Davide Bimbatti

Metabolic alterations in renal cell carcinoma

Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies.

Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach

Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.

Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer

AbstractDespite the development of novel effective therapeutic strategies, metastatic castration-resistant prostate cancer (mCRPC) remains a disease with a lethal course and a high biological and molecular heterogeneity. To date, germline mutations in the BRCA gene represent one of the main risk factors for developing prostate cancer, with a strong association with aggressive phenotype and poor clinical outcomes. A better understanding of the genomic landscape of prostate cancer has strengthened the idea that “synthetic lethality” of this disease might be useful in cancer-drug discovery, focusing on agents such as platinum compounds and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). In this review, we summarize the main data available on BRCA mutations and discuss the clinical implications of these genomic aberrations in the management of prostate cancer, stressing the need to identify prognostic and predictive biomarkers and to deeply understand the mechanisms of treatment resistance, in order to maximize personalized medicine protocols and therefore clinical benefit.

Metastatic castration-resistant prostate cancer: targeting the mechanisms of resistance to abiraterone acetate and enzalutamide

Persistent androgen receptor (AR) axis is a functionally important pathway for prostate cancer cells and it is currently regarded as a critical therapeutic target. Although the impressive clinical activity of new hormonal agents, such as the second-generation AR antagonist enzalutamide (formerly MDV3100) and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone acetate (AA), in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises. To date, emerging hypotheses are different, but the mechanisms of resistance to these drugs have not yet been clarified. The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies. Understanding how the AR is activated may have clinical implications in defining which patients will respond to existing therapeutic agents and provide a proof for making novel strategies.

The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer

&NA; We analyzed the cardiovascular toxicities related to the use of abiraterone and enzalutamide in prostate cancer. We found that these agents are associated with an increased risk of all‐ and high‐grade cardiac toxicity as well as an increased risk of all‐ and high‐grade hypertension. Follow‐up for the onset of treatment‐related cardiovascular events should be considered in these patients treated with abiraterone and enzalutamide. Introduction: The cardiovascular toxicity related to abiraterone and enzalutamide has been previously studied by our group. In this analysis, we aim to update our previous findings related to abiraterone and enzalutamide, including the new available evidence, both in castration‐resistant and hormone‐sensitive prostate cancer. Patients and Methods: Prospective studies were identified by searching the MEDLINE/PubMed, Cochrane Library, and ASCO Meeting abstracts. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects methods. Results: We included 7 articles in this meta‐analysis, covering a total of 8660 patients who were used to evaluate cardiovascular toxicity. The use of new hormonal agents was associated with an increased risk of all‐grade (RR, 1.36; 95% CI, 1.13‐1.64; P = .001) and high‐grade (RR, 1.84; 95% CI, 1.21‐2.80; P = .004) cardiac toxicity. The use of new hormonal agents was also associated with an increased risk of all‐grade (RR, 1.98; 95% CI, 1.62‐2.43; P = .001) and high‐grade (RR, 2.26; 95% CI, 1.84‐2.77; P = .004) hypertension compared with the controls. Abiraterone was found to significantly increase the risk of both cardiac toxicity and hypertension, whereas enzalutamide significantly increases only the risk of hypertension. No differences were found based on the dose of prednisone used with abiraterone. The major limitation of this study is that data are available only as aggregate, and no single‐patient information could be analyzed. Conclusions: Abiraterone and enzalutamide significantly increase the incidence and RR of cardiovascular toxicity in patients affected by metastatic prostate cancer. Follow‐up for the onset of treatment‐related cardiovascular events should therefore be considered in these patients.

Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma.

Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.

De novo metastatic castration sensitive prostate cancer: State of art and future perspectives

De novo metastatic castration sensitive prostate cancer (mCSPC) accounts for about 4% of all prostate tumors in Western Countries. This condition has a heterogeneous biological e clinical behavior, ranging from indolent to aggressive and rapidly fatal forms. Recently, the therapeutic landscape for mCSPC has been broadly enriched; indeed robust evidence supports the addiction of chemotherapy (docetaxel) or abiraterone acetate to androgen deprivation therapy (ADT), the latter considered for long the unique standard of care. However, the prognostic stratification and the definition of the ideal therapeutic approach for the subpopulation of de novo mCSPC - albeit largely represented in pivotal clinical trials enrolling mCSPC patients - have yet to be prospectively outlined. The aim of this review was to describe the current state of art about clinical presentation, prognostic classification, and different therapeutic options available for de novo mCSPC patients. Furthermore, we shed light on ongoing clinical trials and future perspectives for this disease setting.

