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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(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.

ZusammenfassungNeuroendokrine Neoplasien (NEN) des GastroEnteroPankreatischens Systems (GEP-Systems) im inoperablen fortgeschrittenen Stadium erfordern eine differenzierte Systemtherapie abhängig von Klassifikation und Grading, Primärtumorlokalisation, Somatostatinrezeptorexpression, Tumordynamik, Tumorlast und Funktionalität. Somatostatinanaloga, Peptid Rezeptor Radionuklid Therapie (PRRT), Streptozotocin- oder Temozolomid-basierte Chemotherapieprotokolle und molekular zielgerichtete Therapien mit Everolimus oder Sunitinib sind jeweils etablierte Therapieoptionen bei verschiedenen neuroendokrinen Tumoren (NET). Neue vielversprechende Therapieansätze sind Multityrosinkinaseinhibitoren (TKIs) wie Surufatinib, Cabozantinib, Lenvatinib oder Pazopanib. Cisplatin/Etoposid ist die Standard 1st-line Chemotherapie bei neuroendokrinen Karzinomen (NEC). Bisher zeigten die meisten klinischen Studien zur Immuntherapie bei NET G1/G2 enttäuschende Studienergebnisse, aber die mögliche Effektivität der kombinierten Checkpoint-Inhibition sollte bei höherproliferativen NEN G3 weiter untersucht werden. Molekularpathologie mit Next Generation Sequencing (NGS) und personalisierte Therapie spielen auch bei den NEN eine zunehmende Rolle.

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

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

Aim: To survey European physicians managing patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and understand differences in baseline characteristics, diagnostic methods, symptoms and co-morbidities. Materials & methods: Patient record inclusion criteria were: ≥18 years old, metastatic PDAC diagnosis and completion of first-line treatment between July 2014 and January 2016. Records were grouped by patient age, gender and primary tumor location. Results: Records (n = 2565) were collected from nine countries. Baseline characteristics varied between subgroups. Computed tomography was the most frequently used diagnostic technique. Symptoms at diagnosis included abdominal and/or mid-back pain (72% of patients) and weight loss (61.5%). Co-morbidities varied with patient age. Conclusion: Greater awareness of symptoms, diagnostic methods and co-morbidities present at PDAC diagnosis may support better patient management decisions.

Background and objectives In treatment of colorectal liver metastases (CRC-LM), liver surgery combined with systemic therapies and local ablation (LAT) allows improved survival. This study aims at the outcomes of patients with complex bilobar CRC-LM who were intended to undergo multimodal therapy with liver resection and LAT. Methods Forty-three CRC-LM patients with recommendation for multimodal treament were extracted from 5878 tumor board decisions between 2014 and 2017. Outcome variables included patient survival, as well as completion of hepatic clearance. Prognostic factors were identified by correlation and a Cox proportional hazards model. Results Out of 43 patients only 23 achieved complete clearance of CRC-LM. One- and 3-year overall survival of patients with cleared liver disease was 100% and 91.7%, respectively, as compared to 83.8% and 12.1%. Incomplete hepatic clearance was the strongest independent risk factor for overall survival (hazards ratio [HR], 5.86; p = .009). Risk factors for incomplete clearance were higher age (r = .34; p = .026), comorbidities (r = .40; p = .008), major complications (r = .34; p = .024), and prolonged intensive care unit stay (r = .41; p = .017). Conclusion Completion of hepatic clearance is crucial to achieve long-term survival in patients with complex bilobar CRC-LM. Careful patient selection and treatment planning should avoid treatment failure before completing the intended therapy plan when multimodal treatments are planned.

Aim of the study Next-generation sequencing (NGS) might represent a valuable diagnostic tool to identify somatic alterations and enable personalised medicine in uro-oncology. We aim to determine feasibility and impact of routine NGS in clinical practice. Methods Tumours from patients with genitourinary cancers were subjected to NGS. Results were discussed in a dedicated molecular tumour board. Statistical analyses included chi-square test and Mann-Whitney U test. Results Between 2017 and 2020, 65 patients with advanced genitourinary cancers were consecutively enrolled. Number of tests increased (28 tests in 2020) and diagnostic turnaround time for generating output decreased (17.5 days [range 13–35]). Median patient's age was 62 years (range 33–84), and most NGS assays were performed upon start of systemic treatment (range 0–6 of treatment lines). 62/66 sequenced samples generated a report. Fifty samples (80.6%) showed at least one molecular alteration. Most prevalent alterations were TP53 (32.3%), PIK3CA (14.5%) and TMPRSS2-ERG (9.7%). Sequencing revealed potentially druggable targets in 29 samples (46.8%). Based on NGS results, six patients underwent therapy change, whereas for three patients, coverage of recommended off-label therapy was denied by health insurances. Conclusions NGS is increasingly feasible in clinical routine for patients with genitourinary cancers. Number of performed analyses is constantly growing, and turnaround time to therapy recommendation is decreasing. While the majority of tumours harbour clinically relevant mutations, alterations related to urologic cancers are underrepresented, thus treatment changes occurred only in a minority of patients. Further, access to target agents remains a considerable obstacle in the consequent implementation of precision uro-oncology.

