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Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of “NE lineage plasticity,” whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type–agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how “NE lineage plasticity” can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.

Background: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. Objective: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. Findings: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. Conclusion: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis and significant symptom burden. This prospective observational study aimed to evaluate expectations and priorities of patients with advanced PDAC and their clinicians through a study survey and two quality of life (QoL) questionnaires (QLQ-C30 and PAN26) at three time-points: baseline (T1), before (T2) and after (T3) their 1st on-treatment CT scan. Over a 1-year period, 106 patients were approached, 71 patients and 12 clinicians were recruited. Choosing between treatment options, patients prioritised: 54% overall survival (OS), 26% balance between side-effects and OS, 15% could not choose and 5% favoured symptom control. These were significantly different from the clinician’s answers (p < 0.001). Patients who prioritised OS had higher symptom burden (p = 0.03) and shorter OS compared to those who prioritised balance (p = 0.01). Most (86%) patients had personal goals they wanted to reach; clinicians knew of these in 12% of instances. Patient and clinicians’ views regarding survival improvement from chemotherapy were significantly different: 81% of clinicians and 12% of patients thought 1–2 or 3–6 months extension, 58% of patients and 0% physicians thought 1–5 or >5 years (p < 0.001). At T1, patients had low QoL and worst symptoms were: ‘Future worries’, ‘planning of activities’, fatigue and pain. Patients were willing to accept significantly higher amounts of side-effects as a trade-off for extra time, than clinicians thought (p < 0.001). Overall, there are significant discrepancies between patient and clinicians’ views about the aims, priorities and expected extension of life.Keywords: pancreatic cancer; quality of life; patient views on treatment

BACKGROUND Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare diagnosis, mainly encountered in the gastro-entero-pancreatic tract. There is limited knowledge of its epidemiology, prognosis and biology, and the best management for affected patients is still to be defined. AIM To investigate clinical-pathological characteristics, treatment modalities and survival outcomes of a retrospective cohort of patients with a diagnosis of MiNEN. METHODS Consecutive patients with a histologically proven diagnosis of MiNEN were identified at 5 European centres. Patient data were retrospectively collected from medical records. Pathological samples were reviewed to ascertain compliance with the 2017 World Health Organisation definition of MiNEN. Tumour responses to systemic treatment were assessed according to the Response Evaluation Criteria in Solid Tumours 1.1. Kaplan-Meier analysis was applied to estimate survival outcomes. Associations between clinical-pathological characteristics and survival outcomes were explored using Log-rank test for equality of survivors functions (univariate) and Cox-regression analysis (multivariable). RESULTS Sixty-nine consecutive patients identified; Median age at diagnosis: 64 years. Males: 63.8%. Localised disease (curable): 53.6%. Commonest sites of origin: colon-rectum (43.5%) and oesophagus/oesophagogastric junction (15.9%). The neuroendocrine component was; predominant in 58.6%, poorly differentiated in 86.3%, and large cell in 81.25%, of cases analysed. Most distant metastases analysed (73.4%) were occupied only by a poorly differentiated neuroendocrine component. Ninety-four percent of patients with localised disease underwent curative surgery; 53% also received perioperative treatment, most often in line with protocols for adenocarcinomas from the same sites of origin. Chemotherapy was offered to most patients (68.1%) with advanced disease, and followed protocols for pure neuroendocrine carcinomas or adenocarcinomas in equal proportion. In localised cases, median recurrence free survival (RFS); 14.0 mo (95%CI: 9.2-24.4), and median overall survival (OS): 28.6 mo (95%CI: 18.3-41.1). On univariate analysis, receipt of perioperative treatment (vs surgery alone) did not improve RFS (P = 0.375), or OS (P = 0.240). In advanced cases, median progression free survival (PFS); 5.6 mo (95%CI: 4.4-7.4), and median OS; 9.0 mo (95%CI: 5.2-13.4). On univariate analysis, receipt of palliative active treatment (vs best supportive care) prolonged PFS and OS (both, P < 0.001). CONCLUSION MiNEN is most commonly driven by a poorly differentiated neuroendocrine component, and has poor prognosis. Advances in its biological understanding are needed to identify effective treatments and improve patient outcomes.

