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We performed an updated meta-analysis to explore the role of maintenance therapy in SCLC. Clinical trials with randomization to maintenance/consolidation (V)placebo or observation or best supportive care in SCLC, both extended and limited disease were searched from January 2009 to March 2022. The hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) with the relative 95% confidence interval (CI) were extracted from each study. Summary HR was calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. A total of 9 studies were identified. Neither PFS nor OS were improved with maintenance/consolidation (PFS: random-effect; HR 0.93; 95% CI 0.71–1.21; P=0.10; OS: fixed-effect; HR 0.98; 95% CI 0.89–1.08; P=0.14). Among the different strategies, immunotherapy maintenance showed a significantly decreased risk of progression (V)standard of care (random-effect; HR 0.80; 95% CI 0.66–0.97; P=0.03). The current updated meta-analysis did not demonstrate a benefit of maintenance/consolidation therapy in SCLC, with only a PFS benefit for immunotherapy approach.

Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.

ABSTRACTIntroductionDespite recent advances in the molecular characterization of triple-negative breast cancer (TNBC), the standard treatment for early-stage TNBC is represented by the historically used anthracycline and taxane-based chemotherapy. In this modern era of precision medicine, several new therapeutic strategies and novel agents have been investigated in the neoadjuvant setting of TNBC, in order to individualize treatment.Areas coveredThis review provides a comprehensive overview of the currently available evidence regarding the activity and efficacy of platinum agents, PARP- and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, highlighting the available data on potential predictive biomarkers of response or resistance to such treatments.Expert opinionThe genomic and immune landscape of TNBC has encouraged the exploration of drugs that interfere with the DNA repair mechanism and that modulate immune response. Overall, these drugs seem to improve the pCR rate in TNBC, despite preliminary and heterogeneous results. Taking into account the economic issues and the side effects of these drugs, it is crucial to further explore the potential predictive role of BRCA mutational status and homologous recombination deficiency score, for platinum agents and PARP-inhibitors, and tumor infiltrating lymphocytes and other immune biomarkers for checkpoint inhibitors, respectively.

Supplemental Digital Content is available in the text.Limited prospective data about the activity of immune checkpoint inhibitors (ICIs) are available for elderly patients. The aim of our analysis was to determine the relative efficacy of ICIs versus available standard therapies [standard of care (SOC)] in subgroups defined by patients’ age. Searching the MEDLINE/PubMed, Cochrane Library, and American Society of Clinical Oncology (ASCO) Meeting abstracts randomized clinical trials were identified. Data extraction was conduced according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The measured outcome was overall survival (OS). Twenty-nine randomized clinical trials (18,839 patients) were selected. As for the distribution of patients by age, all but 3 of the selected studies considered young the patients younger than 65 years (n=10,832) and elderly those with 65 years and older (n=7723); 7 studies identified a third subgroup of very elderly patients aged 75 years and above (n=421). In elderly and very elderly patients ICIs significantly reduced the risk of death by 23% compared with SOC [hazard ratio (HR), 0.77; P<0.00001)]. On the contrary, a lack of a survival advantage of immunotherapy was observed in the subgroup of very elderly patients (HR, 0.85; P=0.39). When comparing the efficacy of ICIs between the 2 subpopulations (elderly vs. young), no significant difference in OS was observed (HR, 0.76; P=0.66). ICIs prolonged OS compared with SOC in both elderly and young patients affected by lung cancer, melanoma, and renal carcinoma, regardless of the age. In conclusion, ICIs (as monotherapy or combinations) significantly improved OS compared with SOC in both young and elderly patients with advanced cancers, regardless of the tumor type. The magnitude of this benefit is debated in patients aged 75 years and above.

ABSTRACTCancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients’ outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors(P) or non-progressors(NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.

DNA mutational profiling showed that atypical carcinoids (ACs) share alterations with large cell neuroendocrine carcinomas (LCNECs). Transcriptomic studies suggested that LCNECs are composed of two subtypes, one of which shares molecular anomalies with SCLC. The missing piece of information is the transcriptomic relationship between ACs and LCNECs, as a direct comparison is lacking in the literature.

