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Background HER2 overexpression has been investigated as a potential biomarker and therapeutic target in biliary tract cancer (BTC), but a prognostic role of such alteration has not been demonstrated yet. Materials and Methods We retrospectively evaluated HER2 protein expression by immunohistochemistry (IHC) in 100 patients with radically resected BTC. HER2 gene amplification was assessed by fluorescence in situ hybridization (FISH) in 2+ and 3+ cases at IHC. High HER2 protein expression was defined as either IHC 3+ or 2+ associated with FISH positivity. The primary objective of the study was to evaluate the prognostic role of HER2 overexpression in terms of disease-free survival (DFS) and overall survival (OS). Secondary endpoints were the prevalence of HER2 overexpression and the possible correlation with other clinicopathological features. Results HER2 overexpression was identified in 11 patients and was not related to other clinicopathological factors. DFS was significantly shorter in HER2-positive compared with HER2-negative patients (10.6 vs. 20.9 months, log-rank p = .017). HER2 confirmed its prognostic value for DFS at multivariate analysis (hazard ratio 2.512; 95% confidence interval, 1.232–5.125; p = .011) together with nodal stage (p < .001), resection margin (p = .027), and tumor site (p = .030). There was no difference in OS between HER2-positive and -negative patients (p = .068). Conclusion HER2 overexpression represents an independent prognostic factor for disease recurrence in patients with BTC treated with potentially curative surgery.

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

Background Neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) does not achieve effective control of distant metastases. Induction chemotherapy is a promising strategy, and bevacizumab (BV) could improve the results of CRT. 5-Fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) plus BV is a treatment option in metastatic colorectal cancer. We evaluate feasibility and efficacy of neoadjuvant treatment comprising induction FOLFOXIRI plus BV followed by CRT with fluoropyrimidines plus BV. Methods In this phase II single-arm trial, patients node-positive or clinical T4 or high-risk T3 LARC underwent 6 cycles of induction FOLFOXIRI plus BV, followed by CRT (50.4 Gy plus concomitant capecitabine) and BV (5 mg/kg on days 1, 15 and 28). Surgery was planned 8 weeks after completion of CRT. Primary end-point was 2-year disease-free survival (DFS). Results We enrolled 49 patients: All but one (withdrewing consent after enrolment) were included in the per-protocol analyses. The study met its primary end-point: 36 patients were free of recurrence at 2 years (2-y DFS: 80.45%, 95% confidence interval [CI]: 78.79–82.10). Forty-four patients underwent surgery; pathologic complete response rate was 36.4%. Forty-six patients completed induction: neutropenia (41.6%) and diarrhoea (12.5%) were main G3/4 toxicities. Forty-five patients received CRT, but the protocol was amended and the capecitabine schedule during CRT was slightly modified after 13 patients due to the incidence of G3 hand-foot syndrome and proctitis (23.1%). After amendment, no severe events during CRT were reported. Conclusions FOLFOXIRI plus BV followed by CRT plus BV is feasible and active. Results in terms of DFS suggest that this strategy may improve distant disease control in LARC.

International audience; BACKGROUND:FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) is an option for fit patients with metastatic (MPC) and locally advanced unresectable (LAPC) pancreatic cancer. However, no criteria reliably identify patients with better outcomes.PATIENTS AND METHODS:We investigated putative prognostic factors among 137 MPC/LAPC patients treated with triplet chemotherapy. Association with 6-month survival status (primary endpoint) was assessed by multivariate logistic regression models. A nomogram predicting the risk of death at 6 months was built by assigning a numeric score to each identified variable, weighted on its level of association with survival. External validation was performed in an independent data set of 206 patients. The study was registered at ClinicalTrials.gov (NCT03590275).RESULTS:Four variables (performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio) were found to be associated with 6-month survival by multivariate analysis or had sufficient clinical plausibility to be included in the nomogram. Accuracy was confirmed in the validation cohort (C index = 0.762; 95% confidence interval, 0.713-0.825). After grouping all cases, 4 subsets with different outcomes were identified by 0, 1, 2, or > 2 poor prognostic features (P < .0001).CONCLUSION:The nomogram we constructed accurately predicts the risk of death in the first 6 months after initiation of FOLFIRINOX in MPC/LAPC patients. This tool could be useful to guide communication about prognosis, and to inform the design and interpretation of clinical trials.

