Need for randomized clinical trials testing targeted therapies in malignant pleural mesothelioma

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive tumour affecting the internal lining of the pleura. It is characterized by a poor prognosis and patients normally do not live longer than 12 months. The main cause of this disease is known to be asbestos, although there are some studies pointing at the involvement of Simian virus 40 in its pathogenesis. Other factors that may be involved in the pathogenesis include environmental exposure to erionite, fluoro-edenite and ionizing radiation as well as exposure to ceramic fibres [1,5]. The current standard treatment is the combination of cisplatin with pemetrexed [6,7]. However the average survival for this tumour still remains around 1 year. Hence there is an urgent need for a better understanding of the underlying biology of the disease to identify new actionable targets and improve patients\u2019 outcomes. In fact, no targeted therapies have been approved so far for the treatment of the disease. Using data collected from the literature on the very few randomized MPM clinical trials available, we performed a meta-analysis with the aim of investigating the efficacy of targeted therapies in MPM

Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC

Clinical outcomes and safety of patients treated with NAb-Paclitaxel plus Gemcitabine in metastatic pancreatic cancer:the NAPA study

BACKGROUND: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice.METHODS: From January 2015 to December 2018, patients with metastatic PDAC receiving first-line treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed.RESULTS: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95 % CI; 9-13) and the median progression free survival (PFS) was 6 months (95 % CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 haematological toxicity frequency was 22.61% for neutropenia, 5.22% for anaemia and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 nonhaematological events were reported. Dose reduction was necessary in 51.3 % of the patients.CONCLUSIONS: Our results confirm the efficacy and safety of a first line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.</p

VALIDATION OF PREDICTIVE AND PROGNOSTIC BIOMARKERS AS A GUIDE FOR A PERSONALIZED APPROACH IN SOLID TUMOURS

Breast cancer (BC), Colorectal Cancer (CRC) and Non-Small Cell Lung Cancer (NSCLC) are among the most commonly diagnosed solid tumors, and occupy the first places in the mortality rankings. Compared to an old fashioned one-size-fits-all approach, precision medicine offers the possibility to accurately choose the most appropriate therapeutic strategy, that fits the patients not only from the clinical (age, comorbidities) but also from a molecular point of view. A genetic and biological understanding of the tumor, integrated with a weighted analysis of results can help the clinician in designing a therapeutic pathway that, ideally from the start, gives the patients the best response rates. The aim of my research is to evaluate the markers that have the greatest impact on the prediction of therapy response. Mutational analysis revolutionized the NSCLC treatment paradigm and, consequently, improved the prognosis. EGFR mutated patients benefit from target therapy with tyrosine kinase inhibitors. A fluid and longitudinal monitoring of mutational status is becoming a key factor in disease management. Firstly we extracted circulating free DNA (cfDNA) from the plasma of 30 patients with EGFR-mutated NSCLC and assessed mutational status with real-time PCR. We then monitored such mutation during target therapy in 19 patients. The liquid biopsy had a sensitivity of 60% in confirming the tissue mutation. Patients whose EGFR mutation was not detectable on plasma had a longer Progression free survival (PFS) and Overall survival (OS). Next step will be assessing if cfDNA analysis allows early detection of resistance mutation such as T790M. Next part of my research focused on luminal BC, working partially retrospectively on data from a phase III study of 90 ER-positive, HER2 negative locally advanced breast cancer patients that were randomly assigned 1:1 to receive Let 2,5 mg daily and metronomic oral Cyc 50 mg daily with (arm B; n=45) or without (arm A, n=45) sorafenib 400 mg/bid daily for six months as neoadjuvant treatment. The predictive role of Ki67, SUV variations and metabolic response and its changes with regards to clinical response and survival was analyzed. The serum of 32 patients was analyzed via Luminex Multiplex Panel technology. 38 analytes (cytokines and growth factors) were simultaneously measured according to arm of treatment and time of sample collection (before and after treatment). Patients were divided into groups according to response to therapy (RECIST). Then we investigated a possible link between chemotherapy-induced RNA disruption and survival/progression. Analysis were performed on 40 biopsies taken at baseline and 15 days after the beginning of the neoadjuvant therapy. The RNA for each sample or subdivided sample was then assessed using the RNA Disruption Assay. The maximum RNA disruption Index (RDI) value for each patient at day 15 was used for all analyses. Finally, We investigated the discordance of mutational status between primary and metastatic site in colorectal cancer.Patients with metastatic CRC who underwent surgery of both primary and metastasis were retrospectively evaluated, and mutational status assessment of K-RAS, N-RAS, BRAF and PIK3CA was performed on 21 patients. Median DFS was 20.5 months (95% CI 9.9-29.6) in patients with concordance in mutational status versus 10.4 months (95% CI 6.1-not reached) in patients with discordance (p=0.01) and median OS was 35.9 months (95% CI 26.3-not reached) in patients with concordance in mutational status 25.6 months (95% CI 6.6-not reached) in patients with discordance (p=0.038). In conclusion discordance seems related to clinical outcome. Overall my results show that new strategies and technologies allow the researchers and the clinicians to strive for a better and more complete understanding of solid tumors complex evolution, an integrated and focused approach to the early disease could become the future of disease management

