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Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.

IntroductionExpression of human epidermal growth factor receptor (HER)2 and HER3 have been investigated in small BTC studies using variable scoring systems. Methods HER2 and HER3 overexpression/amplification were explored following internationally agreed guidelines using immunohistochemistry (IHC) and fluorescent in-situ hybridisation (FISH), respectively. Logistic regression and survival analysis (Kaplan Meier, Log rank test and Cox Regression) were used for statistical analysis.Results Sixty-seven eligible patients with Stage I/II (31.3%) or III/IV (68.7%) disease at diagnosis were included. Membrane HER2 overexpression/amplification was identified in 1 patient (1%). HER3 overexpression was predominantly cytoplasmic; the rate of overexpression/amplification of HER3 in membrane and cytoplasm was 16% [ampullary cancer (AMP) (1/13; 8%), gallbladder cancer (GBC) (1/10; 10%), intra-hepatic cholangiocarcinoma (ICC) (6/26; 23%), extra-hepatic cholangiocarcinoma (ECC) (3/18; 17%)] and 24% [AMP (1/13; 8%), GBC (1/10; 10%), ICC (10/26; 38%), ECC (4/18; 22%)], respectively. ConclusionsA significant subset of patients with BTC expressed HER3. Inhibition of HER3 warrants further investigation. A better understanding of the downstream effects of HER3 in BTC requires further mechanistic investigations to identify new biomarkers and improve patient selection for future clinical trials.

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status

Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.

Background: Cholangiocarcinoma (CC), gallbladder cancer (GBC) and ampullary cancer (AC) (collectively BTCs) are poor-prognosis cancers. Cisplatin-gemcitabine chemotherapy is the standard treatment for patients (pts) with advanced BTC. New treatment targets are warranted; the human epidermal growth factor receptor (HER)-2 and HER-3 pathways may be potential candidates. High-quality data regarding expression and/or amplification rates in BTC are lacking.Methods: Pts diagnosed with BTC and with available paraffin-embedded archival tissue were eligible. Seventy consecutive pts were required (power 0.91; assumptions: 5% (no expression) vs. 15% (expression of interest); α-error 0.1). All pts had been previously consented for tissue storage for research purposes. The study was approved by the local BioBank Ethics Committee. Overexpression of HER-2 and HER-3 was analysed by immunohistochemistry (IHC) following standard guidelines (gastric criteria were followed for HER-2); samples with “2+; borderline” IHC expression underwent additional fluorescence in-situ hybridisation (FISH). Kaplan Meier and Cox Regression analyses were employed for survival. Logistic regression was used to identify factors associated with HER overexpression.Results: Of 167 screened pts between Jan-13 and Jul-15, 76 samples were retrieved for quality assessment; 67 were eligible with a median age of 65.6 years (range 32.9-79.3); 51.2% were female; 85.1% had ECOG performance status 0-1; all were adenocarcinomas. Primary site was GBC (n = 10, 14.9%), CC (n = 44, 65.7%; n = 26 intra-hepatic (ICC), n = 18 extra-hepatic (ECC)) and AC (n = 13, 19.4%). Stage at diagnosis: I/II (n = 21, 31.3%) or III/IV (n = 46, 68.7%). Estimated median overall survival (OS) for all pts was 15.9 months (95% CI 11.1-20.3). HER-2 overexpression was identified in 1 pt (1.5%). HER-3 overexpression was identified in 16 (23.9%): 1 pt was classified as “3+; positive” by IHC and 15 were confirmed by FISH following a “2+” expression in IHC. Neither HER-2 (p = 0.103) nor HER-3 (p = 0.087) impacted on OS. No factors related to HER-3 overexpression were identified.Conclusions: HER-3 is overexpressed in a significant subset of pts diagnosed with BTC; treatment targeting this pathway may warrant evaluation.

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and it's the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is

We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient’s clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma.

Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.

Purpose: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. Methods: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. Results: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. Conclusion: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

After years of limited progress in the treatment of neuroendocrine neoplasms (NENs), an increasing number of therapeutic targets have recently emerged as potential tools to improve disease outcome. The mammalian target of rapamycin (mTOR) pathway and vascular endothelial growth factor (VEGF) signalling are implicated in the regulation of cell growth, proliferation, neo-angiogenesis and tumour cell spread. Their combined blockade, in a simultaneous or sequential strategy, represents an intriguing biological rationale to overcome the onset of resistance mechanisms. However, is becoming increasingly imperative to find the optimal sequential strategy according to the best toxicity profile, and also to identify predictive biomarkers. We will provide an overview of the pre-clinical and clinical data relating to mTOR pathway/VEGF signalling as a potential targets of treatment in NENs.

The role of Streptococcus bovis (S. bovis) as an aetiological agent in the development of colorectal cancer (CRC) is intriguing but uncertain. A relationship between infective endocarditis (IE) and CRC was established by McCoy and Mason in 1951 and, for the first time, an association between S. bovis and endocarditis was successfully recognized by Watanakunakorn in 1974. In the same year, Hoppes and Lerner hypothesized that some previous reports of endocarditis caused by penicillin-sensitive “enterococci”, including that of McCoy, were probably unrecognized examples of S. bovis. In 1977, Klein and coworkers showed the prevalence of S. bovis in fecal cultures from patients with S. bovis septicemia and carcinoma of the colon was significantly increased. Thus, S. bovis infection should be considered a silent sign of gastrointestinal malignancy. Over the past 50 years, several case reports and studies – most retrospective – have been publishing on this topic often producing contradictory results. Currently, only Streptococcus gallolyticus subspecies gallolyticus (SGG) – formerly known as S. bovis biotype I – has been recognized to be directly related to colonic neoplasia. Hence, in order to demonstrate the presence of a colon cancer, all patients with S. bovis/gallolyticus infection would require an endoscopic investigation.