Circulating tumor DNA, circulating tumor cells and tumor-related exosomes may offer new opportunities to provide insights into the biological and clinical characteristics of a neoplastic disease. They represent alternative routes for diagnostic and prognostic purposes, and for predicting and longitudinally monitoring response to treatment and disease progression. Hence, circulating biomarkers represent promising noninvasive tools in the scenario of pancreatic cancer, where neither molecular nor clinical predictors of treatment benefit have been identified yet. This review aims to provide an overview of the current status of circulating biomarker research in pancreatic cancer, and discusses their potential clinical utility to facilitate clinical decision-making.

FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p

Epigenetic mechanisms are involved in gastrointestinal (GI) cancer pathogenesis. Insights into the molecular basis of GI carcinogenesis led to the identification of different epigenetic pathways and signatures that may play a role as therapeutic targets in metastatic colorectal cancer (mCRC) and non-colorectal GI tumors. Among these alterations, O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation is the most investigated biomarker and seems to be an early and frequent event, at least in CRC. Loss of expression of MGMT as a result of gene promoter methylation has been associated with interesting activity of alkylating agents in mCRC. However, the optimal methods for the definition of the MGMT status and additional predictive factors beyond MGMT in GI malignancies are lacking. Here we review the current role of MGMT methylation and other epigenetic alterations as potential treatment targets in GI tumors.

Introduction: Basal cell carcinoma (BCC) is the most common skin cancer. Treatment options for metastatic or locally advanced BCC inappropriate for surgery or radiotherapy were poor until vismodegib was approved for use in this setting. This drug can be safely used in patients with mild to moderate renal impairment, but limited data are available for its use in case of severe kidney failure. We present the case of a patient with severe renal failure on hemodialysis treated with vismodegib. Case description: An 83-year-old patient with relapsing BCC of both auricles and severe renal failure on hemodialysis was treated with vismodegib for 7 months. The treatment proved to be effective with a striking reduction of the tumor masses. The patient was on therapy with vismodegib for 7 months and no severe adverse event was observed. Conclusion: Vismodegib could be used in patients with severe renal impairment, but these patients must be attentively followed and strict cooperation among healthcare professionals, such as nephrologists, dermatologists, and medical oncologists, is required.

Purpose The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. Methods Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. Results EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). Conclusions EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.

Aim: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. Patients & methods: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. Results: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p 0.05). Conclusion: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.

Supportive care in oncology is a primary need for every oncology department nowadays. In 2012, in our institution, a dedicated supportive care service (SCS) was created in order to deal with any need our on-treatment patients might have (e.g. tumour-related or treatment-related symptoms). We hypothesized that this service had a positive impact on the number of unplanned hospitalizations; to confirm our hypothesis, we decided to review admission data in 2011 and 2012. Using our internal software, we compared admission data in 2011 (that is, the year before the dedicated service was created) and 2012 (when such service began, that is April of that year). We also made an evaluation of the costs of these hospitalizations. Despite an increase of the number of patients treated in our day hospital (+6.5 %), the number of unplanned hospital admissions decreased by 3.2 % (from 17.3 to 14.1 %). The number of patients accessing to emergency room went from 66 to 61 % (a reduction of 5 %). The costs of these hospitalizations were reduced by 2.2 %. The introduction of the dedicated SCS in our oncology department caused a net reduction by 3.2 % of the number of unplanned hospitalizations of on-treatment cancer patients.

