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Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry ( https://www.clinicaltrialsregister.eu ): EudraCT: 2014-005341-44

Background Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed. Methods We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX. Results In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329). Conclusion This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.

BACKGROUND: Soft tissue sarcomas (STS) are generally considered non-immunogenic, although specific subtypes respond to immunotherapy. Antitumour response within the tumour microenvironment relies on a balance between inhibitory and activating signals for tumour-infiltrating lymphocytes (TILs). This study analysed TILs and immune checkpoint molecules in STS, and assessed their prognostic impact regarding local recurrence (LR), distant metastasis (DM), and overall survival (OS). METHODS: One-hundred and ninety-two surgically treated STS patients (median age: 63.5 years; 103 males [53.6%]) were retrospectively included. Tissue microarrays were constructed, immunohistochemistry for PD-1, PD-L1, FOXP3, CD3, CD4, and CD8 performed, and staining assessed with multispectral imaging. TIL phenotype abundance and immune checkpoint markers were correlated with clinical and outcome parameters (LR, DM, and OS). RESULTS: Significant differences between histology and all immune checkpoint markers except for FOXP3+ and CD3−PD-L1+ cell subpopulations were found. Higher levels of PD-L1, PD-1, and any TIL phenotype were found in myxofibrosarcoma as compared to leiomyosarcoma (all p

Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl 2 and eGFR ≥ 50 ml/min/1.73m2 (i.e. a “false negative” result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5–2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m2). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.

To quantify the magnitude of benefit of metastasectomy as compared to medical treatment alone in patients with metastatic renal cell carcinoma (mRCC).We therefore conducted a propensity score analysis of overall survival (OS) in 106 mRCC patients with metachronous metastasis, of whom 36 (34%) were treated with metastasectomy, and 70 (66%) with medical therapy alone.The most frequent metastasectomy procedures were lung resections (n = 13) and craniotomies (n = 6). Median time-to-progression after metastasectomy was 0.7 years (25th-75th percentile: 0.3-2.7). After a median follow-up of 6.2 years and 63 deaths, 5-year OS estimates were 41% and 22% in the metastasectomy and medical therapy group, respectively (log-rank P = .00007; Hazard ratio (HR) = 0.38, 95%CI: 0.21-0.68). Patients undergoing metastasectomy had a significantly higher prevalence of favorable prognostic factors, such as fewer bilateral lung metastases and longer disease-free intervals between nephrectomy and metastasis diagnosis. After propensity score weighting for these differences and adjusting for immortal time bias, the favorable association between metastasectomy and OS became much weaker (HR = 0.62, 95%CI: 0.39-1.00, P = .050). Propensity-score-weighted 5-year OS estimates were 24% and 20% in the metastasectomy and medical therapy group, respectively (log-rank P = .001). In exploratory analyses, the benefit of metastasectomy was confined to patients who achieved complete resection of all known metastases.Within the limitations of an observational study, these findings support the concept of metastasectomy being associated with an OS benefit in mRCC patients. Metastasectomies not achieving complete resection of all known lesions are likely without OS benefit.

Introduction Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC. Methods Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE. Results Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3–24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5–4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21–2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08–2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87–3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09–5.18]), while the Khorana score (SHR: 0.78 [0.57–1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83–71.22], p Conclusion Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.

Background: Molecular diagnosis has become an established tool in the characterisation of adult soft-tissue sarcomas (STS). FoundationOne® Heme analyses somatic gene alterations in sarcomas via DNA and RNA-hotspot sequencing of tumour-associated genes. Methods: We evaluated FoundationOne® Heme testing in 81 localised STS including 35 translocation-associated and 46 complex-karyotyped cases from a single institution. Results: Although FoundationOne® Heme achieved broad patient coverage and identified at least five genetic alterations in each sample, the sensitivity for fusion detection was rather low, at 42.4%. Nevertheless, potential targets for STS treatment were detected using the FoundationOne® Heme assay: complex-karyotyped sarcomas frequently displayed copy-number alterations of common tumour-suppressor genes, particularly deletions in TP53, NF1, ATRX, and CDKN2A. A subset of myxofibrosarcomas (MFS) was amplified for HGF ( n = 3) and MET ( n = 1). PIK3CA was mutated in 7/15 cases of myxoid liposarcoma (MLS; 46.7%). Epigenetic regulators (e.g. MLL2 and MLL3) were frequently mutated. Conclusions: In summary, FoundationOne® Heme detected a broad range of genetic alterations and potential therapeutic targets in STS (e.g. HGF/MET in a subset of MFS, or PIK3CA in MLS). The assay’s sensitivity for fusion detection was low in our sample and needs to be re-evaluated in a larger cohort.

In this short review we aim to summarize the role current clinical role of immunotherapy in particular of immune checkpoint inhibition in gastrointestinal malignancies and highlight the most important clinical trials.

Background: The level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) versus ASC alone in aESCC. Methods: We conducted a tri-center retrospective cohort study ( n = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC ( n = 92, 55%) versus ASC alone ( n = 74, 45%). Results: The most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35–0.69, p Conclusion: This real-world study supports the concept that systemic second-line therapy prolongs survival in patients with aESCC.