De novo metastatic castration-sensitive prostate cancer (mCSPC) is small subgroup of prostate cancer associated with poor prognosis. The aim of our study was to assess the expression of programmed death-ligand 1 (PD-L1) in tumor cells of de novo mCSPC patients. Patients referred to our institution from January 2007 to October 2017 with de novo mCSPC and available diagnostic tissue were included. We tested the PD-L1 pharmaDx qualitative immunohistochemical assay, a monoclonal rabbit anti-PD-L1, clone 28-8 intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded. Kaplan-Meier method was used to estimate survivals according to the expression of PD-L1. The study population included 32 de novo mCSPC patients, analyzed for PD-L1 expression using 2 cut-off values (1% and 5%) to define the positivity. Total of 46.9% of cases had tumor PD-L1 expression ≥1%, and 31.3% had expression ≥5%. No differences were found between the PD-L1 expression ≥1% and the involvement of liver, lung, and number of bone metastases, and the disease volume based on CHAARTED classification. PD-L1−tumors had higher incidence of Gleason score ≥8 compared with PD-L1+tumors (P=0.037), while the incidence of lymph node metastases was higher in PD-L1+tumors (P=0.044). No difference in the median overall survival (mOS) was observed between the PD-L1−population and the PD-L1+patients (43.8 vs. 29.6 mo; P=0.88). The tumor PD-L1 expression cannot be considered a prognostic factor for de novo mCSPC, even if its prognostic and predictive significance have to be thoroughly investigated to better define the selected group of prostate cancer patients that might benefit from checkpoint blockade immunotherapy.

There is no second-line standard of care universally accepted for platinum-refractory metastatic urothelial carcinoma. Immunotherapy and anti-VEGF(R) targeted therapies are 2 emerging strategies with promising though inconclusive results. We perform a systematic meta-analysis to assess the available options. We searched MEDLINE/PubMed, the Cochrane Library, and American society of clinical oncology (ASCO) Meeting abstracts to identify prospective studies. Data extraction was conduced according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The measured outcomes were overall survival (OS) and progression free survival (PFS). Seven randomized controlled trials were selected for final analysis, with a total of 2,451 evaluable patients. Chemotherapy with vinflunine did not reduce the risk of progression (HR = 1.11; 95%CI 0.78–1.57; P= .56) or death (HR = 0.97; 95%CI 0.70–1.34; P = .87) compared to taxanes. Immunotherapy with anti-PD-1/PD-L1 mAb improved OS over chemotherapy (HR = 0.81; 95% CI 0.71–0.92; P<.0009). The OS benefit of immunotherapy was retained when compared to taxanes, but not compared to vinflunine, although without a significant difference between the 2 subgroups (P = .30). A lack of PFS (HR = 0.73; P = .08) and OS (HR = 1.0; P = .99) benefit was observed with an anti-VEGF(R) plus chemotherapy compared to chemotherapy alone. No PFS (P = .14) or OS (P = .13) differences were detected when comparing anti-VEGF(R) ± chemotherapy and immunotherapy. Immunotherapy significantly improved OS compared to chemotherapy in metastatic urothelial carcinoma unselected for PD-L1 status. The addition of anti-VEGF(R) to chemotherapy did not provide any statistically significant benefit in terms of PFS or OS. Single agent taxanes or vinflunine can be considered given their similar efficacy but different toxicity profiles.

ABSTRACTWe carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test.Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached.When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06).The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively).In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.

IMPORTANCE: Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non–small cell lung cancer (NSCLC) are unknown. OBJECTIVES: To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. INTERVENTIONS: The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. MAIN OUTCOMES AND MEASURES: The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. RESULTS: Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. CONCLUSIONS AND RELEVANCE: Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

We hypothesized that activating KRASmutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype.