Background: FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. Material & methods: We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. Results: Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1–2.9 months) and median overall survival was 6.2 months (95% CI: 5.3–7.1 months). At multivariate analysis, CA19.9 level ≥59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12–4.78; p = 0.023). Conclusion: Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.

Purpose: The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. Methods: We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. Conclusions: Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.

Background After progression to a standard first-line platinum and gemcitabine combination (GP), there is no established second-line therapy for patients with advanced biliary tract cancers (aBTC). Indeed, literature data suggest limited activity of most second-line agents evaluated so far. Methods We collected a large retrospective series of aBTC patients treated with second-line chemotherapy after progression to a first-line GP regimen at different Italian institutions. We then pooled the data with those reported in previous studies, which were identified with a Medline search and the on-line abstract datasets of major international oncology meetings. Results A total of 174 patients were included in the multicenter survey: response rate (RR) with second-line chemotherapy was low (3.4 %), with median PFS and OS of 3.0 months and 6.6 months, respectively. At multivariate analysis, preserved performance status, low CA19.9 levels and absence of distant metastases were favorable prognostic factors. Data from other five presented or published series were identified, for a total of 499 patients included in the pooled analysis. The results confirmed marginal activity of second-line chemotherapy (RR: 10.2 %), with limited efficacy in unselected patient populations (median PFS: 3.1 months; median OS: 6.3 months). Conclusions The current analysis highlights the limited value of second-line chemotherapy after a first-line GP combination in aBTC. While waiting for effective biologic agents in this setting, ongoing randomized trials will identify the optimal second-line chemotherapy regimen and validate prognostic factors for individual patient management.

e24128Background: Pancreatic ductal adenocarcinoma (PDAC) is considered a poorly immunogenic tumor and treatment with immune checkpoint inhibitors lacks efficacy in this disease. Recently, the use ...

394 Background: FOLFIRINOX achieved a significant step forward in the treatment of mPC. However, patient prognosis remains dismal, and better discrimination of outcomes could be useful to guide clinical decision-making and patient stratification. We aimed at developing and validating a prognostic model and nomogram able to predict the risk of early death (within 6 months post-treatment initiation) in mPC pts treated with first-line FOLFIRINOX. Methods: Data from 137 mPC treated with the GONO FOLFOXIRI schedule at a single institution were used as developing set. Univariate associations with death in the first 6 months after treatment initiation were investigated. Based on the multivariate model, a nomogram was developed assigning points equal to its weighted relevance to each significant variable. The nomogram was externally validated on an independent, parallel cohort of 206 mPC pts treated with FOLFIRINOX at different Italian and French centers. Predictive ability was assessed with the concordance index (C-index) and visual inspection of the calibration plot. Results: 4 out of the 27 considered variables were retained in the multivariable model: ECOG performance status (PS), neutrophils-to-lymphocytes ratio (NLR), liver metastases, and basal serum CA19.9. The nomogram demonstrated adequate discriminative ability in the validation set with a C-index of 0.754. When grouped in different prognostic categories (according to none, 1, 2, or > 2 risk factors), pts included in our study showed significantly different outcomes with median OS ranging from 6.2 ( > 2 risk factors) to 19.5 months (no risk factors, P < 0.05). Conclusions: PS, NLR, liver metastasis, and CA19.9 were the major determinants of 6-month OS. Our nomogram may help clinicians in discussing with pts the benefits and risks of therapy, and in designing future clinical trials. A visual format of the nomogram will be presented. [Table: see text]