Neuroendocrine neoplasms are a low-incidence and heterogeneous group of malignancies. In the advanced stage, several therapeutic options can be discussed, including molecular-targeted agents, but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade leading to several phase II studies; however, very few agents progressed to phase III clinical trials. The RAF family of proteins belongs to the mitogen-activated protein kinase (MAPK) pathway, that has a role in several types of cancers, particularly related to BRAF mutations. Indeed BRAF inhibitors have been reported as being effective, mainly in melanoma. However, in neuroendocrine neoplasms BRAF mutations are extremely rare and RAF-1 activation has been reported to inhibit tumor growth in a pre-clinical setting. Therefore, in this field, RAF-1 activators rather than BRAF inhibitors should be clinically investigated. This article reviews the basic science as well as clinical data of RAF signaling in advanced neuroendocrine neoplasms with special emphasis on the potential role of both RAF activators and inhibitors.

Background: HER2 overexpression and/or amplification has been reported as predictive factor to HER2 targeted therapy in breast and gastric cancer, whereas HER3 is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 up-regulation in biliary tract cancers (BTCs).Methods: An electronic search of MEDLINE, ASCO, ESMO and AACR was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridisation (ISH) in BTCs.Results: Out of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5% (95% CI, 18.9% - 34.1%). Studies were classified as “high-quality” (HQ; 27 studies) [IHC overexpression defined as presence of moderate/strong staining] and “low-quality” (11 studies) [“any” expression was considered positive]. When HQ studies were analysed, extra-hepatic BTCs (EH-BTCs) showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma (IHCC) [19.9% (95% CI, 12.8 – 27.1%) vs. 4.8% (95% CI, 0 – 14.5%); p-value 0.0049]. HER2 amplification rate was higher in those patients selected by HER2 overexpression [57.6% (95% CI, 16.2 - 99%)] compared to “unselected” patients [17.9% (95% CI, 0.1 – 35.4%); p-value 0.0072]. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9% (95% CI, 9.7 - 46.1%) and 26.5% (one study), respectively.Conclusions: Up to 20% of EH-BTCs might be HER2 overexpressed, ∼60% of HER2 overexpressed BTCs can be considered amplified while HER3 is overexpressed or amplified in ∼25% of BTCs. These findings may be considered in future trial development.

e15174 Background: Capecitabine (CAP) and temozolomide (TEM) have been reported to be active as first-line treatment in pancreatic neuroendocrine neoplasms (pNENs). We retrospectively evaluated act...

281 Background: A combination of capecitabine (CAP) and temozolomide (TEM) has been successfully used as first-line treatment in low-grade pancreatic neuroendocrine neoplasms (PNEN). We reviewed activity and toxicity of the same regimen in patients with advanced NEN with different primary and grading. Methods: Clinical data of patients who had received oral CAP 1500 mg/m2/day over 14 days bid plus oral TEM 150-200 mg/m2/day on days 10-14 of each 28-day cycle, were retrospectively reviewed. The methylenguanilmetiltransferase (MGMT) methylation-status (MGMT-gene >5% = responders) and TS-polymorphisms (2R/2R, 2R/3R = responders, 3R/3R = non-responders) in tumor-tissue/peripheral-blood were evaluated by pyrosequencing. Results: Since March 2012, 29 patients were selected. The primary tumor was: pancreas in 14 patients (48%), gastrointestinal (GI) in 5 (17%), unknown in 2 (7%), lung in 8 (28%). According to 2010 WHO classification, Ki67 was 20% (G3) in 21% with two "low G3" (Ki67 21-30%), and unknown in 3%. Among lung: 7% typical and 21% atypical (Travis’ classification). 72% patients (21/29) were progressive on different therapies: peptide-receptor-radiotherapy (38%), chemotherapy (38%), everolimus (14%). Partial-response (PR) occurred in 14% (4/29) of patients (95% CI: 4-32), stable-disease (SD) in 59% (17/29) (95% CI: 39-77) mainly PNET. The two "low G3" responded. Disease control rate (PR+SD): 72% (95% CI: 53-87). Median TTP: 9 months (95% CI: 5.6-N.E.). Thrombocytopenia was the most frequent grade 3 toxicity, always temporary. All 4 PR patients had genotype 2R/3R-2R/2R investigated for the 28 base-pair (bp) variable number of tandem repeats (VNTR) in the 5'UTR of the TS-gene, and MGMT-gene inactivation by epigenetic silencing. Conclusions: This analysis suggests that CAP-TEM chemotherapy could be active and well tolerated in pretreated patients with advanced NEN of different origins and grading. This warrants a prospective investigation in a more homogeneous population (G2 and “low-G3” GEP NEN or lung carcinoids), in order to validate the predictive value of MGMT methylation-status and TS-polymorphisms.

A relationship between infective endocarditis and colon cancer was established in 1950, and Streptococcus bovis was successfully isolated in 1970. However, this association and its pathogenesis still remain unclear. In this paper, we describe the clinical case of a patient with a history of colon cancer and infective endocarditis caused by Streptococcus bovis. The role of S bovis as an aetiological agent in the development of colon cancer is intriguing but uncertain. S bovis infection should be considered a silent sign of gastrointestinal malignancy or hepatic disease. We believe that in order to demonstrate the presence of colon cancer, all patients with S bovis infection require an endoscopic investigation of the colon.