ABSTRACTIntroduction: Over the last decade, epidermal growth factor receptor (EGFR) signaling was investigated as a potential target for tyrosine kinase inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Necitumumab is a fully humanized IgG1 monoclonal antibody directed against the binding domain of EGFR, approved in combination with cisplatin–gemcitabine for the first-line treatment of squamous NSCLC.Areas covered: The purpose of this manuscript is to systematically review the state of the art of necitumumab for the treatment of metastatic NSCLC, focusing on predictive factors, cost-effectiveness, and future potential combinations with additional agents.Expert opinion: Despite recent therapeutic advances, platinum-based chemotherapy still represents the most widely used first-line treatment for advanced NSCLC, particularly for the squamous histotype. Necitumumab is nowadays the first targeted agent providing an (statistically significant) additional survival gain to squamous NSCLC patients when combined with first-line chemotherapy at the cost of an increased (although manageable) toxicity, as shown in the SQUIRE trial. Hopefully, improvement in patients’ selection by identifying reliable predictive markers and the combination with new agents may help to maximize the benefit of this targeted treatment, which is currently limited by a not optimal cost–benefit ratio.

Supplemental Digital Content is available in the text.Pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare subtype of lung adenocarcinoma recently recognized in the WHO classification. It is defined as an adenocarcinoma in which the enteric component exceeds 50% and have to show the expression of at least 1 immunohistochemical marker of enteric differentiation. Although the definition of this tumor type is very important, above all in the differential diagnosis between a primary lung tumor and a metastasis of colorectal adenocarcinoma, this cancer still lacks a distinctive immunohistochemical and molecular signature. We recruited the largest series in the literature of PAEDs according to the morphology and the positivity for intestinal markers. Then, we evaluated the immunohistochemical and molecular profile of these adenocarcinomas. In our series, CDX-2 and CK7 were the immunohistochemical markers mostly expressed by PAEDs. There was an inverse relationship between the expression of pnuemocytes markers, such as TTF-1, and intestinal markers. Molecular analysis revealed KRASas the most frequently mutated gene (>60% of cases), with very few cases harboring abnormalities affecting EGFR, BRAF, and ALKgenes. PAEDs are morphologically very heterogenous. The immunohistochemical profile based on CDX-2 and CK7 positivity of PAEDs appears very robust to support this diagnosis, and it is applicable also on small biopsies. KRASappears as the most important mutated gene in such tumors.

Patients with nonsmall-cell lung cancers expressing high levels of PD-L1 present a therapeutic dilemma for clinicians who have to choose between pembrolizumab as a single agent or in combination with chemotherapy. In order to help them as they ponder over this decision we performed a meta-analysis using the data available from randomized clinical trials that enrolled patients with untreated advanced nonsmall-cell lung cancers with PD-L1 expression level ≥50%. We evaluated interactions according to type of treatment–add-on strategy: pembrolizumab plus chemotherapy versus chemotherapy or head-to-head strategy: pembrolizumab alone versus chemotherapy. Hazard and Odds Ratios (HR/OR) for primary (overall survival, OS) and secondary endpoints (progression-free survival, PFS and objective response rate, ORR) were extracted and cumulated by adopting a random-effect model with 95% confidence interval. Four clinical trials that enrolled 2,754 patients including 1,252 with PD-L1 expression in ≥50% of cells were examined. We did not find a significant interaction (P= 0.16) between an add-on strategy and head-to-head comparisons with pembrolizumab for OS (HRs in favor of immunotherapy of 0.50 and 0.67, respectively). A significant quantitative interaction favoring the add-on strategy was found for PFS and ORR (P< 0.001), with a HR for PFS of 0.36 with the add-on strategy and 0.65 in head-to head comparisons, and an OR for ORR of 5.35 and 1.58, respectively. In absence of planned prospective noninferiority trials addressing this issue, addition of chemotherapy to pembrolizumab appears to decrease tumor size and delay disease progression significantly more than pembrolizumab alone, but has no impact on OS. We conclude that the data support deciding between both treatment options on an individual basis by considering a patients’ clinical status and disease characteristics.

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.

