Pancreatic Cancer: Beyond Brca Mutations.

Pancreatic cancer is the fourth-leading cause of cancer-related deaths worldwide. The outcomes in patients with pancreatic cancer remain unsatisfactory. In the current review, we summarize the genetic and epigenetic architecture of metastatic pancreatic cancer beyond the BRCA mutations, focusing on the genetic alterations and the molecular pathology in pancreatic cancer. This review focuses on the molecular targets for the treatment of pancreatic cancer, with a correlation to future treatments. The potential approach addressed in this review may lead to the identification of a subset of patients with specific biological behaviors and treatment responses.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. METHODS: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. RESULTS: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. CONCLUSIONS: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

RNA-based next-generation sequencing in non-small-cell lung cancer in a routine setting: an experience from an Italian referral center.

Aim: ALK, ROS1, NTRK and RET gene fusions and MET exon 14 skipping alterations represent novel predictive biomarkers for advanced non-small-cell lung cancer (NSCLC). Therefore, testing patients for these genetic variants is crucial for choosing the best selective treatment. Over the last couple of decades, next-generation sequencing (NGS) platforms have emerged as an extremely useful tool for detecting these variants. Materials & methods: In the present study, we report our NGS molecular records produced during a year of diagnostic activity. Results: Overall, our in-house developed NGS workflow successfully analyzed n = 116/131 (88.5%) NSCLC samples. Of these, eight (6.8%) and five (4.3%) out of 116 patients harbored ALK and RET gene rearrangements, respectively: one case harbored ROS1 gene fusion (0.7%). Conclusion: Our results highlight that an RNA-based NGS analysis can reliably detect gene fusion alterations, thereby playing a pivotal role in the management of NSCLC patients.

Epigenetic Regulation in Melanoma: Facts and Hopes.

Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.

Bone Metastases from Gastric Cancer: What We Know and How to Deal with Them.

Gastric cancer (GC) is the third cause of cancer-related death worldwide; the prognosis is poor especially in the case of metastatic disease. Liver, lymph nodes, peritoneum, and lung are the most frequent sites of metastases from GC; however, bone metastases from GC have been reported in the literature. Nevertheless, it is unclear how the metastatic sites may affect the prognosis. In particular, knowledge about the impact of bone metastases on GC patients' outcome is scant, and this may be related to the rarity of bone lesions and/or their underestimation at the time of diagnosis. In fact, there is still a lack of specific recommendation for their detection at the diagnosis. Then, the majority of the evidences in this field came from retrospective analysis on very heterogeneous study populations. In this context, the aim of this narrative review is to delineate an overview about the evidences existing about bone metastases in GC patients, focusing on their incidence and biology, the prognostic role of bone involvement, and their possible implication in the treatment choice.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib.

BACKGROUND: Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer (mCRC). Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy. AIM: To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib. METHODS: Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers. The proteins evaluated (TNF-α, TGF-ß, VEGF, CCL-2, CCL-4, and CCL-5) were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis. RESULTS: We found that TNF-α basal level was significantly higher in mCRC patients compared to healthy individuals. Non Responder (NR) patients showing progression of disease (n = 12) had higher basal level of TGF-ß, TNF-α, VEGF, CCL-2 and CCL-5 compared to Responder (R) patients (complete response CR, n = 1; partial response PR, n = 1; Stable Disease SD, n = 3). On the contrary, plasma basal level of CCL-4 was higher in R compared to NR patients. High values of TGF-ß and TNF-α negatively correlated with progression free survival. CONCLUSION: These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.

Complete response to capecitabine in a frail, elderly patient with metastatic colorectal cancer: A case report.

The clinical management of frail, elderly patients affected by colorectal cancer (CRC) remains a subject of debate. The present study reports the case of an elderly man with metastatic CRC (mCRC) who was successfully treated with capecitabine. The patient survived for 29 months, thus highlighting its potential activity in terms of obtaining a complete response and high efficacy. A 77-year-old man presented with adenocarcinoma of the rectum with multiple and synchronous liver metastases, in addition to several comorbidities. The patient received single-agent capecitabine chemotherapy (825 mg/mq twice a day) on days 1-14 of a 21-day cycle. Following 12 cycles of well-tolerated therapy, a computed tomography scan revealed a complete response with no evidence of liver metastases. An overall survival of 29 months was documented, and the patient eventually succumbed to a diabetes-related complication. In compromised patients with mCRC, reduced-dose capecitabine is an excellent therapeutic option due to its positive safety profile, activity and efficacy.

Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy.

AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling. METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21(st), 2016 using these following terms: ''colorectal cancer'', "predictive biomarkers'', "anti-EGFR therapy", "KRAS", "NRAS'', "PIK3CA", "TP53", "PTEN", ''EGFR", "MET", "HER2", "epiregulin", "amphiregulin", "prognostic biomarkers", "BRAF", "miRNA" and "antibody-dependent cell-mediated cytotoxicity (ADCC) activity". Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion. RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mRNA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3CA. The prognostic value of selected microRNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial. CONCLUSION: This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.

Aflibercept a new target therapy in cancer treatment: a review.

Angiogenesis is the process through which new blood vessels are formed from pre-existing vessels and is essential for the growth of all solid tumors. Vascular endothelial growth factor (VEGF) is a regulator of angiogenesis, which is crucial for tumor growth and metastasis. Its inhibition with antiangiogenic drugs is thought to improve delivery of chemotherapy through vascular normalization and disruption of tumor vasculature. Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR)1 and VEGFR2 extracellular domains that binds to VEGF-A, VEGF-B, placental growth factor (PlGF) 1 and 2. Aflibercept has demonstrated preclinical efficacy in different tumor types and exerts its antiangiogenic effects through regression of tumor vasculature, remolding of vasculature, and inhibition of new tumor vessel growth. This review examines the effects of aflibercept on tumor vasculature and on different types of solid tumors, and explores the preclinical and clinical benefits of inclusion aflibercept into anticancer treatment strategies.

Metastatic melanoma: an unusual presentation.

In this report we describe a case of a malignant cutaneous melanoma metastasizing to the pleural surface and peritoneal cavity 5 years after surgical resection of the primary lesion. Malignant cutaneous melanoma is a very aggressive cancer able to metastasize anywhere in the body. Pleural secondary lesions represent a rare event described only in a small number of patients and the association with peritoneal localizations may suggest an uncommon pattern of spread that we discuss.

Perspectives in adjuvant therapy of gastric cancer.

Although the incidence of gastric cancer has been declining in Western countries, it is still a major health problem and a leading cause of cancer mortality. Surgery is the mainstay of treatment for gastric adenocarcinoma. However, even among patients undergoing gastrectomy with curative intent, 5-year survival rates are disappointing due to locoregional relapse and distant metastases. This emphasizes the importance of multidisciplinary management of patients with gastric cancer. In contrast to the preoperative approach, several phase III trials have been carried out in the adjuvant setting, but postoperative chemotherapy has not proven to be superior to surgery alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.