NeuroEndocrine Carcinomas (NECs) are rare yet lethal diseases; they are frequently metastatic and have limited treatment options. Whilst progress has been made in understanding the biology of Small Cell Lung Cancer (SCLC), the most studied NEC, research on NECs from other anatomical sites lags behind. In SCLC, circulating tumor cells (CTCs) can be used to generate patient-relevant mouse models; termed CTC-Derived eXplants (CDX) which are faithful in biology and chemotherapy response to donor patients1,2. A pilot prospective study is on-going to assess the potential utility of cell-free DNA (cfDNA) and/or CellSearch (CS) CTCs (EpCAM/cytokeratin positive) as liquid biopsies and feasibility of CDX generation from patients with advanced stage extrapulmonary NECs undergoing palliative chemotherapy. CS CTCs are enumerated before and during treatment and marker-independent RosetteSep-enriched CTCs from parallel blood samples are implanted in immunodeficient mice to attempt CDX generation. Twenty-seven patients were recruited from Jun-19 to Nov-21. CS-CTCs were present in 19/27; 70% pre-treatment samples (mean 57, median 2, range 0-685 CTCs per 7.5mL of blood). CDX generation was successful from a pre-treatment CTC sample from a patient originally diagnosed with a NEC of unknown origin who responded to Platinum/Etoposide. Whole-exome sequencing of this CDX and matched pre-treatment cfDNA from the donor revealed largely overlapping copy number changes and common mutations including an activating PIK3CA mutation. In addition, there was no evidence of TP53 or RB1 loss (hallmarks of SCLC) in neither the CDX nor the donor’s cfDNA. Immunohistochemical (IHC) analysis of this CDX showed a small cell NEC morphology, 90% Ki-67 positive cells, expression of EpCAM, pan-cytokeratins and neuroendocrine (NE) diagnostic markers, concordant with the donor’s biopsy. Further IHC and RNA sequencing revealed expression of the NE transcription factor atonal homolog 1 (ATOH1)2, CK20 and abundant Merkel cell polyomavirus (MCPyV) transcripts. These characteristics prompted reclassification of the original patient diagnosis as Merkel cell carcinoma (MCC). There was only 1 CS-CTC in the parallel pre-treatment blood sample implying that EpCAM-negative CTCs may have given rise to the CDX. The CDX showed in vivo sensitivity to Platinum/Etoposide, mirroring treatment response of the donor. Ex vivo cultures from CDX-derived cells grow as suspension clusters similar to ‘classic’ SCLC and MCPyV-positive MCC cell lines. In summary, this first Merkel Cell Carcinoma CDX recapitulates the biology of the donor’s tumor. As the donor remains alive 25 months from diagnosis of advanced disease, their CDX can serve as an avatar to guide future treatment. 1. Hodgkinson et al., Nature Med 2014, 20: p. 897-903. 2. Simpson et al., Nature Cancer 2020, 1: p. 437-451. Citation Format: Melissa Frizziero, Elaine Kilgour, Kathryn L. Simpson, Dominic Rothwell, Kristopher Frese, Melanie Galvin, Yitao Chen, Alastair Kerr, Sam Humphrey, Mukarram Hossain, Juan W. Valle, Mairéad G. McNamara, Caroline Dive. The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3098.

BACKGROUND Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence. METHODS A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier). RESULTS Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had >10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care. CONCLUSION BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.

Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC.

BACKGROUND The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy AIM To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63–76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs. Chiramel J, Almond R, Slagter A, Khan A, Wang X, Lim KHJ, Frizziero M, Chakrabarty B, Minicozzi A, Lamarca A, Mansoor W, Hubner RA, Valle JW, McNamara MG. Prognostic importance of lymph node yield after curative resection of gastroenteropancreatic neuroendocrine tumours. World J Clin Oncol 2020; 11(4): 205-216 [PMID: 32355642 DOI: 10.5306/wjco.v11.i4.205]

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.

Extra-Pulmonary NeuroEndocrine Carcinomas (EP-NECs) are aggressive tumours (Ki-67>20%, poorly differentiated morphology), with a median overall survival Citation Format: Melissa Frizziero, Elaine Kilgour, Kathryn Simpson, Kristopher Frese, Juan W. Valle, Mairéad G. McNamara, Caroline Dive. Liquid biopsy-based precision medicine for extra-pulmonary neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 601.

The incidence of neuroendocrine neoplasms (NENs) is increasing, especially for patients with early stages and grade 1 tumours. Current evidence also shows increased prevalence, probably reflecting earlier stage diagnosis (e.g. at the time of endoscopy) and improvement of treatment options.Definition of adequate post-surgical follow-up for NENs is a current challenge. There are limited guidelines and heterogeneity in adherence to those available is notable. Unfortunately, the population of patients at greatest risk of recurrence has not been defined clearly. Some studies support that for patients with pancreatic neuroendocrine tumours (PanNETs), factors such as primary tumour (T), stage, grade (Ki-67), tumour size and lymph node metastases (N) are of relevance. For bronchial (LungNETs) and small intestinal (siNETs), similar factors have been identified. This review summarises the evidence supporting the rationale behind follow-up after curative resection in well-differentiated PanNETs, siNETs and LungNETS. Since surgery for poorly-differentiated tumours has a limited role, the focus of these recommendations will be limited to patients with well-differentiated tumours. Published evidence informing relapse rate, disease-free survival and relapse patterns are discussed, together with an overview of current guidelines informing post-surgical investigations and duration of follow-up.