e15754 Background: Elevated pre-treatment NLR is a well-known poor prognostic factor in several tumours, including aPC. However, the role of NLR changes during first-line chemotherapy is less investigated. Methods: We retrospectively evaluated aPC patients (pts) treated with FOLFOXIRI (infusional 5-fluorouracil, oxaliplatin, irinotecan). NLR was calculated before the first (NLR-0) and the fourth (NLR-3) cycle, high NLR being defined as > 4. We evaluated the correlation between NLR change and overall survival (OS), progression-free survival (PFS), response rate (RR) and disease-control-rate (DCR). Survival curves were estimated using the Kaplan-Meier method. Log-rank and chi-square tests were applied. Multivariate analysis was performed by Cox proportional hazards model. Results: Ninety-four pts were evaluable. Median age was 62 years; at diagnosis, 38 (40.4%) pts had unresectable stage III and 56 (59.6%) had stage IV disease. In the overall population, median PFS (mPFS) and OS (mOS) were 8.0 and 12.9 months, respectively. NLR-0 was significantly associated with poor prognosis: among the 12 pts with NLR-0 > 4 mOS was 5.1 months compared with 13.5 months for the 82 pts with NLR-0 ≤4 (p < 0.001). As regards NLR dynamics, NLR-3 remained high or was increased (H/I) in 5 pts (5.3%) while was stably low or decreased (L/D) in 89 pts (94.7%). mOS was 5.1 months (95%CI 0.4-9.8) in H/I and 13.5 months (95%CI 10.9-16.1) in L/D (p < 0.001) pts. The same association was found for PFS, with 4.7 (95%CI 2.1-7.3) vs 8.3 months (95%CI 6.2-10.4, p = 0.004), respectively, but not for RR and DCR. At multivariate analysis, NLR change was confirmed as independent predictor of OS (HR 6.854, 95%CI 2.109-22.269, p = 0.001) and, when added to performance status, liver metastases and NLR-0, allowed a better risk stratification in good (no negative factors), intermediate (1-2 factors) and poor (3-4 factors) risk groups, with mOS of 18.0, 10.0 and 5.1 months, respectively (p = 0.012). Conclusions: Not only NLR-0, but also changes after 3 cycles of first-line FOLFOXIRI could predict OS in aPC pts. Early variations in NLR might be a cheap, reproducible and useful factor to predict prognosis and to better refine treatment strategy.

e15719 Background: After the intensification of first-line treatment in metastatic PC the number of patients fit and able to receive a SL treatment is increasing; despite these results, the choice of SL chemotherapy remains a challenging issue. The role of OXA in SL setting has given conflicting results in CONKO-003 and PANCREOX trials; the reasons of this inconsistency are difficult to understand. Methods: In order to detect a possible advantage from the use of oxaliplatin in SL, we pooled together the results of randomized phase II/III studies adding OXA to fluoropyrimidines after a gemcitabine-based first-line. Hazard ratios (HRs) for progression-free (PFS) and overall survival (OS) with 95% confidence intervals (CIs) were extracted, while the number of events was used for RR to determine odds ratio (OR) with corresponding 95%CIs. Fixed-effect and random-effect models were used as appropriate, on the basis of the evidence of a non-significant or significant heterogeneity among trials, respectively. The Review Manager software was used (version 5.3). Results: Three studies were identified; main characteristics and results are summarized in the table. No benefit in overall survival derived from the use of OXA (HR 1.03, 95% CI, 0.64-1.67; p=0.90) but significant heterogeneity was reported (p=0.003); the addition of OXA produced a significant benefit in terms of PFS (HR 0.81, 95% CI 0.68-0.97; p=0.02) with a higher chance of response (OR 1.81, 95% CI 1.01-3.24; P=0.05). Interestingly heterogeneity between trials was less evident in PFS and RR than in OS suggesting that this could be a confounding element in the interpretation of data. Conclusions: The reasons of conflicting results concerning the use of oxaliplatin doublets in SL setting are not clear. Given the recent advances in first-line setting, it would be interesting to identify an optimal sequential strategy, hopefully in a personalized approach. [Table: see text]

