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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.

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.

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 cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O

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Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x

Introduction: Breast cancer in men is less common than in women and treatment recommendations are often derived from clinical trials exclusively involving women. Data on efficacy of CDK 4/6 inhibitors, which are the mainstay of treatment for hormone receptor–positive/HER2-negative advanced breast cancer, are lacking in male patients. Case report: We present a clinical case of prolonged benefit from palbociclib in combination with letrozole and LHRH analogue in a man who had previously been treated with six lines of endocrine therapies and chemotherapy regimens but was still in excellent clinical condition. Conclusions: This clinical case demonstrates that male breast cancer stands out as an endocrine-sensitive disease, which could potentially benefit from CDK 4/6 inhibitors in combination with endocrine agents even in very heavily pretreated settings of disease, underscoring both the importance of an accurate selection of patients for later treatment lines, taking into account disease history and previous treatment responses, and the peculiarity of breast cancer in men, which deserves dedicated clinical trials to tailor future recommendations.

Exocrine pancreatic neoplasms represent up to 95% of pancreatic cancers (PCs) and are widely recognized among the most lethal solid cancers, with a very poor 5-year survival rate of 5%-10%. The remaining < 5% of PCs are neuroendocrine tumors that are usually characterized by a better prognosis, with a median overall survival of 3.6 years. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for roughly 85% of all exocrine PCs. However up to 10% of exocrine PCs have rare histotypes, which are still poorly understood. These subtypes can be distinguished from PDAC in terms of pathology, imaging, clinical presentation and prognosis. Additionally, due to their rarity, any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective analyses. Therefore, treatment strategies are generally deduced from those used for PDAC, even if these patients are often excluded or not clearly represented in clinical trials for PDAC. For these reasons, it is essential to collect as much information as possible on the management of PC, as assimilating it with PDAC may lead to the potential mistreatment of these patients. Here, we report the most significant literature regarding the epidemiology, typical presentation, possible treatment strategies, and prognosis of the most relevant histotypes among rare PCs.

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.

590 Background: Biliary Tract Cancers (BTC) have poor prognosis and limited therapeutic options. There is mounting evidence for biomarker-directed therapy for BTC, with several potentially actionable molecular targets reported in up to ~50% of patients and significant biological differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gallbladder cancer (GBC). ESMO and ASCO recommends the use of tumour multigene next generation sequencing (NGS) for CCA. Methods: This was a monocentric study assessing real-life clinical actionability of molecular alterations identified with expanded NGS for patients (pts) affected by advanced BTCs treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from January 2016 to July 2022. NGS was performed either via the “Hotspot Cancer Panel, Ion Torrent”, the “Oncomine Comprehensive Assay Plus” or the FoundationOne CDx panel; FGFR2 testing was also performed via fluorescence in situ hybridisation. Molecular alterations were classified according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with targeted treatments administered and efficacy endpoints. Benefit from targeted treatment was evaluated by means of progression-free survival (PFS) ratio, as defined as the ratio of each patient’s PFS2 (i.e. PFS on molecularly informed therapy) to the PFS1 (PFS on his/her most recent previous treatment), with d for efficacy equal to 1. Results: Out of 340 pts with adequate tissue for NGS, 231 (68%) were affected by ICC, 61 (32%) by ECC and 48 (14%) by GBC. Actionable alterations as per ESCAT I-III were found in 33 % of pts (N= 113, including IDH1 mutation, FGFR2 fusions/rearrangement/mutations, MSI-H, BRAFV600E mutations, ERBB2 mutations/amplifications, BRCA1/2 mutations); 88% of these alterations were found in pts with ICC. Targeted therapy was actually started for 48 pts (14 %), with 9 pts treated with ivosidenib, 32 with FGFR2 inhibitors, 2 with PD-L1 inhibitor, 6 with BRAF+MEK inhibitor and 1 with an HER2 inhibitor). Overall response rate and disease control rate were 18% and 62%, respectively.Median PFS was 5.4 months(95% CI 3.0 - 6.4) overall and 10.12 months on BRAF+MEK inhibitors, 5.55 months on FGFR2 inhibitors, 2.92 months on ivosidenib and 6.23 months on PD-L1 inhibitors. Median PFS ratio was 1.1 (95%CI 0.7 - 1.4), with benefit rate of 51%. Of note, 5 (10%) received targeted therapy as > III line. Median overall survival of targeted therapy was 10 months. Conclusions: Expanded sequencing for BTCs is feasible in real-life and can improve treatment strategy. Analysis of PFS ratio and of treatment outcomes shows clinically meaningful benefit of targeted treatment in pretreated patients.