Background: There is no standard second-line treatment for patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC). This study explored data evaluating second-line treatment in these patients. Methods: A search of MEDLINE and EMBASE identified studies reporting survival and/or response data for patients with EP-PD-NEC receiving second-line therapy. Association between various factors (age, gender, ECOG performance status, primary tumour location, morphology, Ki-67, treatment and grade 3/4 haematological toxicity) and response rate (RR), progression-free (PFS) and overall survival (OS) were assessed with a mixed effects meta-regression weighted by individual study sample size. Due to a small sample size, associations were reported quantitatively, based on magnitude of beta coefficient rather than statistical significance. Results: Of 83 identified studies, 19 were eligible, including 4 prospective and 15 retrospective studies. Analysis comprised 582 patients, with a median number of 19 patients in each study (range 5–100). Median age was 59 years (range 53–66). Median RR was 18% (range 0–50; 0% for single-agent everolimus, temozolomide, topotecan; 50% with amrubicin), median PFS was 2.5 months (range 1.15–6.0) and median OS was 7.64 months (range 3.2–22.0). Studies with a higher proportion of patients with a Ki-67>55% had lower RR (β = –0.73) and shorter OS (β = –0.82). Conclusion: Second-line therapy for patients with advanced EP-PD-NEC has limited efficacy and the variety of regimens used is diverse. Ki-67>55% is associated with worse outcomes. Prospective randomised studies are warranted to enable exploration of new treatment strategies.

Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate.A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis.Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function.CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).

Background Platinum-etoposide (PE) chemotherapy (CH) is a globally established combination for extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC); the optimal schedule has not been established. Methods An international survey was designed, and completed by clinicians with an expertise in the field to assess consistency in clinical practice. Results Seventy-five replies were received (June-Nov’17). A minority of physicians (13; 17.6%) did not take Ki-67 or morphology (9; 12.0%) into consideration for selection of CH. Most (72; 96.0%) selected PE-CH as first-line treatment for EP-G3-NEC. CH schedules varied: cisplatin-based (37/71; 52.1%), carboplatin-based (34/71; 47.9%); intravenous etoposide (64/71; 90.1%), oral etoposide (7/71; 9.9%). Choice of second-line CH depended on time to progression on PE-based first-line: if > 6 months, re-challenge with PE was the preferred choice (34; 45.9%); if

Background: Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. Objectives: To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. Methods: Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. Results: We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3–4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). Conclusions: CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.

Background: Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI). Methods: In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. Results: The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15–59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. Conclusion: This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.

The rearrangements of the anaplastic lymphoma kinase (ALK) gene are key drivers in the carcinogenesis of a portion of anaplastic large cell lymphomas (ALCL) and non-small cell lung cancers (NSCLC). Crizotinib, an orally available small molecule, has been the first ALK inhibitor to demonstrate a significant clinical activity in patients with ALK-positive tumors and, thus, to achieve the US food and drug administration approval for the treatment of advanced NSCLC harboring ALK-rearrangements. However, despite initially dramatic and quite durable responses in most cases, acquired resistance to crizotinib arises unavoidably often within the first year of treatment. Three main mechanisms of resistance to crizotinib have been identified to date: mutations in the ALK kinase domain, amplifications of ALK gene, and activation of escape signaling pathways. As ALK signaling dependence is retained in most cases become refractory to crizotinib, newer and more potent ALK-inhibitors have been developed and tested in clinical trials with encouraging activity results. Ceritinib has been recently approved by FDA for the treatment of locally advanced and metastatic NSCLC, and several more agents, including alectinib, ASP3026, and X396, are in active clinical development, demonstrating to be safe, selective and potent. Dual inhibition approaches targeting both ALK and the escape pathways bypassing ALK are currently under investigation. Moreover, being ALK a partner of the heat shock protein Hsp90, inhibitors of this chaperone have been proposed as potential alternative therapeutic strategies for ALKdriven tumors.

Background: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor β activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. Methods: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT–PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. Results: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P

Introduction: MANEC is a rare diagnosis and little is known on its epidemiology/prognosis/management. Methods: Demographic/clinical-pathological/survival data of patients with a diagnosis of MANEC (2010 WHO criteria) from five European centres were retrospectively reviewed. Results: Sixty-six patients were identified (09/80–07/17); median age: 62.5 years (range 34–89); male: 66.7%; ECOG-PS 0-1: 59%; primary tumours from: small/large bowel 62.1%, oesophagus/stomach 22.7%, pancreas/biliary tract 13.6%, unknown 1.5%; adult-comorbidity-evaluation (ACE)-27 score 0: 36.4%. The NE component (predominant histology in 58.1% of 43 cases where this information was available) was poorly-differentiated (PD) in 80.3%, with a median Ki-67 value of 70% (95%-Confidence-Interval (CI): 60–73.6). Most frequently expressed IHC markers were: synaptophysin (87.9%), chromogranin-A (CgA) (54.5%) and CDX2 (48.5%). Histology from recurrent/metastatic sites (14 patients) was PD-NE in 71.4%. Median follow-up time was 11.5 months (mo). Of 34 (51.5%) patients with localised-stage (LA) disease, 91.2% had curative surgery (22.5% had neoadjuvant chemo-radiotherapy (CT-RT), 29% had adjuvant or peri-operative CT), 5.9% had definitive CT-RT and 2.9% had unknown management; 77.4% recurred. Fifty-four (81.8%) patients were treated for advanced-stage (adv) disease: 50% had platinum-based CT, 5.5% irinotecan-based CT, 1.8% gemcitabine, 1.8% 5-fluorouracil/leucovorin, 3.7% unknown CT regimen, 1.8% CT-RT, 1.8% RT, 24% best-supportive-care (BSC), and 9.25% unknown management. Median overall-survival (OS) for all patients was 16.2 mo (95%-CI 12.1–21). Median recurrence-free-survival and OS in patients with LA disease were 12.9 mo (95%-CI 6.7–21) and 21 mo (95%-CI 14.57–35). Median progression-free-survival (PFS) and OS in patients with adv disease were 4.9 mo (95%CI 3.5–7.2) and 14.6 mo (95%CI 9.6–19.4). On univariable analysis, age

