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Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5-year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers. [ABSTRACT FROM AUTHOR]

[Display omitted] • LC screening programs through LDCT showed a reduction of LC-related mortality. • Risk models in LC screening should include patient's characteristics and biomarkers. • LC screening programs will lead to a higher rate of early stage disease diagnoses. • Targeted therapies and immunotherapy will have a key role in perioperative settings. • This new landscape will affect the multidisciplinary team decision making process. Lung cancer (LC) is the leading cause of cancer-related death worldwide, mostly because the lack of a screening program so far. Although smoking cessation has a central role in LC primary prevention, several trials on LC screening through low-dose computed tomography (LDCT) in a high risk population showed a significant reduction of LC related mortality. Most trials showed heterogeneity in terms of selection criteria, comparator arm, detection nodule method, timing and intervals of screening and duration of the follow-up. LC screening programs currently active in Europe as well as around the world will lead to a higher number of early-stage Non Small Cell Lung Cancer (NSCLC) at the diagnosis. Innovative drugs have been recently transposed from the metastatic to the perioperative setting, leading to improvements in terms of resection rates and pathological responses after induction chemoimmunotherapy, and disease free survival with targeted agents and immune checkpoint inhibitors. The present review summarizes available evidence about LC screening, highlighting potential pitfalls and benefits and underlining the impact on the diagnostic therapeutic pathway of NSCLC from a multidisciplinary perspective. Future perspectives in terms of circulating biomarkers under evaluation for patients' risk stratification as well as a focus on recent clinical trials results and ongoing studies in the perioperative setting will be also presented. [ABSTRACT FROM AUTHOR]

The last decade has witnessed important advances in the field of managing cancer during pregnancy. However, still limited data is available on the safety of administering targeted agents in pregnant cancer patients. Given the increasing use of targeted agents in clinical practice, it is becoming vital to properly understand how far they can be used in a pregnant patient without compromising the outcome of the fetus. Unlike chemotherapy, monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus. On the other hand, similarly to chemotherapy, small molecules like tyrosine kinase inhibitors (TKIs) can cross the placenta throughout the pregnancy period. The majority of targeted agents have worrying preclinical data discouraging their use during pregnancy. Multi-TKIs are of particular concern given their potential interference with other vital physiological functions that could be necessary in fetal development. Yet this does not mean that all targeted agents should be avoided completely during pregnancy. The current review provides a critical evaluation on all targeted agents that are currently in clinical use and provides a guide in order to help clinicians counseling their pregnant cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: An increasing number of women are diagnosed with cancer during pregnancy and lactation. Women are usually advised to interrupt breastfeeding during systemic anticancer treatment for fear of serious adverse effects to the nursed infant. However, the issue is poorly addressed in the literature and very few studies have evaluated the safety of breastfeeding during or after cytotoxic drugs or target agents administration. In this review we will analyze the available evidence that addresses the issue of anticancer drugs, targeted agents, antiemetics and growth-factors excretion in human milk. This could serve as a unique resource that may aid physicians in the management of breastfeeding cancer patients interested in maintaining lactation during treatment. [Copyright &y& Elsevier]

Abstract: Dysfunction of protein kinases has been associated with the development of the various molecular subtypes of breast cancer. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this article, we review the state of the art knowledge on protein kinases involved in breast cancer. Special attention is given to those that are potentially druggable and those for which targeted agents are currently under clinical evaluation. Options for targeted drug combinations will be discussed, as well as the optimal way to integrate new kinase inhibitors in the clinical armamentarium to fight breast cancer. We will review recent results from clinical studies with agents targeting different kinases involved in the pathophysiology of breast cancer. In addition, we will evaluate the clinical development of kinase inhibitors to identify areas of knowledge that could be explored in future preclinical and clinical studies. [Copyright &y& Elsevier]

Abstract: Targeted agents have substantially improved patient outcomes in metastatic renal cell carcinoma (mRCC) and have now replaced cytokines as standard of care. Despite the clinical benefits observed, resistance to targeted agents has been shown to develop after a median of 5–11months of treatment. Furthermore, a small subset of patients does not experience any clinical benefit from targeted therapy. Two general modes of resistance have been proposed: intrinsic (pre-existing) and evasive (adaptive). Evasive resistance is thought to be the mechanism involved when patients progress after initial clinical benefit. It has been suggested that upregulation of alternative pro-angiogenic factors and/or downregulation of angiostatic factors may be involved. Several strategies have been shown to enable clinical benefit in patients who have experienced disease progression during prior therapy. These strategies include: adjusting the dose of the drug, combination therapy or switching to an alternative agent, with or without a different mechanism of action. Improvements in our understanding of the mechanisms of resistance associated with targeted agents and refinement of management strategies may help to improve patient outcomes further. In this article, we review the available evidence supporting mechanisms of resistance to targeted agents in mRCC, with a focus on tyrosine kinase inhibitors, and consider the potential management strategies which may allow further clinical benefit to be achieved. [Copyright &y& Elsevier]

