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IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy.We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis.Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile.We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652).BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

Biliary tract cancer’s (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians’ confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8–9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0–51.5). A substantial heterogeneity across hospitals was found (I2: 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital’s risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.

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Purpose:After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342].Patients and Methods:This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate.Results:A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P < 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041).Conclusions:The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice.

Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

Background: Gemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population. Methods: We collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05). Conclusion: Gem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.

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.

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma.

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.

Objectives Although gastric cancer (GC) incidence rises with age, older patients are poorly represented in clinical trials, whose results are therefore difficult to translate into standard management of older patients. Purpose of this study was to compare clinico-pathological features and survival outcomes between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Materials and Methods Clinico-pathological characteristics, basal values, and treatment data of older (≥70 years at second-line start) and non-older patients were compared using chi-square test or 2-tailed Fisher exact test. The Kaplan-Meier estimation was used to calculate progression-free survival (PFS) and overall survival (OS), which were examined by log-rank test. Results Older patients represented 31.8% of the population (N = 868). Intestinal type was more frequent in older patients (P = .02). Poorly differentiated tumours were more often observed in non-older patients (P = .009). At stage IV diagnosis, the rate of liver metastases was higher in older patients (P = .02), while peritoneal spread was more represented in non-older patients (P = .002). Although older patients were more often treated with monotherapy (P = .001), they had similar PFS (HR 0.86, 95%CI 0.71–1.03, P = .102) and OS (HR 0.82, 95%CI 0.65–1.02, P = .08) compared to the non-older counterpart. No statistical differences were observed in treatment-related adverse events, hospital admissions, or further treatment lines between age groups. Conclusion In our large cohort study, despite some differences in tumour characteristics and treatment intensity, no survival difference was found between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Incidence of adverse events was similar between age groups.

Andrea Casadei-Gardini,1 Francesco Montagnani,2 Chiara Casadei,1 Francesca Arcadipane,3 Kalliopi Andrikou,4 Deborah Aloi,5 Alessandra Anna Prete,6,7 Maria Giulia Zampino,8 Antonella Argentiero,9 Giuseppe Pugliese,4 Stefania Martini,10 Giuseppe Carlo Iorio,10 Mario Scartozzi,11 Massimiliano Mistrangelo,12 Lorenzo Fornaro,13 Paola Cassoni,14 Giorgia Marisi,15 Veronica Dell’Acqua,16 Paola Simona Ravenda,8 Sara Lonardi,6 Nicola Silvestris,7 Berardino De Bari,5 Umberto Ricardi,3 Stefano Cascinu,4 Pierfrancesco Franco91Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Oncology Department, SOC Oncology, ASL (Health Local Authority), Biella, Italy; 3Department of Oncology, Radiation Oncology, AOU Città della Salute e della Scienza, Turin, Italy; 4Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy; 5Radiation Oncology Department, Centre Hospitalier Régional Universitaire “Jean Minjoz”, Besançon Cedex, France; 6Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; 7Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I University Hospital, Rome, Italy; 8Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; 9Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy; 10Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy; 11Department of Medical Oncology, University of Cagliari, Cagliari, Italy; 12Department of Surgical Sciences, University of Turin, Turin, Italy; 13Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana University, Pisa, Italy; 14Department of Medical Sciences, Pathology Unit, University of Turin, Turin, Italy; 15Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy; 16Department of Radiotherapy, IRCCS, European Institute of Oncology, Milan, ItalyBackground: In anal cancer, there are no markers nor other laboratory indexes that can predict prognosis and guide clinical practice for patients treated with concurrent chemoradiation. In this study, we retrospectively investigated the influence of immune inflammation indicators on treatment outcome of anal cancer patients undergoing concurrent chemoradiotherapy.Methods: All patients had a histologically proven diagnosis of squamous cell carcinoma of the anal canal/margin treated with chemoradiotherapy according to the Nigro’s regimen. Impact on prognosis of pre-treatment systemic index of inflammation (SII) (platelet x neutrophil/lymphocyte), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were analyzed.Results: A total of 161 consecutive patients were available for the analysis. Response to treatment was the single most important factor for progression-free survival (PFS) and overall survival (OS). At univariate analysis, higher SII level was significantly correlated to lower PFS (p

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.

Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by χ2-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (p = 0.44) and overall survival (OS) (p = 0.88). However, sarcopenia influences the development of high-grade neutropenia (p = 0.048) and mucositis (p = 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (p = 0.02) and outcome (PFS, p = 0.001, OS, p = 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (p = 0.03) and a neutrophil–lymphocyte ratio &gt, 3. The same factors remain significant for OS (each p = 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008) and number of metastatic sites ≥2 (p &lt, 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia.

Simple Summary Management of gastric and gastroesophageal junction (GEJ) adenocarcinoma remains challenging, because of the heterogeneity in tumor biology within the upper gastrointestinal tract. This manuscript is the product of a formal consensus process conducted in three Delphi rounds and a consensus meeting by the GAIN (GAstric cancer Italian Network) group. The goal of this document is to present a synthesis of available evidence and, where this is lacking, to provide expert opinion directed at prevention, diagnosis, and proper management of gastric and GEJ adenocarcinoma, and in particular aspects of practical management not fully supported by guidelines. Abstract Background: Management of gastric and gastroesophageal junction (GEJ) adenocarcinoma remains challenging, because of the heterogeneity in tumor biology within the upper gastrointestinal tract. Daily clinical practice is full of grey areas regarding the complexity of diagnostic, staging, and therapeutic procedures. The aim of this paper is to provide a guide for clinicians facing challenging situations in routine practice, taking a multidisciplinary consensus approach based on available literature. Methods: The GAIN (GAstric cancer Italian Network) group was established with the aims of reviewing literature evidence, discussing key issues in prevention, diagnosis, and management of gastric and GEJ adenocarcinoma, and offering a summary of statements. A Delphi consensus method was used to obtain opinions from the expert panel of specialists. Results: Forty-nine clinical questions were identified in six areas of interest: role of multidisciplinary team; risk factors; diagnosis; management of early gastric cancer and multimodal approach to localized gastric cancer; treatment of elderly patients with locally advanced resectable disease; and treatment of locally advanced and metastatic cancer. Conclusions: The statements presented may guide clinicians in practical management of this disease.

e16068 Background: The FLOT4-AIO phase II/III trial established perioperative FLOT regimen as the new standard in Western countries for patients (pts) with locally advanced resectable gastric (GC) or gastroesophageal junction cancer (GEJC). Microsatellite instability (MSI-H) showed a favorable prognostic role and a concomitant negative predictive impact on the benefit of adjuvant and neoadjuvant 5-fluorouracil-based doublets, but its prognostic and predictive role in pts receiving perioperative FLOT treatment still remains unclear. Our study aims to explore the real-world efficacy of FLOT regimen and to describe histopathological features and clinical outcomes in the MSI-H subgroup population. Methods: This is a retrospective multi-center analysis including pts with GC and GEJC, treated with perioperative FLOT regimen in clinical practice and whose microsatellite status and survival data were available. The association of baseline characteristics, biomolecular and pathological features and overall survival (OS) were firstly assessed in univariate analyses by means of log-rank test, and significantly prognostic variables (p < .05) were included in a multivariable COX proportional hazard model. Results: A total of 250 pts (median age, 62, range 37-81, male 71.6%, ECOG PS 0, 82%) were treated at 11 Italian Oncology Units from January 2017 to June 2021. At a median follow-up time of 22.5 months (mos) (2.3 - 66.7 mos), 123/250 (49.2%) patients relapsed and 77/250 (30.8 %) died. In the global population the median disease-free survival (DFS) was 16,7 mos (95% CI 13,8–21,2) and the median OS 34,9 mos [95% confidence interval (CI) 28–NA]. MSI-H phenotype was found in 26 (10.4%) out of 250 analyzed tumors. Compared to MSS cases, MSI-H were more frequently identified in female (50% vs 25.9%, p = .001), elderly pts (age ≥ 70 years, 76.9% vs 9.4%, p = .003), Laurens’s intestinal type (54% vs 12%, p = .0076) and in pts with primary location tumor in antrum (38.5% vs 13.8%, p = .0004). No relevant differences have been noticed in R0 resections (88% and 96%, p = .06) and pathological complete responses (4.9 % and 3.8%, p = .718), however a statistically significant difference in the rate of pathological negative lymph-nodes between MSS and MSI-H cohort emerged (29.3% vs 65.4%, p = .0004). Compared to MSS tumor population, MSI-H subgroup has a tendency to better DFS (median not reached (NR) vs 15.7, p = .06), metastasis free survival (MFS, median NR vs 17.2 mos, p = .06) and OS (median 41 vs 34 mos, p = .07). Conclusions: These real-world data confirm the efficacy of FLOT perioperative regimen in pts with locally advanced GC/GEJC, maintained also in the MSI-H pts. Our study suggests a better outcome of MSI-H GC and GECJ pts treated with FLOT in comparison to MSS, due to increased rate of nodal status downstaging and despite a poor histological response in the resected tumor tissue of MSI-H pts.

