Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

Pemetrexed has been widely used in patients with advanced non-small cell lung cancer (NSCLC). The clinical relevance of polymorphisms of folate pathway genes for pemetrexed metabolism have not been fully elucidated yet. The aim of this study was to evaluate the expression levels of circulating miR-22, miR-24, and miR-34a, possibly involved in folate pathway, in NSCLC patients treated with pemetrexed compared with healthy controls and to investigate their impact on patient clinical outcomes. A total of 22 consecutive patients with advanced NSCLC, treated with pemetrexed-based chemotherapy and 27 age and sex matched healthy controls were included in this preliminary analysis. miR-22, miR-24, and miR-34a targets were identified by TargetScan 6.2 algorithm, validating the involvement of these microRNAs in folate pathway. MicroRNAs were isolated from whole blood and extracted with miRNAeasy Mini Kit (Qiagen). miRNA profiling was performed using Real-Time PCR. SPSS 17 was used to data analysis. miR-22, miR-24, and miR-34a were found upregulated (P < 0.05) in NSCLC patients versus healthy controls. Higher expression levels were recorded for miR-34a. Nevertheless, significantly higher miR-22 expression was observed in patients developing progressive disease (P ¼ 0.03). No significant associations with clinical outcome were recorded for miR-24 and miR-34a. Albeit preliminary, these data support the involvement of miR-22, miR-24, and miR-34a in advanced NSCLC. The correlation between high expression of miR-22 in whole blood and the lack of response in pemetrexed treated NSCLC patients indicates that miR-22 could represent a novel predictive biomarker for pemetrexed-based treatment.J. Cell. Physiol. 229: 97-99, 2014. ß 2013 Wiley Periodicals, Inc.Despite significant improvements in the treatment of non-small cell lung cancer (NSCLC) over the past several years, the prognosis for patients with advanced disease remains poor. Chemotherapy resistance is a key contributor to the dismal prognoses for lung cancer patients.However, important advances have been achieved in the treatment of advanced NSCLC with the introduction of new antiblastic and biological agents.Lung cancer is driven by genomic alterations, and cancer cells use multiple mechanisms to alter the activity of key genes: mutation, amplification, deletion, intrachromosomal and interchromosomal translocation, and epigenetic mechanisms (MacConaill, 2012).The progresses in the field of genomics during the past decade have greatly advanced our understanding of the genomic alterations that contribute to lung cancer, but additional challenges must be addressed before the goal of personalized cancer therapy can become a reality for lung cancer patients.Pemetrexed, a chemotherapeutic agent already approved in the second-line setting (Hanna et al., 2004), has demonstrated its efficacy also in the first-line treatment combined with cisplatin (Scagliotti et al., 2008) and in the maintenance treatment as single-agent in non-squamous NSCLC (Ciuleanu et al., 2009;Paz-Ares et al., ...

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Until recently, few therapeutic options were available for patients with castration-resistant prostate cancer (CRPC). Since 2010, four new molecules with a demonstrated benefit (sipuleucel-T, cabazitaxel, abiraterone, and denosumab) have been approved in this setting, and to-date several other agents are under investigation in clinical trials. The purpose of this review is to present an update of targeted therapies for CRPC. Presented data are obtained from literature and congress reports updated until December 2011. Targeted therapies in advanced phases of clinical development include novel androgen signaling inhibitors, inhibitors of alternative signaling pathways, anti-angiogenic agents, inhibitors that target the bone microenvironment, and immunotherapeutic agents. Radium-223 and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab) or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan). The optimal timing, combination, and sequencing of emerging therapies remain unknown and require further investigation. Additionally, the identification of novel markers of response and resistance to these therapies may better individualize treatment for patients with CRPC.

e14617 Background: Nivo is a novel therapeutic option in 2nd line NSCLC. However, predictive biomarkers are lacking. The presence of systemic inflammation correlated with poor outcome in many cancer types, including NSCLC. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response in patients (pts) treated with Nivo or Docetaxel (D). Methods: 23 consecutive pts with NSCLC receiving Nivo were analyzed. Baseline white cell count (WBC) and ANC were collected and correlated with tumor response. 27 NSCLC pts treated with D were used as controls. An ANC ≥ 7500 cell/µl was defined neutrophilia. dNLR was calculated as: ANC/(WBC-ANC). Platelet count (PLT) ≥ 450 × 103/μL was defined as thrombocytosis. PLR ratio was defined as PLT/lymphocyte count. dNLR ≥3 and PLR ≥160 were defined high. Results: Baseline characteristics: median age 66 years (range 45-82); sex M 74%; histology squamous 42%, adenocarcinoma 48%, and 10% mixed histology/NOS. Smoking status: 90% smokers/former smokers. Among non-squamous pts, 13,7% were EGFR mutated and 10,3% were KRAS-mutated, with an equal distribution in both treatment groups. Lines of therapies: range 2-8 in Nivo group and 2-3 in D group. Overall response rate (ORR): 13.6% with Nivo vs. 7.7% with D; 9% of pts with Nivo experienced unconventional responses. Baseline neutrophilia (17.4% with Nivo and 27% with D) and thrombocytosis (4.3% and 3.8%, respectively) were not associated with response (ORR 0%). High dNLR (13% and 38% with Nivo and D) correlated with no response (0% ORR), whereas high PLR correlated with no responses to D and reduced ORR to Nivo (10%). Conclusions: The results of this preliminary study suggest that baseline neutrophilia, thrombocytosis and high dNLR are associated with no response to both D and Nivo, whereas high PLR is associated with no response to D and reduced activity with Nivo. Given their relative easy estimation, baseline evaluation of these indicators of inflammation should be included before 2nd line therapy start, especially for highly expensive treatments, such as immunotherapy.