Hospitalized cancer patients are at increased risk for Thromboembolic Events (TEs). As untailored thromboprophylaxis is associated with hemorrhagic complications, the definition of a risk-assessment model (RAM) in this population is needed. INDICATE was a prospective observational study enrolling hospitalized cancer patients, with the primary objective of assessing the Negative Predictive Value (NPV) for TEs during hospitalization and within 45 days from discharge of low-grade Khorana Score (KS = 0). Secondary objectives were to assess KS Positive Predictive Value (PPV), the impact of TEs on survival and the development of a new RAM. Assuming 7% of TEs in KS = 0 patients as unsatisfactory percentage and 3% of as satisfactory, 149 patients were needed to detect the favorable NPV with one-sided α = 0.10 and power = 0.80. Stepwise logistic regression was adopted to identify variables included in a new RAM. Among 535 enrolled patients, 153 (28.6%) had a KS = 0. The primary study objective was met: 29 (5.4%) TEs were diagnosed, with 7 (4.6%) cases in the KS = 0 group (NPV = 95.4%, 95% CI 90.8–98.1%; one-sided p = 0.084). However, the PPV was low (5.7%, 95% CI 1.9–12.8%); a new RAM based on albumin (OR 0.34, p = 0.003), log(LDH) (OR 1.89, p = 0.023) and presence of vascular compression (OR 5.32, p

Background: Hospitalized cancer patients are at increased risk for Thromboembolic Events (TEs). As untailored thromboprophylaxis is associated with hemorrhagic complications, the definition of a risk-assessment model (RAM) in this population is needed. Objectives: INDICATE was an observational study enrolling hospitalized cancer patients, with the primary objective of assessing the Negative Predictive Value (NPV) for TEs during hospitalization and within 45 days from discharge of low-grade Khorana Score (KS=0). Secondary objectives were to assess KS Positive Predictive Value (PPV), the impact of TEs on survival and the development of a new RAM. Materials and Methods: Assuming 7% of TEs in KS=0 patients as unsatisfactory percentage and 3% of as satisfactory, 149 patients were needed to detect the favorable NPV with one-sided a= 0.10 and power=0.80. Stepwise logistic regression was adopted to identify variables included in a new RAM.Results: Among 535 enrolled patients, 153 (28.6%) had a KS=0. The primary study objective was met: 29 (5.4%) TEs were diagnosed, with 7 (4.6%) cases in the KS=0 group (NPV=95.4%, 95%CI: 90.8-98.1%; one-sided p=0.084). However, the PPV was low (5.7%, 95%CI: 1.9-12.8%); a new RAM based on albumin (OR 0.34, p=0.003), log(LDH) (OR 1.89, p=0.023) and presence of vascular compression (OR 5.32, pConclusion: INDICATE showed that the KS has a good NPV but poor PPV for TEs in hospitalized cancer patients. A new RAM was developed, and deserves further assessment in external cohorts.

Aim: Data from 69 well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy + somatostatin analogs (SSAs) after SSA treatment failure were evaluated. Methods: We identified two groups: S1 – patients who kept the same SSA treatment beyond progression; S2 – patients who switched the SSA with another SSA after progression. Results: Median progression-free survival was 53 and 127 months in S1 and S2, respectively (p = 0.001; hazard ratio: 0.31; 95% CI: 0.15–0.63). Median overall survival was 69 versus 150 months in S1 and S2, respectively (p = 0.004; hazard ratio: 0.32; 95% CI: 0.14–0.71). Conclusion: In patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy plus SSA after SSA failure, the ‘switch’ strategy of SSA after progression improve progression-free survival and overall survival.

