Emanuela Fantinel

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.

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.

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.

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies

AIM Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment-related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti-PD1/PD-L1 mAbs. RESULTS 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any-grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT.

Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.