The aim of this analysis was to determine the risk of malnutrition and the prognostic value of nutritional intervention in patients affected by pancreatic ductal adenocarcinoma (PDAC) undergoing chemotherapy. Clinical–pathological and nutritional data were correlated with overall survival (OS) using a Cox model. Nutritional status was determined by Malnutrition Universal Screening Tool (MUST), body mass index, weight loss in the past 6 months, presence of nutrition-related symptoms, and current energy intake. Nutritional intervention included appropriate individual dietary counseling. Data from 109 patients were gathered (median age 63 years). The majority of patients (64.2%) presented a MUST value of ≥ 2, corresponding to a high risk of malnutrition. At multivariate analysis for OS in locally advanced and metastatic PDAC patients, the time between the diagnosis and the nutritional intervention (HR 2.22, p= 0.017), the performance status (HR 1.38, p= 0.075), the surgery of the primary (HR 5.89, p= 0.005), and the response to the first line (HR 5.9, p= 0.03) were independent significant predictors of outcome. Furthermore, a weight gain > 2% from the baseline weight was correlated with the time between the diagnosis and the nutritional intervention (p= 0.021): in patients receiving a nutritional support within 3 months from diagnosis, a 2% weight gain was associated with a 2-year OS benefit (50.3% vs. 33.0%, p= 0.04). This analysis suggests that the early nutritional support may contribute to influence the prognosis of patients affected by advanced PDAC undergoing chemotherapy.

We developed one of the first clinicopathological prognostic nomograms for resected squamous cell lung cancer (SQLC). Herein, we validate the model in a larger multicenter cohort and we explore the impact of adjuvant and neoadjuvant treatment (ANT).

A series of evidence demonstrated that obesity represents an established risk factor for an increase in the incidence of multiple cancer types and for poor cancer survival. Nevertheless, recent studies suggested that, in a series of cancers, patients with a normal body mass index (BMI) have worse outcomes than obese patients. This phenomenon, named ‘obesity paradox’ or ‘reverse epidemiology’ in cancer, is not well understood and presents controversial aspects. Therefore, this review aims to explore the available studies concerning the relationship between obesity and cancer incidence or survival and to highlight the hypothetical explanations and the methodological framework. In this regard, we underline the limits of BMI as a potential marker of adiposity and the relevance to assessing body composition, beyond the body size. Further studies are needed to define the impact of obesity in cancer patients, to tailor weight management after cancer diagnosis and to hopefully improve overall clinical outcome.

ABSTRACTIntroduction: Angiogenesis plays a fundamental role in breast cancer (BC) growth, progression and metastatic spread. After the promising introduction of bevacizumab for the treatment of advanced BC, the initial enthusiasm decreased when the FDA withdrew its approval in 2011. Nevertheless, several clinical studies exploring the role of bevacizumab have been subsequently published.Areas covered: The aim of this study is to review the available clinical trials exploring the potential effectiveness of bevacizumab in BC, regardless of the disease setting.Expert opinion: Even if the evidence suggests that bevacizumab must be ruled out from the HER2-positive and adjuvant setting, bevacizumab’s benefit remains uncertain in the neoadjuvant setting and in the advanced treatment of HER2-negative patients. In the first setting, the addition of bevacizumab to chemotherapy increased the pathological complete response (pCR) rate in most clinical trials. However, the current absence of evidence that pCR is a trial-level surrogate for survival requires waiting for long-term results. In the advanced setting, all trials showed a benefit in progression-free survival, but not in overall survival, highlighting an increase of adverse events. The lack of predictors of response represents the main unmet need in which future clinical research will undoubtedly invest.

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.

Nearly 1% to 2% of NSCLCs harbor RETfusions. Characterization of this rare population is still incomplete.

Angiogenesis, one of the hallmarks of cancer, occurs when new blood vessels feed malignant cells, providing oxygen and nutrients, promoting tumor growth, and allowing tumor cells to escape into the circulation, thus leading to metastases. To date, a series of antiangiogenic drugs (either monoclonal antibodies or small molecules) have been approved by regulatory agencies for the treatment of advanced non–small cell lung cancer, and they are currently available for both first- and second-line therapy. The overall benefit of these drugs seems modest (although clearly significant), especially when administered as a single agent, and there is no clear consensus with regard to which patients should be candidates to receive these drugs across the different disease settings. From the biological perspective, angiogenesis represents a difficult and complex process to explore, given the interference with other key pathways and the dynamicevolution during the disease's history. Indeed, this process is complicated by the presence of multiple targets to hit, polymorphisms, hypoxia-dependent modifications, and epigenetics. These difficulties do not allow capture of which specific key pathways can be identified as biomarkers of efficacy so as to maximize to overall benefit of such drugs. An International Experts Panel Meeting was inspired by the absence of clear recommendations to address which patients should receive antiangiogenic drugs in the context of advanced non–small cell lung cancer so as to support decisions for clinical practice on a daily basis and determine priorities for future research. After a literature review and panelists consensus, a series of recommendations were defined to support decisions for the daily clinical practice and to indicate a potential road map for translational research.

