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Aim: IL-2 is one of the first immunomodulating cytokines to be tested in the treatment of cancer patients. The effects of this agent in the treatment of solid tumors other than renal cancer and melanoma are poorly understood. Materials & methods: We have carried out a meta-analysis of randomized studies. We fixed the response rate as the primary outcome. Results: The pooled risk ratio for an objective response with IL-2 plus chemotherapy versus chemotherapy alone was 1.43 (95% CI: 1.12–1.81; p = 0.004), in favor of colorectal cancer. Conclusion: Further investigation in the treatment of patients with colorectal cancer or other solid malignancies with IL-2 is required, alone or in combination with chemotherapy.

Several new biological agents have been investigated as second line of treatment in advanced Hepatocellular Cancer (HCC). We performed a meta -analysis to assess the effect of targeted therapies in advanced HCC patients beyond the first line of treatment. A literature-based metaanalysis of randomized controlled trials was undertaken. The primary outcome was the overall survival. The secondary endpoints were the progression-free survival (PFS), the response rate (RR) and disease control rate (DCR) and the safety. Pooled analysis of targeted agents revealed a modest increase in overall survival compared with control arm (Hazard Ratio (HR) = 0.93, 95%CI: 0.83-1.04; P = 0.21). On the counterpart, all the secondary endpoints were in favoured to the targeted agents-based treatment (PFS: HR = 0.68, 95% CI:0.56–0.83; P = 0.0002; RR: 3.50,95% CI 1.81–6.76; P = 0.0002, DCR: RR:1.19, 95% CI 1.06–1.32; P = 0.002). To date, there is a clinical need of a more efficacious second line of therapy in treatment of the advanced HCC. This study showed some activity of the new targeted therapies in second line of treatment in advanced HCC.

Abiraterone acetate and orteronel are two CYP-17 inhibitors that have been studied in prostate cancer. They have shown relevant toxicities, including fluid retention/oedema, hypokalaemia, hypertension, liver function test abnormalities and cardiac events. The goal of this study was to determine the risk of special adverse events related to CYP- 17 inhibitor in patients with metastatic castration-resistant prostate cancer (CRCP). Summary data from four randomized phase III trials comparing CYP-17 inhibitors and prednisone versus placebo and prednisone in metastatic CRCP patients were meta-analysed. Pooled risk ratios (RRs) for the risk of all-grade and grade 3-4 adverse events of special interest were calculated. Data from 4916 patients (2849 in the AA experimental arm; 2067 in the control arm) were analysed. The incidence of grade 3-4 adverse events was never more than 10% of the patients. However, compared with placebo, the CYP-17 inhibitor significantly increased the all-grade events of hypertension (RR=1.53; 95% CI=1.3-1.8; p

Breast cancer is a complex disease with heterogeneous presentation and clinical course. The last decade has witnessed the development, commercialization, and increasing use of multigene assays, designed to support physicians and patients in clinical decision making in early-stage breast cancer. These include Oncotype DX®, MammaPrint®, and Prosigna™ assays. The assays differ in the technological platforms used for assessment of gene expression, in the number of genes and in the specific genes that are being tested, in the patient populations used for their development and validation, and in their clinical utility. This review focuses on these three commercialized assays, their development, validation, and clinical utility. The review also addresses ongoing prospective trials investigating these assays and health-economic considerations relating to their use.

EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib changed dramatically the history of metastatic non-small cell lung cancer (NSCLC) harbouring EGFR mutations. However, not enough data are available on the efficacy of these targeted drugs in elderly patients. The aim of this study is to analyse the available clinical data evaluating the efficacy of anti-EGFR therapies in elderly patients with advanced NSCLC carrying EGFR mutations. A literature-based meta-analysis of the results of randomized clinical trials was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. Progression-free survival (PFS), as a measure of the efficacy of treatment, was the primary outcome investigated. The pooled analysis revealed an overall significant improvement in PFS (HR = 0.44, 95% CI 0.28-0.69; p = 0.0004) with the use of EGFR TKIs in EGFR-mutated NSCLC. The data stratification per age subgroups showed that EGFR TKIs were more effective in prolonging PFS in elderly patients, with HR 0.39 (p = 0.008), in comparison with young patients (HR = 0.48; p = 0.04). The results of this study suggest that EGFR TKIs have a significant effect in slowing down diseases progression in elderly patients with advanced NSCLC, therefore representing a valid therapeutic option in this age group.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic neoplasm, with five-year survival rate below 30%. Early disease detection is of utmost importance to improve HGSOC cure rate. Sera from 168 HGSOC patients and 65 healthy controls were gathered together from two independent collections and stratified into a training set, for miRNA marker identification, and a validation set, for data validation. An innovative statistical approach for microarray data normalization was developed to identify differentially expressed miRNAs. Signature validation in both the training and validation sets was performed by quantitative Real Time PCR (RT-qPCR). In both the training and validation sets, miR-1246, miR-595 and miR-2278 emerged significantly over expressed in the sera of HGSOC patients compared to healthy controls. Receiver Operating Characteristic curve analysis revealed miR-1246 as the best diagnostic biomarker, with a sensitivity of 87%, a specificity of 77% and an accuracy of 84%. This study is the first step in the identification of circulating miRNAs with diagnostic relevance for HGSOC. According to its specificity and sensitivity, circulating miR-1246 levels are worthy to be further investigated as potential diagnostic biomarker for HGSOC.

