receiving first-line cisplatin-based chemotherapy predicted overall survival independent of clinical factors.

Kinase analysis of penile squamous cell carcinoma on multiple platforms to identify potential therapeutic targets

Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevated kinase activity and gene over-expression with coexisting missense mutations at DNA level. Top pathways upregulated in both the kinase activity and gene expression platforms were PTEN, STAT3, GNRH, IL-8 and B cell receptor signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH, NF-kB and STAT3 signaling. ERBB2, ERBB3 and SYK were altered on NGS and also exhibited elevated kinase activity. To summarize, multiplatform comprehensive analysis of kinases discovered potential drivers of PSCC and actionable therapeutic targets. Translational studies are necessary to validate the functional relevance of our data to make advances in this rare malignancy.

Kinomic profiling identifies focal adhesion kinase 1 as a therapeutic target in advanced clear cell renal cell carcinoma

The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity. Pharmacologic and genetic loss of function experiments were used to assess the biologic significance of the top scoring kinase on in vitro and in vivo tumor phenotypes. Kinomics identified 7 peptides with increased tyrosine phosphorylation in metastases that were significantly altered (p<0.005). Based on these peptides, bioinformatics analyses identified several candidate kinases activated in metastases compared to primary tumors. The highest ranked upstream kinase was Focal Adhesion Kinase 1 (FAK1). RCC lines demonstrate evidence of elevated FAK1 activation relative to non-transformed renal epithelial cells. Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes. In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth. Collectively, these data demonstrate functional activation of FAK1 in metastases and provide preclinical rationale for targeting this kinase in the setting of advanced ccRCC.

Disparities in hospitalization outcomes among African-American and White prostate cancer patients

OBJECTIVES This paper aims to determine whether racial disparities exist in hospitalization outcomes among African-American and White hospitalized prostate cancer patients in the United States. We evaluated racial differences among matched groups of patients in post-operative complications, hospital length of stay and in-hospital mortality. METHODS We identified a total of 183,856 men aged 40 years and older with a primary diagnosis of prostate cancer, of which 58,701 underwent prostatectomy, through the Nationwide Inpatient Sample, and matched all African-American patients with White patients on: 1) Demographics, 2) Demographics+Clinical presentation and 3) Demographics+Clinical presentation+Treatment. Multivariable regression analyses were conducted in SAS and estimates were reported with 95% confidence intervals. RESULTS African-American patients were more likely to be admitted with metastatic disease (24.8%) compared with White patients matched on demographics (17.9%), and demographics+presentation (23.6%). However, 23.9% of African-American patients received surgery compared with 38.2% and 34.2% of Whites matched on demographics and demographics+presentation, respectively. White patients had lower in-hospital mortality compared with African-American patients matched on demographics (OR: 0.72, 95% CI: 0.66-0.79), demographics+presentation (OR: 0.88, 95% CI: 0.81-0.96), but was no longer significantly lower when matched on demographics, presentation and treatment (OR: 0.92, 95% CI: 0.85-1.00). CONCLUSION There were significant racial differences in outcomes among prostate cancer patients within the inpatient setting, even after accounting for demographic and presentation differences.