Introduction:Angiogenesis plays a major role in the development and progression of solid tumors, including lung cancer. Although some anti-angiogenic agents have demonstrated a statistically significant advantage in terms of primary outcome in clinical trials, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. To better clarify this complex scenario and definitively establish the concrete benefits of anti-angiogenic strategies in lung cancer, several clinical trials have been conducted with others currently ongoing.Areas covered:In this review, the authors highlight the data ascertained from Phase II trials conducted in NSCLC patients who are treated with recently discovered innovative anti-angiogenic molecules. The authors also discuss older widely investigated anti-angiogenic drugs that have been repurposed or used in different contexts and combinations.Expert opinion:Globally considered, the results of the countless clinical trials evaluating anti-angiogenic agents suggest that angiogenesis (with its molecules and pathways) represents a non-ideal druggableprocess for several biologically relevant reasons. Consequently, it is important that the conceptual development and clinical validation of anti-angiogenic agents is different from those employed for traditional target agents (i.e., erlotinib, gefitinib and crizotinib). Indeed, the development and validation of these agents still represents a major challenge for modern scientific research.

Introduction:Angiogenesis plays a pivotal role in the development and progression of tumors and it represents a crucial target for therapeutic strategies. Until now, regulatory agencies approved antiangiogenic agents targeting the VEGF and multi-target agents carrying antiangiogenic and anti-proliferative effects. They often provide only a modest survival benefit and their role in clinical practice is debated. The limited efficacy may be partially explained by the complexity of the molecular background of angiogenic processes, composed of several pathways interacting with both tumor cells and the microenvironment.Areas covered:Ramucirumabis a fully human monoclonal antibody selectively binding and inhibiting the VEGF receptor 2 (VEGFR-2), a crucial molecule involved in angiogenesis. A series of Phase I–II trials conducted in a wide spectrum of malignancies reported promising antitumor activity. In 2014, data from large Phase III clinical trials in gastrointestinal, lung and breast malignancies were released.Expert opinion:Considering the evidences of efficacy emerging from the available Phase III trials, the antiangiogenic approach emerged as a promising strategy particularly for the treatment of gastric cancer. Nevertheless, the identification and validation of potentially predictive biomarkers are necessary to improve the selection of patients and the globally awaited clinical benefit.

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective ‘magic bullet’, able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

We sought to evaluate the expression of HSP27 and HSP90 chaperones in renal cell carcinomas as a target for cancer therapeutics. A total of 127 clear cell renal cell carcinomas stratified according to the Mayo Clinic SSIGN (size, staging, grading, and necrosis) risk groups (good, 1; poor, 5) and 20 cases with metastases, were available. Immunostaining for both HSP27 and HSP90 was performed on tissue microarrays. Results were detailed per scorable arrays per SSIGN risk groups. Immunolabelling for HSP90 and HSP27 was seen in 109 of 127 (86%) and 114 of 127 (89%) cases, respectively. HSP90 scored 4.9 in 32 cases risked SSIGN 1,3.5 in 41 cases SSIGN 2,4.8 in 11 cases SSIGN 3,4.2 in 22 cases SSIGN 4, and 5.0 in three cases SSIGN 5. HSP27 scored 4.6 in 33 risked SSIGN 1, 3.1 in 43 SSIGN 2, 2.6 in 11 SSIGN 3, 3.6 in 24 SSIGN 4, and 2.7 in three SSIGN 5. Metastases ranged from 2.9–5.0. A trend of increasing value for HSP90 was observed when comparing SSIGN 1–2 versus SSIGN 3–5 risk groups (4.2 versus 4.6 mean values; p=0.06); no difference has been observed for HSP27 (3.8 to 3.9; p=0.08). A score modulation of HSPs is observed in renal cell carcinoma and may affect the efficacy of targeted therapy.