e15777 Background: FOLFIRINOX is a reasonable option in LAPC. GONO FOLFOXIRI has been shown to provide similar efficacy in advanced disease. ETS and DoR, emerging as relevant endpoints in colorectal cancer, have been rarely investigated in LAPC. Methods: Unresectable LAPC pts treated with FOLFOXIRI were identified. Computed tomography (CT) scan was performed every 8 weeks; after that, multidisciplinary team assessed resectability. ETS was defined as the reduction of ≥20% of target lesions’ diameters at first evaluation. DoR was the % of maximal tumor shrinkage at the nadir compared to baseline. Primary endpoint was the correlation of ETS and DoR with radical (R0) resection. Secondary endpoints were correlation of ETS and DoR with overall survival (OS) and progression-free survival (PFS). Radiologist was blinded to survival data. Survival curves were estimated using the Kaplan-Meier method. Log-rank and chi-square tests were applied. Results: Sixty pts were included. Median age was 62 years (range: 34-74), tumor location was head in 68% and body-tail in 32%. At a median follow-up of 26.9 months, response rate was 37%, median OS and PFS were 15.7 and 10.3 months, respectively. Thirty patients (50%) underwent R0 surgery after chemotherapy. Two pts died due to early surgical complication and were censored at the date of surgery for survival analyses. Among 55 evaluable pts, ETS was reached in 19 pts and median DoR was -17% (range: -65 to +100). A strong association between ETS (p = 0.0002) and DoR (p < 0.0001) with R0 resection was observed. In the overall population, ETS was significantly associated with better PFS (14.5 vs 9.4 months, p = 0.037), while no difference in OS was shown (p = 0.63). DoR was significantly associated both with PFS (13.6 vs 7.8 months, p = 0.014) and OS (19.8 vs 14.5 months, p = 0.047). Conclusions: FOLFOXIRI may allow achieving resectability in selected pts. ETS and DoR are significantly associated with R0 resection. Maximizing response with active regimens could be an effective strategy in LAPC. Further validation of ETS and DoR as surrogate endpoints in larger prospective series is required.

Despite advances in the management of patients with locally advanced, non-metastatic rectal adenocarcinoma (LARC), prognosis remains largely unsatisfactory due to a high rate of distant relapse. In fact, currently available neoadjuvant protocols, represented by fluoropyrimidine-based chemo-radiotherapy (CT-RT) or short-course RT, together with improved surgical techniques, have largely reduced the risk of local relapse, with limited impact on distant recurrence. Available results of phase III trials with additional cytotoxic agents combined with standard CT-RT are disappointing, as no significant reduction in the risk of recurrence has been demonstrated. In order to improve the control of micrometastatic disease, integrating targeted agents into neoadjuvant treatment protocols thus offers a rational approach. In particular, the antiangiogenic agent bevacizumab has demonstrated synergistic activity with both CT and RT in pre-clinical and clinical models, and thus may represent a suitable companion in the neoadjuvant treatment of LARC. Preliminary results of phase I-II clinical studies are promising and suggest potential clinical parameters and molecular predictive biomarkers useful for patient selection: treatment personalization is indeed the key in order to maximize the benefit while reducing the risk of more complex neoadjuvant treatment schedules.

ABSTRACT Prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor and is largely influenced by associated liver comorbidities. Moreover, effective treatment alternatives are limited; with the exception of the multitargeted inhibitor sorafenib, established options in the treatment of advanced HCC no longer amenable with ablative or locoregional procedures are lacking. In light of the limited efficacy of chemotherapy in this setting, great efforts have been made in the definition of targetable molecular pathways with a central role in the progression of HCC. Targeting angiogenesis, growth factor receptors, intracellular transduction pathways, or mechanisms of gene-expression regulation represents the main way to improve patient outcome. At the same time, identifying clinical and biological factors, which may help selecting patients with higher chances of benefit, is essential in order to hasten drug development and maximize treatment efficacy.

4124Background: There is no standard of care for 2L T in APDAC. Nab-P + G combination has showed superior efficacy compared to G alone in MPACT phase III study. Here we report data of a retrospecti...