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.

Background Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a ‘switched maintenance’ regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. Patients and methods Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. Results In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2–38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8–5.6) vs 2.8 months (95% CI 1.9–4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3–4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches. The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes. Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy. This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.

e16179 Background: Biliary tract cancers (BTCs) are a group of rare tumors with a dismal prognosis and a complex molecular landscape. In this setting, the incidence and clinical relevance of cancer-associated thrombosis (CAT) is unknown, thus BTCs are not included in common thrombotic risk scores (e.g. Khorana Score). Moreover, retrospective studies highlighted associations between thromboembolic events and some genetic alterations, such as KRAS in lung and colorectal cancer, ALK/ROS1 in lung cancer and IDH1 mutations in glioma. Nevertheless, the impact of different genomic alterations on CAT risk in BTCs patients has never been investigated. The aim of this study was to investigate for the first time the incidence and the clinical relevance of CAT in a cohort of BTC patients. In addition, we investigated the association between tumor genomics and CAT in this patients’ population. Methods: Clinical and genomic data of consecutive BTC patients who underwent extensive molecular profiling with the FoundationOneCDx panel at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, were collected. The association between genomic alterations and CAT incidence was investigated with the Fisher exact test, considering alterations occurring in at least 5% of patients. Cox regression was used to analyze the impact of CAT, considered as a time-dependent covariate, on overall survival (OS). Results: 140 patients were included in the analysis, mostly represented by cases of intrahepatic cholangiocarcinoma (77%). CAT occurred in 18 (13%) patients, the majority being pulmonary embolism (28%) and visceral thrombosis (44%). Pathogenic KRAS and BRCA1 mutations were found in 33% and 11% of patients with CAT, resulting significantly associated with an increased risk of thrombosis ( p = 0.041 for both). Patients who experienced CAT showed a significantly poorer OS (HR 3.29, p = < 0.001). Conclusions: This is the first report describing a non-negligible incidence and significant prognostic impact of CAT in BTC patients. Future studies investigating the clinical and molecular risk factors for CAT in this population are needed to tailor thromboprophylaxis in this rare population.

Purpose: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor—positive (HR+), HER2-negative (HER2−), advanced breast cancer (HR+/HER2− aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2− aBC treated with everolimus-exemestane. Results: We evaluated 809 patients with HR+/HER2− aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15–2.69; P = 0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2− aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2− aBC.

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 The treatment of metastatic non–small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. Patients and methods NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. Results The median age of all the 30 patients was 58 years (25–80 years), most of them were females (73%); ECOG 0–1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6–6.7 months) and the mOS 9.5 months (95% CI: 5.3 – not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. Conclusions Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)).