Role of the IGF-1 Axis in Overcoming Resistance in Breast Cancer

Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.</jats:p

EGFR mutation analysis on circulating free DNA in NSCLC: a single-center experience

importance in non-small cell lung cancer (NSCLC). Our aim is to establish if EGFR mutational status change on cfDNA has predictive value that can impact clinical management of NSCLC patients care. Methods This study included 30 patients with EGFR-mutated NSCLC. Blood samples were collected at diagnosis (T0) and in 19 patients during therapy (T1). Results Concordance between T0 and T1 EGFR mutation status for patients evaluable for both samples (n = 19) was 79%, with a sensitivity of 100% (95% CI: 55.5\u2013100.0) and specificity of 60.0% (95% CI: 26.2\u201386.8). For the patients in oncological therapy with targeted drug and with T1 sample available (n = 18), survival outcomes were evaluated. For both mutationnegative T0 and T1 patients, 12-month progression-free survival (PFS) was 66.7% (95% CI: 27.2\u2013100.0) and 12-month overall survival (OS) was 100% (95% CI: 1.00\u20131.00); for patients mutated both at T0 and T1, PFS was 22.2% (95% CI: 6.5\u201375.4%) and OS was 55.6% (95% CI: 20.4\u201396.1%). Conclusion EGFR mutation status can be assessed using cfDNA for routine purposes and longitudinal assessment of plasma mutation is an easy approach to monitor the therapeutic response or resistance onset

Current Status of Fibroblast Growth Factor Receptors Targeted Therapies in Breast Cancer

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients&amp;rsquo; specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.</jats:p

Advances in systemic therapy for malignant mesothelioma: Future perspectives

10Malignant mesothelioma is a rare and aggressive form of cancer affecting the mesothelium. This mainly occupational disease is becoming more common in those countries where asbestos has been used for industrial applications. Notwithstanding the progress made in the field, patients do not survive more than 12 months on average with standard treatment. With the advent of next generation sequencing, it is now possible to study the mutational landscape of each tumor with the aim of identifying the genetic aberrations driving tumorigenesis. This review encompasses the latest research in the field, with particular attention to new chemotherapy combinatorial regimens, molecular targets and immunotherapies, providing a comprehensive picture of the current and future treatment options for malignant mesothelioma patients.reservedmixedSobhani, Navid; Corona, Silvia Paola; Bonazza, Deborah; Ianza, Anna; Pivetta, Tania; Roviello, Giandomenico; Cortale, Maurizio; Guglielmi, Alessandra; Zanconati, Fabrizio; Generali, DanieleSobhani, Navid; Corona, Silvia Paola; Bonazza, Deborah; Ianza, Anna; Pivetta, Tania; Roviello, Giandomenico; Cortale, Maurizio; Guglielmi, Alessandra; Zanconati, Fabrizio; Generali, Daniel

Clinical Outcomes and Safety of Patients Treated with NAb-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: The NAPA Study

Background: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to Methods: From January 2015 to December 2018, patients with metastatic PDAC receiving firstline treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed. Results: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95% CI; 9-13) and the median progression-free survival (PFS) was 6 months (95% CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients, respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 hematological toxicity frequency was 22.61% for neutropenia, 5.22% for anemia, and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 non-hematological events were reported. Dose reduction was necessary in 51.3% of the patients. Conclusions: Our results confirm the efficacy and safety of a first-line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population. </jats:sec