Background The aim of the present study was to evaluate the activity and tolerability of low-dose oral ethinylestradiol (EE) and luteinizing hormone-releasing hormone analogue with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent for advanced castrate-resistant prostate cancer (CRPC). Patients and Methods The patients received an EE dose of 150 μg daily (50 μg 3 times daily) and an ASA dose of 100 mg once daily. The primary endpoint was the prostate-specific antigen response. Results A total of 32 patients were enrolled. A PSA response was observed in 19 patients (59.3%; 95% confidence interval [CI], 41%-76%). The median progression-free survival was 9.4 months (95% CI, 6.5-14.1 months). The treatment was generally well tolerated and no grade 3-4 toxicity was observed. Only 1 patient interrupted EE because of a cardiac event and 1 patient experienced grade 2 nausea and vomiting. No major bleeding occurred. Conclusion Low-dose EE with concomitant low-dose ASA is safe, showing potential activity in patients with advanced CRPC, and should be investigated further.

Introduction: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models.Areas covered: Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer.Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cancer.

The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, ‘window of opportunity’ Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.

Small cell lung cancer (SCLC) is a lethal disease with a very restricted armamentarium of active treatments. In the new era of targeted therapies, several attempts based on the combination of chemotherapy with new compounds has been made but with a low rate of success. The idea of using the new targeted therapies as maintenance treatment after their combination with chemotherapy has been pursued. The aim of the present study was to analyze the available clinical data regarding the effect of the targeted agents as maintenance therapy on survival in patients with SCLC. A literature-based meta-analysis of randomized controlled trials, in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines, was performed. PubMed, the Cochrane Library, and a search of abstracts presented at American Society of Clinical Oncology meetings were searched for relevant studies. The primary outcome was overall survival (OS). Nine studies, with a total of 1385 patients, were included. The pooled analysis revealed that the new targeted therapies did not improve survival compared with the control arm (placebo, hazard ratio, 1.02; 95% confidence interval, 0.91-1.15; P = .69). However, a small advantage in the 1-year OS rate (risk ratio, 1.21; 95% confidence interval, 0.9-1.63; P = .21) was observed. Maintenance with targeted therapies failed to improve the survival of patients with SCLC with an increased rate of toxicity. The detected survival advantage suggests that perhaps the maintenance approach could be used to increase the 1-year OS rate. However, this finding requires confirmation in further studies, perhaps of patients selected according to their tumor biologic profile.

BACKGROUND: Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic landscape for metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the effect of these novel androgen receptor pathway targeted agents in improving outcome of CRPC patients. METHODS: A literature-based meta-analysis of randomized controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. The primary outcome was overall survival. The secondary end-points were time to the first symptomatic skeletal event, progression-free survival, prostatic antigen specific (PSA) response rate, time to PSA progression and safety. RESULTS: Pooled analysis from RCTs of novel androgen receptor pathway targeted agents revealed significantly increased overall survival compared with placebo or prednisone (hazard ratio [HR] for death: 0.79, 95% confidence interval [CI]: 0.71-0.87; P < 0.00001). All secondary end-points favoured the androgen receptor pathway targeted agents, although heterogeneity was high in some cases. The pooled analysis revealed that the androgen receptor pathway targeted agents significantly improved time to the first skeletal event (HR = 0.69, 95% CI: 0.63-0.75; P < 0.00001), progression-free survival (HR = 0.48, 95% CI: 0.37-0.62; P < 0.00001), time to PSA progression (HR = 0.37, 95% CI: 0.24-0.59; P < 0.0001) and PSA response rate (relative risk [RR] = 4.46, 95% CI: 2.63-7.55; P < 0.00001). The incidence of grade ≥3 adverse events was moderately higher with androgen receptor pathway targeted agents as compared with the control arms (RR = 1.11, 95% CI: 0.98-1.25; P = 0.09). CONCLUSION: This study confirmed the efficacy and safety of the novel androgen receptor pathway targeted agents

Docetaxel or Epirubicin-based regimens are both approved for the treatment of metastatic gastric cancer. We perform a systemic review with metanalysis to evaluate the efficacy and toxicities of docetaxel-based chemotherapy compared with epirubicin-containing regimens. A metaanalysis of randomized studies in accordance with the preference guidelines for reported items in systematic reviews and meta-analyses is performed in which the databases of PubMed, the Cochrane Library, and the ASCO University Meeting were searched for relevant publications. The primary outcome was efficacy, the secondary toxicities. A total of 553 cases were included in the meta-analysis; 278 received epirubicin-based treatment and 313 received docetaxel. The pooled risk ratio to achieve an objective response and a disease control rate were 1.08 (95% CI 0.85-1.37; P=0.52) and 0.90 (95% CI 0.75-1.08; P=0.27) respectively. EPI arm showed a decrease in the risk of neutropenia, anemia, fatigue, asthenia and diarrhea, paraesthesia; docetaxel arm showed a decrease in the risk of leucopenia, thrombocytopenia, anorexia, nausea, nausea-vomiting, stomatitis and neutropenic fever. The results of our study suggest a similar activity of docetaxel and epirubicin-based chemotherapeutic regimens in metastatic gastric cancer. Other parameters as, comorbidity, concomitant diseases and prior therapies should be taken into account to address the clinician's choice in selecting the best therapeutical approach for any single patient.