Background: In the era of precision medicine, cancer treatment is increasingly tailored according to tumor-specific genomic alterations. The analysis of tumor-derived circulating nucleic acids in cerebrospinal fluid (CSF) by next generation sequencing (NGS) may facilitate precision medicine in the field of CNS cancer. We therefore evaluated whether NGS from CSF of neuro-oncologic patients reliably detects tumor-specific genomic alterations and whether this may help to guide the management of patients with CNS cancer in clinical practice. Patient and methods: CSF samples from 27 patients with various primary and secondary CNS malignancies were collected and evaluated by NGS using a targeted, amplicon-based NGS-panel (Oncomine Focus Assay). All cases were discussed within the framework of a molecular tumor board at the Comprehensive Cancer Center Munich. Results: NGS was technically successful in 23/27 patients (85%). Genomic alterations were detectable in 20/27 patients (74%), 11/27 (40%) of which were potentially actionable. After discussion in the MTB, a change of therapeutic management was recommended in 7/27 (26%) of the cases. However, due to rapid clinical progression, only 4/27 (15%) of the patients were treated according to the recommendation. In a subset of patients (6/27, 22%), a high number of mutations of unknown significance suggestive of a high tumor mutational burden (TMB) were detected. Conclusions: NGS from cerebrospinal fluid is feasible in routine clinical practice and yields therapeutically relevant alterations in a large subset of patients. Integration of this approach into a precision cancer medicine program might help to improve therapeutic options for patients with CNS cancer.

Background The presence of mutated KRAS (mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial mutKRAS ctDNA-measurements in PC. Patients and methods The aim of the present study was to explore the potential of repeated mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival. Results mutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%). Conclusion mutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.

Background The COVID-19 pandemic has resulted in significant changes to professional and personal lives of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration aimed to provide contemporaneous reports on the impact of COVID-19 on the lived experiences and well-being in oncology. Methods This online anonymous survey (July-August 2020) is the second of a series of global surveys launched during the course of the pandemic. Longitudinal key outcome measures including well-being/distress (expanded Well-being Index—9 items), burnout (1 item from expanded Well-being Index), and job performance since COVID-19 were tracked. Results A total of 942 participants from 99 countries were included for final analysis: 58% (n = 544) from Europe, 52% (n = 485) female, 43% (n = 409) ≤40 years old, and 36% (n = 343) of non-white ethnicity. In July/August 2020, 60% (n = 525) continued to report a change in professional duties compared with the pre-COVID-19 era. The proportion of participants at risk of poor well-being (33%, n = 310) and who reported feeling burnout (49%, n = 460) had increased significantly compared with April/May 2020 (25% and 38%, respectively; P < 0.001), despite improved job performance since COVID-19 (34% versus 51%; P < 0.001). Of those who had been tested for COVID-19, 8% (n = 39/484) tested positive; 18% (n = 7/39) felt they had not been given adequate time to recover before return to work. Since the pandemic, 39% (n = 353/908) had expressed concerns that COVID-19 would have a negative impact on their career development or training and 40% (n = 366/917) felt that their job security had been compromised. More than two-thirds (n = 608/879) revealed that COVID-19 has changed their outlook on their work-personal life balance. Conclusion The COVID-19 pandemic continues to impact the well-being of oncology professionals globally, with significantly more in distress and feeling burnout compared with the first wave. Collective efforts from both national and international communities addressing support and coping strategies will be crucial as we recover from the COVID-19 crisis. In particular, an action plan should also be devised to tackle concerns raised regarding the negative impact of COVID-19 on career development, training, and job security., Highlights • Compared with survey I, more oncology professionals were at risk of poor well-being (33% versus 25%) and burnout (49% versus 38%). • Job performance since COVID-19 (JP-CV) has improved from 34% to 51%. • About 1 in 5 who tested positive for COVID-19 felt they had not been given adequate time to recover before return to work. • Some 39% expressed concerns that COVID-19 would have a negative impact on their career development or training. • More than two-thirds revealed that COVID-19 had changed their outlook on work-personal life balance.