673 Background: Induction chemotherapy (CT) is a promising option in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. Methods: Patients (pts) with LARC at < 12 cm from the anal verge, N+ or cT4 or high risk cT3 (MRI criteria) underwent 6 cycles of FOLFOXIRI + BV followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 800 mg/m2/bid 5 days/week + BV 5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint is 2-year disease-free survival (DFS). Results: From April 2012 to April 2015 48 pts were enrolled. At now, 46 pts completed induction CT, 43 completed CRT and 39 underwent surgery (5 pts ongoing). Pts characteristics were: median age, 53 years (range 30-74); cT2/cT3/cT4, 4%/60%/36%; cN0/N+, 4%/96%. Main grade (G) 3/4 toxicities during induction were neutropenia (42%), febrile neutropenia (4.2%), diarrhea (12.5. Two pts did not complete induction: one died due to bowel perforation and sepsis and one discontinued CT after acute kidney injury. Response rate (RR) after induction was 77%. Forty-five pts started CRT (1 pts underwent surgery after induction because of SAE). After the first 13 patients, protocol was amended and schedule of capecitabine modified due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%). After amendment all pts completed CRT with acceptable toxicity: G3 proctitis 6.7% and proctalgia 3.3%. One pts died due to early progressive disease (PD) after CRT. RR after CRT was 88%. Surgery was low anterior resection 87%, abdomino-perineal resection 8%, other 5%. Radical resection was achieved in 95% of pts. Early post-surgical complication rate was 31%. Pathologic complete response was reached in 33% and pathological downstaging in 44% of pts. At a median follow up of 17 months, 8 pts had PD and estimated 2y-DFS is 72%. Conclusions: Induction CT with FOLFOXIRI + BV is feasible and highly active. A protocol amendment was needed due to toxicities during CRT. The rate of early post-surgical complications is not negligible. A longer follow up is needed for DFS. Clinical trial information: 2011-003340-45.

The role of second-line treatments after first-line chemotherapy in metastatic gastric cancer is reinforcing. Two different options, chemotherapy and anti-VEGFR therapy, are available and confirmed efficacy in this setting. The combination of the two strategies as used in other cancers is promising and could become a new standard for second-line treatment of metastatic gastric cancer. The results of the RAINBOW trial, a phase III study evaluating ramucirumab in combination with paclitaxel versus paclitaxel alone, will add new information on this topic considering that the study met its primary end point of improved overall survival.

412 Background: Nab-P + G combination represents an optimal first line therapeutic option in APDAC. Actually we have no parameters to predict prognosis in pts receiving this regimen. Here we present data of a multicentre retrospective analysis evaluating prognostic impact of clinical or biological factors in a cohort of APDAC pts treated with Nab-P + G first line CT. Methods: Clinical records of 118 APDAC pts receiving first line Nab-P + G were retrospectively reviewed. Overall survival (OS) and progression free survival (PFS) were evaluated with Kaplan Meier method with 95% CI and curves were compared with log-rank test. Cox-regression model was applied to the data with univariate and multivariate approach. Variables included in analysis were age, gender, ECOG PS, primary tumor site, liver metastases, multiple metastatic sites, baseline CA19-9, bilirubin levels, neutrophil/lymphocyte ratio (NLR), CA19-9 decrease > 50%, biliary stent and symptomatic disease. Results: Median age was 66 (37 - 83), M/F:65/53, ECOG PS 0/1/2: 51/46/21 respectively. 4 complete and 27 partial responses were observed with 26% response rate (RR). Median OS and PFS were 11 months (95% CI 9.58 – 12.41) and 7 months ( 95% CI 5.96 – 8.03) respectively. When considered at univariate analysis primary tumor location to the head, ECOG PS of 2, bilirubin levels higher than median and NLR ≥ 5 had a bad prognostic impact both on PFS and OS. Differently, CA19-9 decrease > 50% was considered a positive prognostic factor for PFS and OS. Multivariate analysis confirmed the negative role of NLR ≥ 5 respect of PFS (HR 3.21; 95%CI 1.61 – 5.68, p = 0.002) and OS (HR 3.38; 95%CI 1.88 – 5.79, p = 0.001) and positive impact of CA19-9 decrease > 50% on PFS (HR 0.37; 95% CI 0.11 – 0.68, p=0.006) and OS (HR 0.53; 95% CI 0.15 – 0.97, p=0.005), as independent prognostic factors. Conclusions: This analysis suggest that in APDAC pts receiving first line Nab-P + G, high NLR value (≥5) could be considered an easy detectable, independent parameter to predict poor outcomes in terms of PFS and OS. Furthermore CA19-9 reduction > 50% from baseline may be, in absence of other clinical and molecular parameters, an early marker of good prognosis.

