Therapeutic options targeting angiogenesis in nonsmall cell lung cancer

There is a major unmet medical need for effective and well-tolerated treatment options for patients with advanced nonsmall cell lung cancer (NSCLC), in both first-line and relapsed/refractory settings. Experimental evidence has validated signalling pathways that regulate tumour angiogenesis, including the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways, as valid anti-cancer drug targets. However, to date, bevacizumab (an anti-VEGF monoclonal antibody) is the only antiangiogenic agent to be approved for the treatment of NSCLC. Many other agents, including antibodies, small-molecule tyrosine kinase inhibitors and vascular disrupting agents, have been assessed in phase III trials but have generally failed to demonstrate clinically meaningful benefits. This lack of success probably reflects the redundancy of proangiogenic pathways and the molecular and clinical heterogeneity of NSCLC. In this review we summarise recently completed and ongoing randomised clinical trials of emerging antiangiogenic agents in patients with NSCLC. We highlight recent promising data with agents that simultaneously inhibit multiple proangiogenic pathways, including the PDGF and FGF pathways, as well as the VEGF pathway. Finally, we discuss the outlook for antiangiogenic agents in NSCLC, emphasising the need for clinically validated prognostic and predictive biomarkers to identify patients most likely to respond to therapy

Clinical utility of continuing trastuzumab beyond brain progression in HER-2 positive metastatic breast cancer

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Is There a Role for Multiple Lines of Anti-HER2 Therapies Administered Beyond Progression in HER2-Mutated Non-Small Cell Lung Cancer? A Case Report and Literature Review

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RET Rearrangement as a Predictor of Unresponsiveness to Immunotherapy in Non-Small Cell Lung Cancer: Report of Two Cases with Review of the Literature

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How to manage KRAS G12C-mutated advanced non-small-cell lung cancer

Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC

Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation

Background: Preclinical evidence suggests that the cyclo-oxygenase-2 (COX-2) enzyme plays an important role in breast cancer progression. The aim of the present phase II study was to determine the activity and safety of the combination of the COX-2 inhibitor celecoxib with capecitabine in metastatic breast cancer (MBC) patients pretreated with anthracyclines and/or taxanes. Methods: Eligible patients received capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 21 days and celecoxib 200 mg twice daily, continuously, until disease progression or unacceptable toxicity. Results: About 42 pretreated MBC patients were enrolled into the study. Median number of previous chemotherapy lines for metastatic disease was 2 (0-3). Seven patients (19%) responded to treatment while disease stabilization occurred in 17 patients (40.5%). Overall, 20 patients (47.5%) achieved clinical benefit [objective responses (CR) plus stable disease (SD) >/=6 months]. Median time to progression (TTP) and median overall survival (OS) were 5.2 and 17.8 months, respectively. Treatment was very well tolerated: grade 3 toxicities were observed in only five patients, respectively, and no grade 4 adverse events were reported. Celecoxib was never discontinued for toxicity. Analysis of COX-2 expression in the 22 patients with available tissue revealed a significantly longer TTP and OS for patients whose tumors over-expressed COX-2. Conclusions: The combination of capecitabine and celecoxib is active and safe in far advanced MBC patients. Interestingly, this association resulted in a lower-than-expected toxicity, as compared to single-agent capecitabine. The clinical relevance of COX-2 as determinant of sensitivity to treatment with celecoxib should be further evaluated in larger series of patients

Gene identification for risk of relapse in stage I lung adenocarcinoma patients. A combined methodology of gene expression profiling and computational gene network analysis

Risk assessment and treatment choice remains a challenge in early non-smallcell lung cancer (NSCLC). The aim of this study was to identify novel genes involved in the risk of early relapse (ER) compared to no relapse (NR) in resected lung adenocarcinoma (AD) patients using a combination of high throughput technology and computational analysis. We identified 18 patients (n.13 NR and n.5 ER) with stage I AD. Frozen samples of patients in ER, NR and corresponding normal lung (NL) were subjected to Microarray technology and quantitative-PCR (Q-PCR). A gene network computational analysis was performed to select predictive genes. An independent set of 79 ADs stage I samples was used to validate selected genes by Q-PCR. From microarray analysis we selected 50 genes, using the fold change ratio of ER versus NR. They were validated both in pool and individually in patient samples (ER and NR) by Q-PCR. Fourteen increased and 25 decreased genes showed a concordance between two methods. They were used to perform a computational gene network analysis that identified 4 increased (HOXA10, CLCA2, AKR1B10, FABP3) and 6 decreased (SCGB1A1, PGC, TFF1, PSCA, SPRR1B and PRSS1) genes. Moreover, in an independent dataset of ADs samples, we showed that both high FABP3 expression and low SCGB1A1 expression was associated with a worse disease-free survival (DFS). Our results indicate that it is possible to define, through gene expression and computational analysis, a characteristic gene profiling of patients with an increased risk of relapse that may become a tool for patient selection for adjuvant therapy

Afatinib in EGFR TKI-naïve patients (pts) with locally advanced/metastatic NSCLC harbouring EGFR mutations: An interim analysis of a phase IIIB trial

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Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center

<p>Abstract</p> <p>Background</p> <p>To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center.</p> <p>Methods</p> <p>Four Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre.</p> <p>Results</p> <p>Clinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients.</p> <p>Conclusions</p> <p>In clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.</p