Background: The ESMO Resilience Task Force has investigated wellbeing since COVID-19 in relation to work, lifestyle and support factors in oncology professionals globally. We reported on the significant impact of the initial surge of the pandemic on wellbeing and job performance (Banerjee et al. 2021). As the pandemic continues, it is imperative to understand experiences and concerns to better inform support measures for the oncology workforce. Methods: Three anonymous online surveys were conducted during the COVID-19 pandemic (S1, Apr/May 2020;S2, Jul/Aug 2020;S3, Feb/Mar 2021). Longitudinal analysis of responses at these timepoints were conducted. Here, we present responses to questions on job demands and resources, and perceived job performance since COVID-19 (JP-CV). Results: We analysed 3894 individual responses (S1, n=1520;S2, n=942;S3, n=1432): 53% (n=1961/3731) female, 45% (n=1679/3731) =/ 100 countries. There has been significant increases from S1 to S3 (p

Background The impact of the coronavirus disease 2019 (COVID-19) pandemic on well-being has the potential for serious negative consequences on work, home life, and patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate well-being in oncology over time since COVID-19. Methods Two online anonymous surveys were conducted (survey I: April/May 2020; survey II: July/August 2020). Statistical analyses were performed to examine group differences, associations, and predictors of key outcomes: (i) well-being/distress [expanded Well-being Index (eWBI; 9 items)]; (ii) burnout (1 item from eWBI); (iii) job performance since COVID-19 (JP-CV; 2 items). Results Responses from survey I (1520 participants from 101 countries) indicate that COVID-19 is impacting oncology professionals; in particular, 25% of participants indicated being at risk of distress (poor well-being, eWBI ≥ 4), 38% reported feeling burnout, and 66% reported not being able to perform their job compared with the pre-COVID-19 period. Higher JP-CV was associated with better well-being and not feeling burnout (P < 0.01). Differences were seen in well-being and JP-CV between countries (P < 0.001) and were related to country COVID-19 crude mortality rate (P < 0.05). Consistent predictors of well-being, burnout, and JP-CV were psychological resilience and changes to work hours. In survey II, among 272 participants who completed both surveys, while JP-CV improved (38% versus 54%, P < 0.001), eWBI scores ≥4 and burnout rates were significantly higher compared with survey I (22% versus 31%, P = 0.01; and 35% versus 49%, P = 0.001, respectively), suggesting well-being and burnout have worsened over a 3-month period during the COVID-19 pandemic. Conclusion In the first and largest global survey series, COVID-19 is impacting well-being and job performance of oncology professionals. JP-CV has improved but risk of distress and burnout has increased over time. Urgent measures to address well-being and improve resilience are essential., Highlights • This is the first global report of well-being in oncology professionals since the coronavirus disease 2019 (COVID-19) pandemic. • In this survey of 1520 oncology professionals, 67% reported a change in professional duties since COVID-19. • About 25% had risk of distress (poor well-being), 38% felt burnout, and 66% were not able to perform their job compared with the pre-COVID-19 period. • Well-being and job performance since COVID-19 (JP-CV) were correlated with COVID-19 crude mortality rate in the country of practice. • The main predictors of well-being, burnout, and JP-CV were resilience and changes to work hours. • JP-CV has improved but risk of distress and burnout has increased over time.