Aim: Nab-P and G combination represents a standard of care in APDAC first line therapy (CT) and it seems to be active and effective also in pretreated pts. Activity, efficacy and safety of Nab-P + G have not been established in elderly patients and clinical trials on APDAC treatment contain fewer elderly patients compared with everyday clinical practice. Aim of our retrospective analysis is to investigate outcomes and toxicities of elderly pts treated with Nab-P + G. Methods: 61 APDAC pts aged ≥65 receiving Nab-P 125 mg/m2 and G 1000 mg/m2 on days 1,8 and 15 of a 28 day cycle as first (39 pts, 64%) or further (22 pts, 36%) line of CT were included in our analysis for activity (Disease Control Rate, DCR: Stable Disease + Partial Response + Complete Response, SD + PR + CR), efficacy (Progression Free Survival, PFS and Overall Survival, OS) and safety. OS and PFS were estimated with Kaplan-Meyer method with 95% CI. Univariate and multivariate analysis were performed using Cox-regression model. Results: 61 pts, median age 69 (range 65-83; 48% pts ≥70 years) and ECOG Performance Status of 0/1/2: 24/26/11 respectively, were included in our analysis. 44 pts (72%) had liver metastases, 21 (34.4%) had multiple metastatic sites and biliary stent was present in 10 pts (16.4%). 14 SD, 9 PR (DCR: 59%) were observed in first line CT pts and 9 SD, 2 PR (DCR 50%) were recorded in pretreated pts. Median PFS was 6 months (mo) (95% CI 3.9-8.1) and 3.5 mo (95% CI 1.6-5.4) in first line and pretreated pts, with median OS of 9.5 (95% CI 7.3-11.7) and 6 mo (95% CI 4.2-7.8) in first line and pretreated pts respectively. Age ≥70 was not significantly associated to PFS and OS at univariate and multivariate analysis. Treatment was well tolerate with no G4 events, 15 (24.5%) G3 neutropenia, 6 (9.8%) G3 thrombocytopenia, 2 (3.2%) G3 anemia, 8 (13%) G3 fatigue, 4 (6.6%) G3 diarrhea and neurotoxicity. Dose reduction was needed in 18 (29.5%) pts. No significative differences in toxicity profile and dose reductions were observed in ≥70 years pts. Conclusions: These data show that APDAC elderly pts may benefit from Nab-P and G combination as well as younger population both in terms of responses and survival, in first line CT as well as further lines, experiencing a low toxicity profile. Disclosure: All authors have declared no conflicts of interest.

Aim: Trastuzumab is effective for the treatment of advanced gastric cancers with HER2 amplification. Beside HER2 amplification, several molecular targets are under evaluation in metastatic gastric tumors. We evaluated the role of HER2, EGFR, MET, AKT1 and phospho-mTOR expression in resected stage II-III adenocarcinomas. Methods: 92 patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated using immunohistochemistry. Antibodies anti- HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded tumors' slides. Using FISH, HER2 amplification was evaluated in cases with a 2+ staining. Results: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p = 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p = 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was mutually exclusive with that of EGFR and together defined a subgroup of tumors with a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p = 0.005). Conclusions: EGFR was confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers. Disclosure: All authors have declared no conflicts of interest.