BackgroundIn the midst of the COVID-19 pandemic, patients with cancer are regarded as a highly vulnerable population. Overall, those requiring hospital admission for treatment administration are potentially exposed to a higher risk of infection and worse outcome given the multiple in-hospital exposures and the treatment immunosuppressive effects.MethodsCOVINT is an observational study assessing COVID-19 incidence among patients receiving anticancer treatment in the outpatient clinic of the Istituto Nazionale dei Tumori di Milano. All consecutive patients with non-haematological malignancies treated with intravenous or subcutaneous/intramuscular anticancer therapy in the outpatient clinic were enrolled. The primary endpoint is the rate of occurrence of COVID-19. Secondary endpoints included the rate of COVID-19-related deaths and treatment interruptions. The association between clinical and biological characteristics and COVID-19 occurrence is also evaluated. COVID-19 diagnosis is defined as (1) certain if confirmed by reverse transcriptase PCR assay of nasopharyngeal swabs (NPS); (2) suspected in case of new symptoms or CT scan evidence of interstitial pneumonia with negative/not performed NPS; (3) negative in case of neither symptoms nor radiological evidence.ResultsIn the first 2 months (16 February–10 April 2020) of observation, 1081 patients were included. Of these, 11 (1%) were confirmed and 73 (6.7%) suspected for COVID-19. No significant differences in terms of cancer and treatment type emerged between the three subgroups. Prophylactic use of myeloid growth factors was adopted in 5.3%, 2.7% and 0% of COVID-19-free, COVID-19-suspected and COVID-19-confirmed patients (p=0.003). Overall, 96 (8.9%) patients delayed treatment as a precaution for the pandemic. Among the 11 confirmed cases, 6 (55%) died of COVID-19 complications, and anticancer treatment was restarted in only one.ConclusionsDuring the pandemic peak, accurate protective measures successfully resulted in low rates of COVID-19 diagnosis, although with high lethality. Prospective patients’ surveillance will continue with NPS and serology testing to provide a more comprehensive epidemiological picture, a biological insight on the impact of cytotoxic treatments on the immune response, and to protect patients and healthcare workers.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak poses a major challenge in the treatment decision-making of patients with cancer, who may be at higher risk of developing a severe and deadly SARS-CoV-2 infection compared with the general population. The health care emergency is forcing the reshaping of the daily assessment between risks and benefits expected from the administration of immune-suppressive and potentially toxic treatments. To guide our clinical decisions at the National Cancer Institute of Milan (Lombardy region, the epicenter of the outbreak in Italy), we formulated Coronavirus-adapted institutional recommendations for the systemic treatment of patients with gastrointestinal cancers. Here, we describe how our daily clinical practice has changed due to the pandemic outbreak, with the aim of providing useful suggestions for physicians that are facing the same challenges worldwide.

Background: In the midst of COVID-19 pandemic, cancer patients (pts) are regarded as a highly vulnerable population Pts requiring hospital admission for treatment (Tx) administration are potentially exposed to a higher risk of infection and worse outcome given the multiple in-hospital exposures and the Tx immunosuppressive effects Methods: COVINT is an observational study assessing COVID-19 incidence among pts receiving anticancer Tx in the outpatient clinic of the Istituto Nazionale dei Tumori di Milano All consecutive pts with non-hematologic malignancies treated with intravenous or subcutaneous/intramuscular Tx in the outpatient clinic were enrolled Pts were admitted to the clinic wearing surgical masks and only if asymptomatic and afebrile The primary endpoint is the rate of occurrence of COVID-19 Secondary endpoints include the rate of COVID-19 related deaths and Tx interruptions The association between clinical and biological characteristics and COVID-19 occurrence is also evaluated using nonparametric tests COVID-19 diagnosis is defined as: a) certain if confirmed by RT-PCR assay of nasopharyngeal swabs (NFS);b) suspected in case of new symptoms and/or CT scan evidence of interstitial pneumonia with negative/not performed NFS;c) negative in case of neither symptoms nor radiological evidence Results: In the first two months (16th February-10th April 2020) of observation, 1083 pts were included Of these, 11 (1%) were confirmed and 73 (6 7%) suspected for COVID-19 No significant differences in terms of cancer and Tx type emerged between the three subgroups Prophylactic use of myeloid growth factors was adopted in 5 3%, 2 7% and 0% of COVID-19-free, -suspected and -confirmed pts (p=0 003) Overall, 96 (8 9%) pts delayed Tx as a precaution for the pandemic Among the 11 confirmed cases, 6 (55%) died of COVID-19 complications, and anticancer Tx was restarted in only one Conclusions: During the pandemic peak, accurate protective measures successfully resulted in low rates of COVID-19 diagnosis, though with high lethality Within the COVINT study, prospective pts surveillance will continue with NFS swabs and IgG/IgM serology performed before each Tx cycle until pandemic resolution Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: F G M De Braud: Advisory/Consultancy: Tiziana Life Sciences;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene;Advisory/Consultancy, Research grant/Funding (institution): Novartis;Advisory/Consultancy: Servier;Advisory/Consultancy: Pharm Research Associated;Advisory/Consultancy: Daiichi Sankyo;Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta;Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer;Advisory/Consultancy: Octimet Oncology;Advisory/Consultancy, Research grant/Funding (institution): Incyte;Advisory/Consultancy: Pierre Fabre;Advisory/Consultancy: Eli Lilly;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche;Advisory/Consultancy: Astra Zeneca;Advisory/Consultancy: Gentili;Advisory/Consultancy, Speaker Bureau/Expert testimony: Dephaforum;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD;Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer;Advisory/Consultancy: Fondazione Menarini;Research grant/Funding (self): NMS;Research grant/Funding (institution): Merck KGAA;Research grant/Funding (institution): Kymab;Research grant/Funding (institution): Tesaro;Speaker Bureau/Expert testimony: Biotechespert Ltd;Speaker Bureau/Expert testimony: Prime Oncology All other authors have declared no conflicts of interest