Introduction: Platinum-etoposide chemotherapy is a globally established chemotherapy combination for EP-G3-NEC. However, there are many different schedules for such chemotherapy, and the preferred one for EP-G3-NEC has not been established. Methods: An international survey was created, and completed by colleagues with an expertise in the field of neuroendocrine neoplasms. The aim was to explore which schedules of platinum-etoposide chemotherapy are used across centres and to assess consistency in clinical practice. Results: Sixty four replies were received (June-August’17); completed by medical oncologists (43;67.2%), clinical oncologists (11;17.2%), gastroenterologists (8;12.5%) and endocrinologists (2;3.1%). United Kingdom was the most represented country (25;39.1%), followed by Spain (13;20.3%). Most of the physicians completing the survey (39;60.9%) had >10 years of experience in the field; 29 (46.0%) were working in European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (CoE). A small minority did not take Ki67 (7;11.1%) or morphology (7;10.9%) into consideration when selecting type of chemotherapy to be administered. Regarding choice of chemotherapy, most (61;95.3%) agreed on selecting platinum-etoposide chemotherapy as first-line treatment for NEC tumours ± poor-differentiation ± Ki67>55%, although there was a large number of different schedules used: cisplatin-based (28/60;46.7%), carboplatin-based (32/60;53.3%). Most centres chose a schedule with intravenous etoposide (53/60;88.3%), while oral etoposide was less popular (7/60;11.7%). Chemotherapy was usually administered up to a maximum of 6 cycles (49;79.0%). At time of progression, choice of second-line chemotherapy was influenced by the time between completion of first-line chemotherapy and tumour progression. When this period was >6 months, re-challenge with platinum-etoposide was the preferred choice (29;46.0%). Conversely, when time to progression was

Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the TH2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of TH1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.

Introduction: Platinum-etoposide is considered standard-of-care first-line treatment for patients diagnosed with advanced EP-PD-NECs. The optimal platinum-etoposide schedule remains undefined; carboplatin is often substituted for cisplatin, although quality data is lacking. Methods: Electronic records of patients with advanced EP-PD-NEC treated with carboplatin-etoposide (06/09-02/17) were reviewed retrospectively, with aim to provide real-life efficacy/safety data on carboplatin-etoposide in this setting. Chi-square test, Kaplan-Meier and univariate/multivariable Cox-regression analyses were performed, as appropriate. Results: Seventy-three patients were screened, 57 eligible; median follow-up 8.57 months (m); median age 70.4 years (range 36.2–88.4). Most patients were male (68.4%), had Eastern-Cooperative-Oncology-Group performance-status (ECOG-PS) 0–1 (79%) and none-mild comorbidities (72%). Site of primary tumour: foregut 35.1%, hindgut 24.6%, unknown 21%, pancreas 8.8%, others 10.5%. Most had stage IV disease (87.7%); median number of metastatic sites: 2 (range 1–6), liver (68%) being the most common. Histopathology: median Ki-67 75% (95%-Confidence-Interval (95%-CI) 60–80%); morphology included small-cell (33.3%), large-cell (22.8%), others (3.5%), not-specified (40.4%). The 57 patients received a total of 64 courses of carboplatin-etoposide: 54 (84.4%) first-line, 9 (14%) second-line and 1 (1.6%) third-line. Etoposide was administered orally (81.2%) or intravenously (18.8%); median number of cycles: 4 (range 1–7). In the first- and second-line settings, median progression-free-survival (PFS) was 5.4 m (95%-CI 3.6–6.9) and 3.4 m (95%-CI 1.6–11.0) and median overall-survival was 7.5 m (95%-CI 6.2–11.5) and 5.8 m (95%-CI 1.6–15.4), respectively. Most common grade 3–4 adverse events in first/second-line were myelotoxicity (29.6%/44.4%), infections (13%/11.1%), venous thromboembolism (11.1%/22.2%); no differences between first-/second-line were identified (all P-values >0.05). Median carboplatin-etoposide dose-intensity was 94.8 and 94.4% in first-/second-line, respectively. Line of chemotherapy did not impact PFS (P-value >0.3). Liver metastases and age were significant in the univariate analysis for PFS and included in the multivariable Cox-regression: presence of liver metastases was the only independent factor related to worse PFS (Hazard-Ratio 1.9 (95%-CI 1.1–3.3); P-value 0.03). Conclusion: Carboplatin-etoposide is associated with survival outcomes in real-life comparable to those reported in current literature. It is an active combination for patients with advanced EP-PD-NECs, with a manageable toxicity profile which allows adequate dose-intensity.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

Despite the global incidence of upper gastrointestinal tract cancers which has significantly declined over the past three decades, the incidence of adenocarcinoma of the esophagogastric junction (EGJ) is continuously and rapidly rising in the Western countries, representing a major health problem [1, 2].