Predictive role of changes in the tumor burden and International Metastatic Renal Cell Carcinoma Database Consortium class during active surveillance for metastatic renal cell carcinoma

BACKGROUND Despite important results achieved for metastatic renal cell carcinoma, some patients could benefit from local treatments or an initial active surveillance (AS) period for recurrent disease. We aim to analyze: changes in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk class, the number of metastases and the disease burden from the start of AS to the beginning of systemic therapy; and if these changes influenced patient outcomes. PATIENTS AND METHODS Patients who started AS at our institution from January 2007 to April 2016 were included. The Kaplan-Meier method was used to estimate total overall survival (tOS) and progression-free survival. Changes in IMDC class, number of metastatic sites, and tumor burden (TB) were evaluated and related to patient survival. Among the patients who started active treatment, progression-free survival and post surveillance OS (psOS) were evaluated. RESULTS 52 patients were included in the analysis. Median time on AS and tOS were 18.3 and 80.1 months respectively. Baseline factors were not related to the time on AS apart from the IMDC classification (HR = 2.15; 95% CI: 1.19-3.87; P = 0.011). The increase in the number of metastatic sites during AS was correlated with poor tOS (HR = 2.86; 95% CI: 1.29-6.34; P = 0.010). The increase of the TB was a negative prognosis factor for tOS (HR = 1.16; 95% CI: 1.02-1.31; P = 0.024) and psOS (HR = 1.21; 95% CI: 1.07-1.40; P = 0.004). Both IMDC class and change in the TB at the start of therapy were related to psOS. The retrospective nature and the lack of an external review of the imaging are its main limitations. CONCLUSIONS During AS, patients rarely experience a deterioration of their IMDC prognostic class, and the change in the TB, more than the increase in the number of metastatic sites, may help physicians to make decisions about the early termination of AS and the start of systemic therapy.

Immunotherapy versus standard of care in metastatic renal cell carcinoma. A systematic review and meta-analysis

BACKGROUND Recently, immune checkpoint inhibitors against PD-1/PD-L1 or CTLA4 have emerged as new treatments for metastatic renal cell carcinoma (mRCC), despite discrepancy between their effects on OS and PFS. We performed a meta-analysis of randomized trials comparing immunotherapy to standard of care (SOC) in mRCC. METHODS Searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts prospective studies were identified. Data extraction was conducted according to the PRISMA statement. The measured outcomes were OS, PFS, and ORR. RESULTS A total of 2832 patients were available for evaluation of OS, and 3033 for PFS and ORR. Compared to SOC, immunotherapy improved OS (HR = 0.75; 95%CI 0.66-0.85; p < 0.001), and PFS (HR = 0.88; 95%CI 0.80-0.97; p = 0.009). The PFS benefit was not confirmed when considering patients treated in first-line only (p = 0.10). Conversely, significant ORR improvement was found in patients treated in first-line only (HR = 1.14; 95%CI 1.02-1.28; p = 0.03) but not in the overall population. CONCLUSIONS Immunotherapy improved OS compared to SOC in mRCC, irrespective of treatment line. In first-line, immunotherapy also increased the ORR compared to sunitinib. A lack of correlation between OS and PFS was confirmed, the latter to be used cautiously for the design and interpretation of trials involving immunotherapy in mRCC.

Renal toxicity in patients treated with anti-PD-1 targeted agents for solid tumors

Aim Immune checkpoint inhibitors of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have recently entered in the therapeutic armamentarium of several types of cancer. Besides the survival benefit, the true revolution of these agents is the distinctive toxicity profile. We aim to assess the incidence and relative risk (RR) of renal toxicity (RT) in patients with solid tumors treated with monoclonal antibodies (mAbs) directed against PD-1/PD-L1. Methods By searching the MEDLINE/PubMed, Cochrane Library, and ASCO Meeting abstracts, prospective studies were identified. Combined RRs and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods. Results Eleven articles were selected for this analysis, with a total of 5,722 patients who were used to evaluate RT. The incidence of anti-PD-1-related RT of all-grades and high-grades was low (1.4% and 0.2%, respectively). However, compared to controls, treatment with PD-1 inhibitors was associated with a significant increased risk of any grade RT (RR = 1.85, 95% CI, 1.07-3.20; p = 0.03) but not high-grade RT (RR = 1.57, 95% CI, 0.56-4.36; p = 0.39). Pembrolizumab significantly increased the risk of any-grade RT (RR = 4.91, p = 0.01) compared to the control arm, and a significant difference was found between nivolumab and pembrolizumab for developing RT of any grade (p = 0.04). Conversely, no differences were identified between the type of prior treatment (prior platinum-containing chemotherapy regimen vs. nonplatinum containing regimen). Conclusions Immune-mediated RT is a rare adverse event that is generally low in severity. Compared to standard therapies, anti-PD-1 mAbs significantly increase the risk of any grade, without conditioning the risk of high-grade RT. The type of PD-1 inhibitor could affect the risk of developing any-grade RT, while prior therapy with platinum-containing regimens does not affect the risk of developing RT.