Simple Summary To elucidate the role of angiogenesis as a prognostic signature in gastric cancer, we analyzed the expression level of 36 angiogenesis-related genes (ARGs) from Stomach Adenocarcinoma (STAD) from The Cancer Genome Atlas (TCGA). Consensus clustering analysis showed two major angiogenesis-related types: one related to more aggressive clinicopathological characteristics and worse survival, and the other related to lower tumor, lymph node, metastasis (TNM) stage and better outcomes. Our analysis of TCGA with a least absolute shrinkage and selection operator (LASSO) regression model identified 10 genes associated with overall survival in gastric cancer patients. With this gene signature, we computed angiogenesis-related gene signature risk scores for individual cancer patients that predicted overall and disease-free survival, which were further validated in the independent dataset Asian Cancer Research Group (ACRG). Moreover, an overall survival (OS)-related nomogram was established and had better performance in prognosis prediction than TNM stage. Our analysis provides a comprehensive map of ARGs that can be serve as useful biomarkers for gastric cancer. Abstract Increasing evidence indicates that angiogenesis is crucial in the development and progression of gastric cancer (GC). This study aimed to develop a prognostic relevant angiogenesis-related gene (ARG) signature and a nomogram. The expression profile of the 36 ARGs and clinical information of 372 GC patients were extracted from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to divide patients into clusters 1 and 2. Least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to identify the survival related ARGs and establish prognostic gene signatures, respectively. The Asian Cancer Research Group (ACRG) (n = 300) was used for external validation. Risk score of ARG signatures was calculated, and a prognostic nomogram was developed. Gene set enrichment analysis of the ARG model risk score was performed. Cluster 2 patients had more advanced clinical stage and shorter survival rates. ARG signatures carried prognostic relevance in both cohorts. Moreover, ARG-risk score was proved as an independent prognostic factor. The predictive value of the nomogram incorporating the risk score and clinicopathological features was superior to tumor, lymph node, metastasis (TNM) staging. The high-risk score group was associated with several cancer and metastasis-related pathways. The present study suggests that ARG-based nomogram could serve as effective prognostic biomarkers and allow a more precise risk stratification.

Background Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non–small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. Patients and methods Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the ‘Burden of Therapy/Toxicity’ (BOTh) for each patient on every day during the clinical study. Results One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). Conclusion The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov ( NCT01728818 ) and Eudra-CT (2011-004063-77).

Background: Clinical trials have proven a survival benefit from applying local therapies for oligometastatic cancers of various origin. Summary: Today, the definition of oligometa­static disease is based on limited lesion numbers and organ systems involved. Treatment guidelines by the European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO) and several other groups suggest a threshold of up to 5 tumours. Established biological markers indicating the aggressiveness of a given tumour (and therefore suggesting local treatment only or the addition of or complete switch to systemic therapies) are missing, except for disease-free survival, the only recommended parameter for patient selection beyond lesion count. Key Message: The following article discusses clinical implications as well as local techniques established for the treatment of oligometastatic disease.

Purpose Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. Methods Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). Results 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. Conclusion The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.

Background Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoural lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1st-line chemotherapy. Methods We examined LPS on tumour tissue from 130 patients treated within the randomised AIO-PK0104 trial and a validation cohort (n = 113) and analysed the association of LPS detection to patient outcome according to treatment subgroups. Results In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumours (HR 1.732, p = 0.010). A difference in OS was detected in 1st-line gemcitabine-treated patients (n = 71; HR 2.377, p = 0.002), but not in the non-gemcitabine treatment subgroup (n = 59; HR 1.275, p = 0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n = 94; HR 1.993, p = 0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n = 19; HR 2.596, p = 0.219). Conclusions The detection of intratumoural LPS as surrogate marker for gram-negative bacterial colonisation may serve as a negative predictor for gemcitabine efficacy in advanced PDAC. Clinical trial registry The Clinical trial registry identifier is NCT00440167.

Background Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology. Material and methods FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34–1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10–0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours. Conclusions RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.

Introduction In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. Patients and methods For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1–4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. Results Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8–50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7–68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. Conclusions First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

Die immer umfassendere molekulare Charakterisierung von Tumoren ermoglicht eine „Prazisionsonkologie“ mit besonders effektiven und nebenwirkungsarmen Therapien. „Targeted Therapies“ erzielen bei bestimmten Tumorentitaten grose Erfolge. Jedoch bestehen Schwierigkeiten in der praktischen Umsetzung und Nutzenbewertung zunehmend individualisierter Behandlungsansatze. Recent developments in genomics allow a more and more comprehensive genetic analysis of human malignancies, and have sparked hopes that this will contribute to the development of novel targeted, effective and well-tolerated therapies. While targeted therapies have improved the prognosis of many cancer patients with certain tumor types, “precision oncology” also brings along new challenges. Highly personalized treatment strategies require new strategies for clinical trials and translation into routine clinical practice. We review the current technical approaches for “universal genetic testing” in cancer, and potential pitfalls in the interpretation of such data. We then provide an overview of the available evidence supporting treatment strategies based on extended genetic analysis. Based on the available data, we conclude that “precision oncology” approaches that go beyond the current standard of care should be pursued within the framework of an interdisciplinary “molecular tumor board”, and preferably within clinical trials.

Background: Mutations in the KRAS gene can be detected in about 70–90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. Methods: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. Results: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2–4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). Conclusions: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.