Background: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. Methods: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. Results: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio = 0.59, 95% CI:0.42-0.84; P = 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio = 0.79, 95%CI: 0.63-0.98; P = 0.03), and response rate (hazard ratio = 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. Conclusion: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumors.

Background The VERITAS (A Phase 1B open-label study to assess the safety and tolerability of e ve rolimus in combination with e ri bulin in t riple-negative bre a st cancer s ) trial (EudraCT number: 2014-000135-17) is a phase Ib, open label, multicenter, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study based on the combination of everolimus with eribulin in sequential cohorts of metastatic triple negative breast cancer (TNBC) patients. Patients and Methods The primary objective of the study is to identify the recommended dose of everolimus in combination with eribulin. Secondary endpoints include the assessment of pharmacokinetics and antitumor activity of the experimental treatment. The sample size is based on the Bayesisan approach with regards to the maximum tolerated dose (MTD) and maximum tolerated dose (MTD) observed. An average sample size of approximately 12 patients is deemed reasonable based on simulations. Conclusion The VERITAS trial is expected to determine the recommended dose of everolimus in combination with eribulin in TBNC. This study may open the way for further analysis of this combination in phase II studies in this orphan disease of active drug combination such as the TNBC subset.

Breast cancer represents a heterogeneous group of diseases with varied biological features, behavior, and response to therapy; thus, management of breast cancer relies on the availability of robust predictive and prognostic factors to support therapy decision-making. Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced, converting an inoperable to a surgical resectable cancer. Neoadjuvant trials, additionally, offer: 1) the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials; 2) to identify and validate the prognostic and predictive value of a marker with its association with clinical outcome in relation to the administered treatment. In this setting, thanks to new, affordable technologies which help to detail the molecular profiles of tumors, new trial designs based on new target therapies, like window-of-opportunity, are also suggested, as they represent the chance to identify tumor sensitivity or to overcome tumor resistance to the treatment used, based on its interaction with tumor biology in early tumor stages. However, clinicians and researchers should pay particular attention: In this setting, the safety of patients is paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience, the definition of the study population and the study design, such as adaptive strategies, should limit patient exposure to ineffective agents, and intensify safety monitoring in the course of the treatment. Here, issues related to outcome determination in breast cancer, including some critical points of view, are presented.

Because its original use as a treatment for hematologic disease, more recently immunotherapy has emerged as a novel effective therapeutic strategy for solid malignancies, such as melanoma and prostate carcinoma. For breast carcinoma, an immunologic therapeutic approach has not been well evaluated, even though there is evidence to suggest it would be a successful novel strategy, especially taking into account the high mortality rate of the most aggressive variants of this heterogeneous disease. Here, we briefly describe the most recently awarded immune-based therapies with a consolidated or potential implication for the treatment of solid malignancies. We focus on immune checkpoints and on the clinical potential of their abrogation, with a further overview of novel vaccine-based approaches and the most relevant immunotherapeutic techniques. We aim to provide an exhaustive review of the most promising immune-therapeutic agents that may have implications for breast cancer treatment.

INTRODUCTION: Recently the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the aromatase inhibitor exemestane has been shown to double the progression-free survival rate in advanced breast cancer. However, the effect of the interrelated pathways of hypoxia-inducible factor-1α (HIF-1α) and mTOR signaling, both of which are associated with a more aggressive breast cancer phenotype and endocrine resistance, on response in the neoadjuvant setting is unknown. We, therefore, have investigated the influence of these pathways with the aim of better defining those patients most likely to benefit from an endocrine-based therapy associated with/without mTOR inhibitors. PATIENTS AND METHODS: A total of 107 women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (LET) or LET plus oral "metronomic" cyclophosphamide (50mg/daily) (LET-CYC). Phospo-mTOR and HIF-1α were evaluated in tumor specimens collected before and after treatment using a tissue microarray format. RESULTS: LET-based therapy induced a downregulation of phospho-mTOR and HIF-1α expression (P = .0001 and P < .004, respectively). The reduction of HIF-1α expression observed was positively correlated with phospho-mTOR reduction (P < .03); however, no treatment interaction between the two proteins was detected. HIF-1α expression was significantly modulated by the treatment (P < .004) with a reduction both in the LET arm (45%, n = 36/80) (P = .05) and LET-CYC arm (55%, n = 44/80) (P = .04). HIF-1α reduction showed a relationship with clinical response confined in LET arm only (P < .03). CONCLUSIONS: In this neoadjuvant population, LET was able to modulate the phospho-mTOR and HIF-1α pathways and may define a subpopulation of nonresponders who may be most likely to benefit from mTOR inhibitors