The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

Background Immune checkpoint blockade (ICB) has improved overall survival (OS) in selected patients (pts) with cancers, but predictive biomarkers are required. TMB has been proposed as a potential biomarker, but challenges exist as to its optimal definition, quantification and utility. Methods A search of Medline and Embase identified studies reporting association of TMB (high vs low) with survival in pts with solid tumors, irrespective of exposure to ICB. The influence of TMB on OS was explored by meta-analysis, utilizing the generic inverse variance method. Association between baseline factors (age, gender, primary tumor site, stage, smoking history, proportion of pts with squamous histology, receipt of ICB) and survival were assessed with mixed effects meta-regression, weighted by study sample size. Results Of 493 studies, 35 were eligible (ICB used in 28); 13 prospective, 22 retrospective; correlation between PD-L1 expression and TMB was not possible due to limited reporting studies. Analysis comprised 10,433 pts; median age: 63 yrs (range 53-73; reported in 18 studies). Median proportion male: 62.5% (range 40-83%), primary tumor site lung: 17 studies (9 squamous histology), melanoma: 5, urothelial: 3, breast: 2, head & neck, biliary and hepatocellular carcinoma: all 1, multiple sites: 5. Eleven different assays for TMB determination were utilized (Foundation One in 15 studies). Amongst 22 studies, where reported, 5 different TMB definitions were used, with only 10 studies reporting a median TMB (Mut/Mb); 11 different TMB “high” thresholds were reported. In the absence of ICB, high TMB was associated with increased risk of death (HR 2.87, 95% CI 1.41-5.82, p=.004). In the presence of ICB, high TMB was associated with improved OS (HR 0.60, 95% CI 0.42-0.86, p=.005), albeit with significant heterogeneity (p=.002). Studies with a higher proportion of male pts had increased hazard of death (β=.75) and those with a higher proportion of pts receiving ICB had a lower hazard of death (β=-.56). Conclusions High TMB is a poor prognostic factor in solid tumors, but is predictive of improved OS with ICB. Standardization of TMB analysis/reporting is imperative for reliable clinical application. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the TH2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of TH1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.

Background: MANEC is a rare entity and evidence on its prognosis and management is limited. Methods: Demographic/clinicopathological/survival data of consecutive patients (pts) with a diagnosis of MANEC (2010 WHO criteria) from 4 European centres were retrospectively reviewed. Results: Fifty-three pts were identified (01/06-03/17); median (med) age: 62 yrs (range 34-89), male: 70%, ECOG PS 0-1: 60%, with primary tumours from small/large bowel in 34 (64%), oesophagus/stomach: 13 (24.5%), pancreas/biliary tract: 5 (9.5%), unknown (UNK): 1 (2%). Forty percent had an adult comorbidity evaluation (ACE)-27 score of 0. The neuroendocrine (NE) component (predominant histology in 40%) was poorly-differentiated (PD) in 45 (85%) [Ki-67≥55%: 58%]. Most frequently-expressed immunohistochemical (IHC) markers were synaptophysin (100%), chromogranin A (CgA) (58.5%) and CDX2 (51%). Histology was PD NE in 64% from recurrent/metastatic sites (n = 14 pts). Of 28 (53%) pts with localised disease (LA), 26 (93%) had curative surgery (7 had neoadjuvant chemo-radiotherapy (CT-RT), 6 adjuvant CT, 1 peri-operative CT), 1 (3.5%) had definitive CT-RT and 1 (3.5%) had UNK management; 16 (57%) recurred. Forty-one pts (77%) were treated for advanced (adv) disease: 20 (49%) platinum-based CT, 3 (7%) irinotecan-based CT, 1 (2.4%) gemcitabine, 3 (7%) UNK CT regimen, 1 (2.4%) RT, 1 (2.4%) CT-RT, 11 (27%) best supportive care (BSC), and 1 (2.4%) UNK management. Med follow-up time was 10.4 months (mo) (95% Confidence Interval (CI) 5.15-13.09). Med overall survival (OS) for all pts was 18.6 mo (95% CI 11.4-40). Med recurrence-free survival and OS in pts with LA was 19.4 mo (95%CI 5.8-30.9) and 21 mo (95%CI 12.1-40). Med progression free survival (PFS) and OS in pts with adv disease was 4.6 mo (95%CI 3.3-6.7) and 13.6 mo (95%CI 8.8-33.1). On univariable analysis, ACE-27 score (0 vs ≥ 1) was prognostic for better PFS and OS (both p