Background:Neoadjuvant anthracycline-taxane-based chemotherapy (ChT) is a standard of care treatment option for stage II–III breast cancer (BC) patients. However, the optimal duration of neoadjuvant ChT has been poorly investigated so far.Material and methods:We retrospectively retrieved clinical data of patients with stage II–III human epidermal growth factor receptor 2-negative (HER2–) BC who were treated between October 2007 and January 2018 with neoadjuvant AT (doxorubicin-paclitaxel) for three cycles followed by CMF (cyclophosphamide-methotrexate-5-fluorouracil) for three cycles (cohort A) or with four AT cycles followed by four CMF cycles (cohort B). The aim of our study was to investigate the impact of neoadjuvant ChT duration (cohort A versus cohort B) on pathological complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS).Results:Of 209 HER2– BC patients included, 62 had triple-negative breast cancer (TNBC) and 147 had hormone receptor-positive (HR+) BC. Median age was 48 years (range 30–74 years). A total of 111 patients belonged to cohort A and 98 patients belonged to cohort B. pCR was detected in 29 (13.9%) patients, 25 (40.3%) of whom had TNBC and four (2.7%) had HR+ HER2– BC. Patients achieving pCR had significantly longer DFS and OS, with statistical significance reached only in patients with TNBC. We found no differences between cohort A and cohort B in terms of pCR rates (15.3% versus 12.2%; p = 0.55), DFS ( p = 0.49) or OS ( p = 0.94). The incidence of grade 3/4 adverse events was similar in cohort A versus cohort B as well (22.5% versus 19.4%; p = 0.54).Conclusion:Shorter duration of neoadjuvant anthracycline-taxane ChT was not associated with worse clinical outcomes in patients with stage II–III BC. Prospective studies are needed to evaluate whether the duration of neoadjuvant anthracycline-taxane-based ChT can be reduced in specific patient subgroups without negatively affecting clinical outcomes.

Background The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Conclusions Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.

Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.

Background: The mTORC1 inhibitor everolimus has been approved in combination with the aromatase inhibitor exemestane for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2&minus, ) metastatic breast cancer (HR+ mBC) progressing on prior therapy with a non-steroidal aromatase inhibitor. To date, no predictive biomarkers of tumor sensitivity/resistance for everolimus-based treatments have been identified. We hypothesized that precocious changes in the Standardized Uptake Volume (∆SUV%), as assessed by 18F-Fluorodeoxyglucosepositron-emission tomography (18F-FDG PET/CT), may be a marker of everolimus efficacy. Methods: This was a retrospective study including 31 HR+ HER2- patients treated with everolimus and exemestane in two Italian centers between 2013 and 2018. The objective of the study was to investigate ∆SUV% as a predictive marker of everolimus antitumor efficacy. 18F-FDG PET/CT scans were performed at baseline and after three months of treatment. Patients were defined as long responders (LRs) if disease progression occurred at least 10 months after treatment initiation and long survivors (LSs) if death occurred later than 36 months after starting therapy. ROC analysis was used to determine the optimal cut-off values of ∆SUV% to distinguish LRs from non-LRs and LSs from non-LSs. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan&ndash, Meier method. Results: The SUVmax values decreased significantly from baseline to 3 months after therapy (p = 0.003). Dynamic changes of SUVmax (Delta SUV) had a higher accuracy in discriminating long-responders from non-long-responders (AUC = 0.67, Delta SUV cut-off = 28.8%) respects to its ability to identify long survivors from no-long survivors (AUC = 0.60, Delta SUV cut-off = 53.8%). Patients were divided into groups according to the Delta SUV cut-offs and survival outcomes were evaluated: patients with a decrease of ∆SUV% &ge, 28.8% had significantly better PFS (10 months-PFS: 63.2%, 95% CI: 37.9&ndash, 80.4% and 16.7%, 95% CI: 2.7&ndash, 41.3% respectively, p = 0.005). As regard as OS, patients with ∆SUV% &ge, 53.8% had longer OS when compared to patients with ∆SUV% &lt, 53.8% (36 month-OS: 82.5% vs. 45.9% vs. p = 0.048). Conclusion: We found two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients, which would achieve long-term benefit or long-term survival during everolimus-exemestane therapy. These results warrant further validation in prospective studies and should be integrated with molecular biomarkers related to tumor metabolism and mTORC1 signaling.