Background: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. Methods: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. Results: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p

Background and Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications. Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics. Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32–0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52–0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26–0.73, p = 0.0016). Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.

Advanced biliary tract cancer (aBTC) comprises a heterogeneous group of rare malignancies with dismal prognosis. Given the scarcity of prospective evidence, the aim of this study was to derive clinically useful insights and prognostic factors from a large, real-world series of aBTC. Clinicopathologic variables and treatment outcomes were retrospectively collected involving 940 patients diagnosed with aBTC between 2001 and 2017, and treated with first-line chemotherapy (CT1) at 14 Italian medical oncology institutions. Median overall survival (OS) was 10.3 months (CI95% 9.5-11.1). CT1 with gemcitabine-Platinum salts doublets achieved OS of 11.7 months vs 7.5 with gemcitabine alone (HR 0.67, p < 0.001). However, a clear temporal trend towards improved OS could not be demonstrated. Radical surgery of recurrent disease achieved a relapse-free survival of 5.9 months. A substantial minority (44.5%) of patients were able to receive a second-line chemotherapy, which achieved a response rate of 7.6%, and disease control in 30% of patients with no significant differences between combination regimens and monotherapies. In a large retrospective series of real-world aBTC, outcomes of standard CT1 closely resembled those of the registrational trials. A limited set of easily retrievable independent prognostic factors was defined. Further research is needed on second-line regimens.

Simple Summary The status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients. Abstract In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Background and Aim: The aim of the present study is to evaluate a new index (PECS (PsECogSii)index) influenced by PS ECOG and systemic immune-inflammation index (SII) in unresectable locally advanced or metastatic BTC patients treated with first-line chemotherapy. Methods: This multicenter, international, study was conducted on a training cohort of 130 patients and in three European and Korean validation cohorts The PECS index was calculated as ECOG × SII index (neutrophil count × platelet count/lymphocyte count). Event-time distributions were estimated using the Kaplan–Meier method and survival curves were compared using the log-rank test. Results: In the training cohort, the median overall survival (mOS) was 13.2months, 8.7months, and 3.8months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR=1; PECS-1: HR 1.41; PECS-2: HR 3.23) (p&nbsp

Background In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). Methods Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. Results 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). Conclusion In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. Trial registration ClinicalTrials.gov, NCT02370498

Introduction : Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. Area covered In the last years a growing interest in BTCs pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory in order to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations which may have an interesting clinical application in the next future. Expert opinion In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.

Background Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. Methods RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. Results Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3–4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. Conclusions These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.

Background Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. Patients and methods Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. Results In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month.

The optimal management of gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma (GEJC) remains a critical challenge for medical oncologists. Indeed, this is a relevant burden since GC still stands fifth among the most common tumors and is the third leading cause of cancer-related death worldwide (1).