Background: Advanced wd-NET patients (pts) are commonly treated with SSAs. PEI may be under-estimated in trials due to difficulties in distinguishing carcinoid syndrome-related diarrhoea and PEI.Methods: In this single-institution, prospective, observational study, sequential pts with advanced wd-NET were commenced on SSAs and followed for a minimum of 12 months (or until disease progression). Toxicity was prospectively assessed monthly. Faecal elastase testing (FE) (for diagnosis of PEI) and quality of life (QoL) questionnaires (QLQ-C30 and QLQ-GI.NET21) were performed 3-monthly.Results: Of 52 pts recruited (Jan 15-Apr 16), 50 were eligible: median age 65.8 yrs; 58% male; ECOG performance status 0 (42%), 1 (46%) or 2 (12%); primary: small bowel (60%), pancreas (22%), lung (12%) and other (6%). Baseline median Ki-67 was 3.1% (range 0.7-25), serum 5HIAA: 195 nmol/L (95%CI 145-318) and chromogranin A (CgA): 327 ng/mL (95%CI 140-582). Most pts were metastatic (92%), non-functional (66%) and started SSA first-line (88%); depot SSA was octreotide in 60%, lanreotide in 40%. Forty-one pts (82%) started full-dose SSA (4-weekly octreotide 30mg or lanreotide 120mg); 96% achieved full dose; 3 pts required dose reduction due to toxicities. Grade (G) 1-2 toxicities were flatulence (50%), abdominal pain (32%), diarrhoea (30%), fatigue (20%), PEI (22%), nausea (16%), hyperglycaemia (6%), anorexia (4%) and constipation (2%). G 3-4 toxicities were few (G3 hyperglycaemia (n = 1) and G3 PEI (n = 1); no G4). Twelve pts (24%) developed SSA-related PEI (4 clinical diagnosis, 8 FE-confirmed) at a median of 2.9 mo (95%CI 1.7-8.6) after starting SSA; 11/12 (92%) pts received enzyme replacement. Questionnaires identified fatigue, insomnia and diarrhoea as the most important baseline symptoms; SSA therapy did not negatively-affect QoL. Estimated median progression-free survival (PFS) was 29.9 mo (95%CI 21.4-not reached). High baseline CgA was an independent factor for shorter PFS (HR 1.01 (95%CI 1.001-1.1); p-value 0.001) after adjustment for other factors (baseline 5HIAA, Ki-67).Conclusions: SSA-induced PEI occurs in 1:4 pts; clinicians should actively identify and treat.

The mTORC1 inhibitor RAD001 (everolimus) has been approved for multiple cancer indications, including ER+/HER2- metastatic breast cancer. The combination of RAD001 with a dual PI3K/mTOR inhibitor BEZ235 was shown to be even more efficacious than RAD001 alone in preclinical models and was evaluated in clinical trials. We identified a male breast cancer patient who experienced a prolonged stable disease with the RAD001/BEZ235 combination as 3rd line treatment for his metastatic disease and investigated molecular mechanisms to explain the extraordinary benefit and subsequent drug resistance. The 66-year old Caucasian male had stage IIIA invasive ductal carcinoma at initial surgery. He then received two sequential adjuvant therapies: a chemo-radiotherapy and letrozole. When the patient developed multiple metastases, he was treated with chemotherapy and then fulvestrant, before received a 200 mg twice daily BEZ235 and 2.5 mg weekly RAD001 combination regimen, when a left axillary nodal metastasis was developed on fulvestrant. The patient sustained a prolonged stable disease of 18 months while under the therapy before his tumor progressed again. Tumor biopsy samples (formalin fixed, paraffin embedded) were taken from the patient at diagnosis and after progression and analyzed by immunohistochemistry (IHC) and whole exome sequencing. Blood samples were collected for germline DNA pharmacokinetic (PK) analysis. PK profile of BEZ235 was collected with Cmax, AUC, and T1/2 of 766 ng/mL, 6308 ng.h/mL, and 5.53 h, respectively. The observed BEZ235 Cmin values ranged from 75.5 to 504 ng/mL over the study. The 2.5 mg weekly RAD001 dose is substantially lower than the standard 10 mg daily dose and the Cmin could not be reliably determined. IHC assays showed low ER/PR expression (ER 30% 1+; PR 20% 1+, 10% 3+) in the diagnosis sample, but an increase of their expression (60% 1+) in the post progression sample. HER2 expression was negative in both samples. Analysis the same tumor samples using more quantitative AQUA platform demonstrated a drastic 10-fold score increase of ER from 31 to 312 and a 5-fold increase of PR from 271 to 1305. All other examined signaling pathway biomarkers (e.g. pS6, pAKT, pMAPK, pMEK and pEGFR) were expressed in both tumor samples but showed minimal expression changes between the time points. Whole exome sequencing of the diagnosis and post-progression specimens provided average coverage at 142X and 179X, respectively . No functional somatic alterations resulting in hyperactive PI3K/mTOR pathway was detected in genes such as PIK3CA, PTEN, MTOR, TSC1/2 in either tumor samples. In both specimens, a somatic deletion of 16 bp was detected in SPEN, which encodes a potential negative regulator of the estrogen signaling pathway1 . In conclusion, no PI3K/mTOR pathway hyperactivity marker was identified in the diagnostic samples. However, the increased ER/PR expression in the post-progression sample suggests that the effect of PI3K/mTOR pathway blockade by RAD001/BEZ235 might have diminished when the tumor gained further dependence on the hormonal receptor signaling. This hypothesis was supported by the observation that the patient's tumor achieved another prolonged disease control of about 13 months by exemestane, after progression from BEZ235/RAD001 treatment. 1Légaré S, et al. SPEN is a novel candidate tumor suppressor gene that regulates response to tamoxifen in estrogen receptor positive breast cancers. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013. Citation Format: A. Rose Brannron, Davide Melisi, Jennifer Hummel, Carmine Carbone, Melissa Frizziero, Wing Cheung, Parul Patel, Jorge Gallo, Giampaolo Tortora, Michael Morrissey, David Chen. Biomarker analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/RAD001. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 26.