Simple Summary Chronic inflammation is known to drive cancer initiation and progression in the liver and other organs. In different genetic mouse models, the role of the pro-inflammatory kinase Tak1 in liver cancer development has been controversial so far. To clarify the role of Tak1 in human hepatocellular carcinoma (HCC), we investigated the expression of Tak1 in a large and clinicopathologically well-characterized patient cohort with HCC. In human livers and HCCs, Tak1 is predominantly present in its isoform Tak1A localizing to the cell nucleus. Tak1 is upregulated in HCCs of the diethylnitrosamine mouse model as well as in human HCCs, independent of etiology, and is further induced in distant metastases. Overexpression of the isoform Tak1A in the HCC cell line Huh7 resulted in increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. In human HCCs, high nuclear Tak1 expression is associated with vascular invasion and short overall survival. Abstract Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.

PD-1 pathway blockade has been shown to promote proatherogenic T-cell responses and destabilization of atherosclerotic plaques. Moreover, preclinical evidence suggests a potential synergy of antiplatelet drugs with immune checkpoint inhibitors (ICIs). We conducted an analysis within a prospective observational protocol (APOLLO study) to investigate the rates, predictors, and prognostic significance of thromboembolic events (TE) and thromboprophylaxis in patients with advanced NSCLC treated with ICIs. Among 217 patients treated between April 2014 and September 2018, 13.8% developed TE events. Current smoking status (HR 3.61 (95% CI 1.52&ndash, 8.60), p = 0.004) and high (&gt, 50%) PD-L1 (HR 2.55 (95% CI 1.05&ndash, 6.19), p = 0.038) resulted in being independent TE predictors. An increased risk of death following a diagnosis of TE (HR 2.93, 95% CI 1.59&ndash, 5.42, p = 0.0006) was observed. Patients receiving antiplatelet treatment experienced longer progression-free survival (PFS) (6.4 vs. 3.4 months, HR 0.67 (95% CI 0.48&ndash, 0.92), p = 0.015) and a trend toward better OS (11.2 vs. 9.6 months, HR 0.78 (95% CI 0.55&ndash, 1.09), p = 0.14), which were not confirmed in a multivariate model. No impact of anticoagulant treatment on patients&rsquo, outcomes was observed. NSCLC patients treated with ICIs bear a consistent risk for thrombotic complications, with a detrimental effect on survival. The impact of antiplatelet drugs on ICIs efficacy deserves further investigation in prospective trials.

Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.

Background TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The “ColonLife” nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. Materials and Methods We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. Results This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences. Conclusion One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach. Implications for Practice Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the “ColonLife” nomogram) may enable excluding from further treatments patients with very limited life expectancy.

Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors. In pancreatic cancer, mesothelin has been investigated mainly to address two unmet issues: the urgent need for new laboratory techniques for early tumor detection and the lack of successfully targetable oncogenic alterations for patients' treatment. In this review, we describe the clinicopathological significance of mesothelin expression in pancreatic cancer initiation and progression, we summarize available studies evaluating mesothelin as a potential diagnostic and prognostic biomarker in this disease, and we discuss current evidence and future perspectives of preclinical and clinical studies testing mesothelin as a molecular target for pancreatic cancer treatment.