Abstract: Maintenance treatment has been intensively investigated in the field of advanced/metastatic non-small lung cancer in order to improve outcomes in this devastating disease. Two different approaches have been evaluated; the so-called continuation maintenance when the maintenance agent was part of initial therapy and is continued in the absence of disease progression (“maintained”) or switch maintenance when a third agent is initiated after a defined number of cycles chemotherapy in the absence of disease progression. Several phase III trials with both chemotherapeutic and targeted agents have demonstrated either PFS prolongation (continuation maintenance) or both PFS and OS benefit (switch maintenance). Currently, erlotinib and pemetrexed are registered as maintenance treatment in patients with NSCLC not progressing after four cycles of standard platinum-based doublet chemotherapy. However, the development of maintenance treatment has raised a series of questions such as the role of treatment-free intervals, the timing of second-line treatment, selection of patients for maintenance treatment and selection of the most proper agent, and trial design issues such as optimal end-points. The purpose of this paper is to present and discuss the current trials investigating the main treatment paradigms and argue on the above mentioned questions. [Copyright &y& Elsevier]

Abstract: In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions. [Copyright &y& Elsevier]

Abstract: Breast cancer is not a single disease. Genetic array tools can define several subtypes. Specific biological processes and distinct gene pathways are associated with prognosis and sensitivity to chemotherapy and targeted agents in different subtypes of breast cancers. As a consequence, breast cancer can be classified by molecular events. A primary challenge for future drug development in breast cancer will be to distinguish genes and pathways that “drive” cancer proliferation (drivers) from genes and pathways that have no role in the development of cancer (passengers). The identification of functional pathways that are enriched for mutated genes will select sub-population of patients the will most likely be sensitive to biology driven targeted agents. The selection of driver pathways in resistant tumors will permit to discover a biology-driven platform for new drug development to overcome resistance. Any of the breast cancer subtypes implies that clinicians should consider cases within the various distinct sub-population in order to properly choose the most personalized therapeutic approach. We will review all new emerging agents targeting the driver pathways within breast cancer molecular subtypes. [Copyright &y& Elsevier]

Abstract: While chemotherapy has been the standard of care for patients with advanced non-small cell lung cancer (NSCLC), efforts have shifted toward evaluating novel targeted agents in an attempt to improve outcome. These targeted agents are directed toward key components in several signalling pathways such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-IR). There is also increasing interest in using combinations of targeted agents to inhibit more than one pathway; for example, inhibition of VEGFR+EGFR and VEGFR+PDGFR+EGFR. Further investigation is needed to identify the most appropriate combinations of these targeted agents in select patient subgroups, and to define optimal treatment doses to thereby achieve the best therapeutic index. This review outlines the rationale for combining targeted agents for the treatment of advanced NSCLC. [Copyright &y& Elsevier]

Abstract: The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy. [Copyright &y& Elsevier]

Summary: Whereas first-line chemotherapy (CT) with single-agent gemcitabine or gemcitabine-based combinations provides a proven benefit in patients with locally advanced or metastatic pancreatic cancer (PC), the role of salvage CT after gemcitabine-failure is not well-established and to date no regimen has emerged as preferred in this setting. Several clinical trials have investigated the efficacy and toxicity-profile of second-line CT and indicated that selected patients may obtain significant benefit from it, also with regard to survival. However, definitive results from large randomized phase III studies are still lacking, and the evidence for clinical benefit of salvage CT is based on small phase II trials that evaluated different treatment schedules in heterogeneous populations. The main goal of this paper is reviewing this topic. [Copyright &y& Elsevier]

Summary: Endometrial cancer is one of the most common gynecologic malignancies. In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Endocrine therapy provides a 10–20% response rate (RR) and survival of less than 1 year. Combination chemotherapy offers a RR of 40–60%, but the survival is still less than 1 year. The combination of cisplatin plus doxorubicin is the most commonly used regimen, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. At this time the focus of future research should be on the use of novel targeted agents, since it is unlikely that further significant advances could be made with chemotherapy and endocrine therapy. mTOR inhibitors represent a promising therapeutic strategy for endometrial cancer. Anti-HER-2/neu targeted therapy might be a novel and attractive therapeutic option in patients with biologically aggressive variants (uterine serous papillary carcinoma, clear cell carcinoma) of endometrial cancer. Research in better understanding the signal transduction pathways in endometrial carcinogenesis will allow the development of specific and selective molecularly targeted inhibitors. [Copyright &y& Elsevier]

Summary: Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC. [Copyright &y& Elsevier]