To obtain a prognostic stratification model for resected gastric cancer patients.Clinicopathological and molecular data (expression of Cdx2, Apc, β-catenin, E-cadherin, Fhit, p53, and human epidermal growth factor receptor-2 (Her2); HER2 and TOPO2A gene copy number; PIK3CA mutations; microsatellite instability) were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Individual patient probability (IPP) was estimated by logistic equation. A continuous score to identify risk-classes was derived according to the model ratios.Two-hundred eight patients were studied (median follow-up 20 months). At multivariate analysis, sex, stage, margins, location, nodes, Apc, and Fhit were independent predictors for CSS; the same factors (and age and Her2, except Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy (0.90 for CSS; 0.91 for OS). A two-class model significantly separated low- and high-risk patients for CSS (23.4% and 85.6%, P0.0001) and OS (21.4% and 82.0%, P0.0001). A three-class model differentiated low-, intermediate-, and high-risk patients for CSS (6.3%, 35.3%, and 88.0%, P0.0001) and OS (6.1%, 34.6%, and 86.5%, P0.0001).A risk classification system comprising the immunohistochemical expression of three proteins (Apc, Fhit, and Her2) and five clinicopathological parameters (stage, resected nodes, margins, location, and sex) accurately separates the resected gastric cancer patients into three classes of risk.

We retrospectively evaluated elderly patients with advanced non-small cell lung cancer (NSCLC) treated with carboplatin (AUC 4-5) and gemcitabine (1,000-1,200 mg/m²). Thirty-six patients with performance Status (pS) 0-1 and median age 73 (range 70-78 years) were considered. Histology was squamous cell carcinoma (8 patients), adenocarcinoma (22) and NSCLC not otherwise specified (6). 149 cycles of chemotherapy were administered with a median of 3 per patient (range 3-6). Grade 3 non-hematologic toxicities were dyspnea (1 patient) and fever (1). Grade 3/4 hematologic toxicities were anemia (6), neutropenia (6) and thrombocytopenia (10), with dose reduction required in 13 patients. The overall disease control rate was 44.4%. We recorded no complete response, 8 partial response, 8 stable disease and 20 progressive disease. After a medium follow-up of 11 months, median progression- free survival and median survival were 5 and 11 months, respectively. Carboplatin and gemcitabine is a safe and active regimen in elderly advanced NSCLC patients with good PS.

The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER+/HER2− metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR+)/HER2− stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patient's sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR+ female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment.