A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29 days (range: 1–124 days). Most common reasons for prolonged TTI (> 21 days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60 days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.

PURPOSE: Increased baseline carcinoembryonic antigen (CEA) serum level is associated with inferior overall survival (OS) in metastatic colorectal cancer (mCRC). However, limited data exist on its predictive relevance for targeted therapies. Therefore, we analysed its relevance in FIRE-3, a randomised phase III study. EXPERIMENTAL DESIGN: FIRE-3 evaluated first-line FOLFIRI plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumour (i.e. wild-type in KRAS and NRAS exons 2-4). Herein, the impact of CEA on patient outcome was investigated. RESULTS: Of 400 patients, 356 (89.0%) were evaluable for CEA. High CEA (\textgreater10 ng/ml; N = 237) compared to low CEA (\textless/=10 ng/ml; N = 119) was associated with shorter OS in the FOLFIRI/Bev arm (hazard ratio HR = 1.50; P = 0.036), while no significant OS difference was observed in the FOLFIRI/Cet arm (HR = 1.07; P = 0.74). In patients with high CEA, FOLFIRI/Cet compared to FOLFIRI/Bev showed a greater OS benefit (HR = 0.56; P {\textless} 0.001) than in patients with low CEA (HR = 0.78; P = 0.30). Furthermore, FOLFIRI/Cet exhibited significantly superior objective response rate in patients with high CEA (odds ratio = 2.21; P = 0.006) in contrast to patients with low CEA (odds ratio = 0.90; P = 0.85). CONCLUSION: In patients with RAS-WT mCRC receiving first-line chemotherapy with FOLFIRI/Cet versus FOLFIRI/Bev, elevated CEA was associated with inferior survival in the bevacizumab arm, while this was not the case when cetuximab was applied. Comparison of OS and objective response rate according to treatment arms indicated that cetuximab was greatly superior to bevacizumab in patients with elevated CEA, while this effect was markedly lower and lost statistical significance in patients with low CEA.

Background We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. Patients and methods OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. Results The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS –intention-to-treat (ITT)/all- RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point ( KRAS -ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44–0.83] and RAS : P = 0.0006; HR, 0.51 [95% CI, 0.35–0.75]). Conclusion The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.

The concept of 'personalised medicine' aims at allocating patients to different treatment options based on individual characteristics to optimise treatment benefit and side effects. In oncology, personalised treatments coupled to biomarkers have led to the approval of targeted agents with high anti-tumour activity. However, these therapies are often limited to narrow, molecularly defined subsets of patients with a specific morphomolecular tumour profile. Recently, it became obvious that the same molecular alteration might drive oncogenesis in many different tumours, and it might be beneficial to target the alteration in a histology informed but entity-overarching way. Consequently, Universal Genomic Testing (UGT) of tumours encompassing panel sequencing to whole-exome and transcriptome sequencing is propagated to revolutionise oncology. This article will describe the developments leading to identification and application of potential biomarkers using UGT. On this basis, it will review the clinical evidence of this approach and summarise recommendations for the ongoing evaluation of UGT as the next step in oncological decision-making.

Venous thromboembolism (VTE) is frequent in advanced pancreatic cancer (APC). Recent studies demonstrated that the Khorana score - an established risk stratification tool for VTE in cancer - performs poorly in identifying pancreatic cancer patients at high risk for VTE.We performed a retrospective cohort study in order to define incidence, treatment and outcome of VTE as well as the performance of VTE risk stratification tools (Khorana score, CONKO score and aPTT ratio) in a "real life" clinical cohort of APC patients undergoing palliative chemotherapy.One hundred and seventy-two eligible APC patients from our comprehensive cancer center were identified. VTE after start of palliative chemotherapy was diagnosed in 71 patients (41.3%). Most VTE events were asymptomatic (n=50, 29.1%) with only 21 symptomatic events (12.2%). On multivariate analysis - including age, performance status and carbohydrate antigen 19-9 (CA 19-9) - symptomatic VTE was an independent risk factor for death (hazard ratio [HR]: 2.22, 95% CI: 1.05-2.60, p0.05). Khorana score, CONKO score and aPTT ratio alone were not able to predict the risk for symptomatic VTE. High risk patients could only be identified by using a combination of either Khorana or CONKO score with aPTT ratio (30% vs. 10% symptomatic VTE events in high vs. low risk patients, p0.05). The combination of Khorana or CONKO score with aPTT thus may represent a novel risk stratification tool for symptomatic VTE in APC and should further be validated within prospective clinical trials.

XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC.

Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in a muscarinic acetylcholine receptor-3 (M3R)-dependent manner, in part through suppression of Yes-Associated Protein (YAP) function. This feed-forward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.

Objective: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. Results: H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Conclusions: Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment., National Institutes of Health (U.S.) (grant 5R01CA093405-11), Columbia University Medical Center (Naomi Berrie Diabetes Center, grant P30DK063608)

Pancreatic ductal adenocarcinoma is the 10th most common cancer and the 4th leading cause of cancer-related death in the United States. Despite great effort, the prognosis for patients with this disease remains dismal with, a 5-year survival rate of just 4-6%. While several important advances have improved our understanding of the underlying biology of pancreatic cancer, this knowledge has not translated into novel therapeutic approaches and effective systemic or targeted therapies. Pancreatic cancer is one of the malignancies most difficult to treat, with remarkable intrinsic resistance to both standard and targeted chemotherapy as well as ionizing radiation. Surgical intervention remains the only potentially curative approach. However, most patients present with inoperable and/or metastatic disease and are therefore excluded from surgery. Accordingly, new therapeutic options are desperately needed. In vivo models to study innovative and alternative treatment approaches are of major importance. A variety of genetically engineered mouse models of pancreatic cancer have been developed over the last decade. However, these models display different characteristics and not all of them are suited for preclinical studies. In this review we aim to review the mouse models currently available, their experimental use, their clinical relevance and limitations as well as future directions.

Past patterns of cancer disease and future changes in the demographic structure have a major influence on the projected incidences of human malignancies. In Germany, nearly a quarter of men and 20% of women die of cancer, and it is estimated that in Germany around 51% men and 43% women will develop cancer during lifetime. Here, we project the cancer incidence case number as well as the number of deaths for the most common cancers in the German population for the years 2020 and 2030. By 2030, prostate cancer will be the most common malignancy, surpassing breast cancer. Lung cancer will rank third most frequent cancer and will remain the most common cause of cancer‐related mortality. Additionally, our projections show a marked increase in liver cancer cases with a continuous rise in liver cancer‐related deaths. Finally, we project a constant increase in the incidence of pancreatic cancer. Based on our projections, pancreatic cancer will surpass colorectal and breast cancer to rank as the second most common cause of cancer‐related deaths in Germany by 2030.

Purpose Liver metastasis represents the first site of dissemination in >80% of metastatic pancreatic cancer (PC) patients. Pulmonary metastasis as first site of dissemination in PC is a rare event and might define a biologically distinct subgroup in metastatic PC. Methods Consecutive PC patients who were diagnosed or treated with isolated pulmonary metastases at our high-volume comprehensive cancer center were included in a prospectively maintained database between 2002 and 2015. Medical records and correlating computed tomography findings (CT) were retrospectively analyzed. Results A total of 40 PC patients with isolated pulmonary metastases were identified. Pulmonary metastases represented disease recurrence after initial resection of PC in 22 patients and disease progression of locally advanced pancreatic cancer in 5 patients. 14 out of 27 PC patients (56%) had received chemoradiotherapy for localized disease prior to pulmonary metastasis. Data on 1st-line treatment for pulmonary metastases was available for 38 patients: most patients (71%) received a gemcitabine-based chemotherapy regimen, 5 patients (13%) received best supportive care. After a median follow-up of 37.3 months, median survival after diagnosis of pulmonary metastasis was estimated with 25.5 months (95% CI 19.1–31.8); a significantly improved survival after diagnosis of pulmonary metastasis was observed for patients with less than 10 lung metastases (31.3 vs 18.7 months, p = 0.003) and for an unilateral localization of lung involvement (31.3 vs 21.8 months, p = 0.03). Conclusions Our results suggest a favorable outcome of PC patients with isolated pulmonary metastases. Further research is warranted to elucidate the specific molecular characteristics of this rare subgroup.

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1⁺ stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12⁺ endothelial cells and Cxcr4⁺ gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche., National Institutes of Health (U.S.) (Grants 54CA126513, R01CA093405, R01CA120979, and R01DK052778)

Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5(-) stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5(+) CBCs in the colon and intestine. In colorectal cancer models, Krt19(+) cancer-initiating cells are also radioresistant, while Lgr5(+) stem cells are radiosensitive. Moreover, Lgr5(+) stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5(+) stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19(+) stem cells are a discrete target relevant for cancer therapy.

Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet. In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD-L1 levels might be caused by an inflammatory tumor type - independent of tumoral PD-L1 expression.