Introduction: Preoperative CRT followed by surgery is the most common approach for patients with resectable esophageal and EGJ cancers. Based on the histology, patients with adenocarcinoma consistently demonstrated significantly lower rate of pathological complete response if compared with patients with squamous cell carcinoma, thus the need for accurate biomarkers to select the patients with esophageal and EGJ adenocarcinoma most likely to benefit from preoperative CRT has become even more critical. We recently demonstrated that the MAP3K TGF-βeta-activated kinase-1 (TAK1) is responsible for the resistance to the proapoptotic effect of chemotherapeutic agents by increasing the transcription of the member of the inhibitor of apoptosis proteins family BIRC3 in preclinical models of pancreatic cancer. Here, we hypothesized that the TAK1-regulated expression of BIRC3 might be responsible for the resistance to CRT in EGJ adenocarcinoma. Materials and methods: TAK1 kinase activity was targeted in FLO-1 and KYAE-1 esophageal cells by using (5Z)-7oxozeaenol. To test the effect of reducing BIRC3 expression on the resistance to CRT, FLO-1 and KYAE-1 cells were treated with increasing doses of cisplatin, 5-fluorouracil, paclitaxel, or radiotherapy in combination with (5Z)-7oxozeaenol. Drug interactions were studied for synergism according to Chou and Talalay method. Apoptotic induction was studied by western blot analysis of PARP and caspase 3 cleavages as well as by AnnexinV staining. BIRC3 expression was measured in 33 pretreatment biopsies from patients with EGJ adenocarcinoma and 34 from patients with esophageal squamous cell carcinoma receiving neoadjuvant CRT by Real-Time PCR. Tumor response was evaluated by Tumour regression grade (TRG) and by Size-based Pathological Response (SPR) scores. Correlation between BIRC3 expression and treatment response was analysed by ROC curve analysis. Results: In vitro, (5Z)-7oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 esophageal cells. Exposure to sublethal equitoxic doses of chemotherapeutic agents plus (5Z)-7oxozeaenol pretreatment resulted in a strong synergistic anti-proliferative effect. Baseline expression of BIRC3 was significantly higher in patients with EGJ adenocarcinoma if compared with the more sensitive squamous-cell carcinoma subtype. Moreover, patients with EGJ adenocarcinoma expressing higher pretreatment levels of BIRC3 had a significantly poorer treatment response than did those with lower expression, indicating that BIRC3 expression significantly correlates with response to preoperative CRT (AUC-ROC = 0.777 and 0.807 for SPR and TRG, respectively). Conclusions: TAK1-regulated expression of BIRC3 might be a valid biomarker to predict resistance to CRT in EGJ adenocarcinoma patients. Citation Format: Geny Piro, Simone Giacopuzzi, Maria Bencivenga, Carmine Carbone, Giuseppe Verlato, Melissa Frizziero, Maria Mihaela Mina, Marco Zanotto, Valeria Merz, Giovanni De Manzoni, Giampaolo Tortora, Davide Melisi. TAK1-regulated expression of BIRC3 is responsible for chemoradiotherapy (CRT) resistance in esophagogastric junction (EGJ) adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 579. doi:10.1158/1538-7445.AM2015-579

e15057 Background: No standard treatment exists in pretreated aPDAC pts, who have already received available active drugs. nab-P has shown to improve survival in combination with GEM in first line and to be active in GEM-resistant aPDAC pts. Methods: aPDAC pts who received off-label single agent nab-P (125 or 100 mg/m2 over 30 minutes on days 1, 8, and 15 of a 28- day cycle) as 2nd or further line of treatment for metastatic disease in three Italian centers were retrospectively reviewed. Results: 29 pts were identified (M/F: 16/13; median age: 66 yrs, range: 39-83); >50% of pts had an ECOG PS 2; median number of previous treatment lines: 2 (range 1-5); 7 pts had received Folfirinox as first line. nab-P starting dose was 125 mg/m2 in 5 pts and 100 mg/m2 in the others. A median of 2 cycles (range 1-10) were administered. Two partial responses (44 and 46-wk duration) were observed; 4 pts had stable disease SD (9, 16, 23, 28-wk duration, respectively); 5 pt are presently not evaluable. Median and mean progression free survival (PFS) were 8 (95% CI: 5-11) and 13 (95% CI: 7-18) wks, respectively; median and mean overall survival (OS) were 13 (95% CI: 9-17) and 25 (95% CI: 15-35) wks, respectively. Three- and 6-month PFS rates were 33% and 15%, respectively; 6- and 12-month OS rates were 36% and 22%, respectively. Toxicity was mild with G4 neutropenia in 1 pt and G3 neuropathy in 1 pts. With at least 10 out of 29 pts free from progression at 3 months (3-month PFS rate: 35%), our results satisfy the following post-hoc statistical hypothesis: p0: 15%, p1: 35%, a: 5%, 1-b: 80%, according to A’Hern exact single stage phase II design. Conclusions: nab-P is well tolerated and moderately active, even in heavily pretreated aPDAC pts. Further analyses are warranted, especially to identify the small proportion of pts who derive exceptionally prolonged benefit from nab-P monotherapy.

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

4076 Background: The dismal prognosis of gastric cancer prompts for the identification of factors predictive of survival/response to treatment. The potential prognostic value of 11 molecular markers was investigated in a retrospective series of 208 resected gastric cancers. Methods: Molecular/clinicopathological data were correlated to cancer-specific/overall survival (CSS/OS) using a Cox model. Molecular data were: microsatellite instability, CDX2, APC, ß-catenin, E-Cadherin, FHIT, P53, p21, HER-2 (IHC/FISH), TOPO2A amplification (FISH) e PIK3CA mutation (exons 9/20). ROC analysis provided optimal cut-offs and model validation. A logistic equation with regression analysis coefficients was constructed to estimate individual patients’ probability (IPP) of death. Internal cross-validation (100 simulations, 80% of the dataset) was accomplished. Multivariate model Ratios served to derive a prognostic continuous score to identify risk classes. Results: 208 patients were studied (median follow-up 16 months, range 1-155). Multivariate analysis selected 8 independent CSS predictors: sex (HR 1.53, p=0.04), stage (HR 5.40, p