Background/aim The Aspartate aminotransaminase/Alanine aminotransaminase ratio (AST/ALT ratio) has been identified as a prognostic marker for several malignancies. In this study, we evaluated the prognostic value of the AST/ALT ratio in a large cohort of non-metastatic colorectal cancer patients (CRC). Patients and methods A total of 536 patients with stage II and III CRC, as well as available AST/ALT ratio were included in this single-center retrospective analysis. Laboratory data were measured within two weeks before histological tumor diagnosis. Co-Primary endpoints for this analysis were disease-free survival (DFS) and overall survival (OS). Results In univariate cox regression DFS was significantly shorter in patients with an elevated AST/ALT ratio (HR=1.568, 95%CI=1.10-2.23, p=0.012). In multivariable analysis, the prognostic association between an elevated AST/ALT ratio and a poor survival prevailed statistically significant (HR=1.53, 95%C=1.05-2.22, p=0.026). No statistically significant association between the AST/ALT ratio and OS was observed (HR=1.4, 95% CI=0.89-2.22, p=0.14). Conclusion In this study, the serum AST/ALT ratio emerged as a valid prognostic marker for DFS in non-metastatic colorectal cancer patients at stage II and III.

Objective Precision oncology depends on translating molecular data into therapy recommendations. However, with the growing complexity of next-generation sequencing-based tests, clinical interpretation of somatic genomic mutations has evolved into a formidable task. Here, we compared the performance of three commercial clinical decision support tools, that is, NAVIFY Mutation Profiler (NAVIFY; Roche), QIAGEN Clinical Insight (QCI) Interpret (QIAGEN) and CureMatch Bionov (CureMatch). Methods In order to obtain the current status of the respective tumour genome, we analysed cell-free DNA from patients with metastatic breast, colorectal or non-small cell lung cancer. We evaluated somatic copy number alterations and in parallel applied a 77-gene panel (AVENIO ctDNA Expanded Panel). We then assessed the concordance of tier classification approaches between NAVIFY and QCI and compared the strategies to determine actionability among all three platforms. Finally, we quantified the alignment of treatment suggestions across all decision tools. Results Each platform varied in its mode of variant classification and strategy for identifying druggable targets and clinical trials, which resulted in major discrepancies. Even the frequency of concordant actionable events for tier I-A or tier I-B classifications was only 4.3%, 9.5% and 28.4% when comparing NAVIFY with QCI, NAVIFY with CureMatch and CureMatch with QCI, respectively, and the obtained treatment recommendations differed drastically. Conclusions Treatment decisions based on molecular markers appear at present to be arbitrary and dependent on the chosen strategy. As a consequence, tumours with identical molecular profiles would be differently treated, which challenges the promising concepts of genome-informed medicine.

Background: Targeted therapies offer novel opportunities to explore biomarkers based on their mode of action. Taking this into consideration, we evaluated six angiogenesis-related proteins as potential predictive biomarkers, which expression might predict the benefit of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). Methods: This was a phase II multicenter, two-armed, randomized study, in which patients with mCRC were treated with XELIRI (capecitabine and irinotecan) plus bevacizumab followed by XELOX (capecitabine and oxaliplatin) plus bevacizumab (Arm A) or the reverse sequence (Arm B). Tissue expression level of six prespecified candidates [microvessel density assessed by CD31, PTEN, αV integrin, CD98hc, uPAR and NRP-1] was analyzed via immunohistochemistry. The prognostic impact on survival was quantified using the Cox regression model. The predictive potential for benefit from Arm A versus Arm B treatment was investigated by fitting an interaction between the biomarkers and treatment assignment within a multivariable Cox model. Results: In total, 74 out of 126 patients were included in the analysis. The expression of PTEN, αV integrin, uPAR and NRP-1 was not associated with progression-free survival (PFS) or overall survival (OS). For the first time, we identified that patients with tumors expressing CD98hc had a longer PFS than patients without CD98hc-expression ( p = 0.032). More importantly, and in accordance with previous studies, low microvessel density was found to be associated with a reduced PFS [adjusted HR per doubling of CD31-expression ( p = 0.53, 95% confidence interval: 0.30–0.95, p = 0.034)]. Conclusions: These results can contribute to the development of a personalized strategy for the treatment of mCRC with bevacizumab.

Diabetes mellitus (DM) and hyperglycemia are known predictors of adverse outcome in different tumor entities. The present study investigated the effect of DM and pre-surgery blood glucose levels on cancer specific survival (CSS), overall survival (OS), and disease-free survival (DFS) in non-metastatic soft tissue sarcoma (STS) patients. A total of 475 STS patients who underwent curative resection were included in this retrospective study. CSS, DFS, and OS were assessed using Kaplan–Meier curves. The association between pre-existing DM as well as mean pre-surgery blood glucose levels and all 3 survival endpoints was analyzed using Cox-hazard proportional (for OS and DFS) and competing risk regression models (for CSS). In unadjusted analysis, DM was significantly associated with adverse CSS (sub-hazard ratio [SHR]: 2.14, 95% confidence interval [CI] 1.18–3.90, p = 0.013) and OS (hazard ratio [HR]: 2.05, 95% CI 1.28–3.28) and remained significant after adjusting for established prognostic factors (CSS: adjusted SHR 2.33, 95% CI 1.21–4.49, p = 0.012; OS: adjusted HR 1.96, 95% CI 1.17–3.28, p = 0.010), respectively. There was no significant association of DM with DFS (p = 0.149). The mean pre-surgery glucose levels were not significantly associated with inferior outcome (CSS: p = 0.510, OS: p = 0.382 and DFS: p = 0.786). This study shows, that DM represents a negative prognostic factor for clinical outcome in STS patients after curative resection.

Background: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. Methods: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. Results: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06–1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00–1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31–0.94, p = 0.020). Conclusions: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Background Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. Methods Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. Results We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. Conclusions Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16&ndash, 1.63, p &lt, 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18&ndash, 1.71, p &lt, 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51&ndash, 0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15&ndash, 1.30, p &lt, 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14&ndash, 154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83&ndash, 0.99, p = 0.036), respectively. Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

Background The ABO blood group system has been previously discussed as a risk factor to develop, as well as a prognostic factor in non-metastatic renal cell carcinoma (RCC). Controversial findings have been reported in different populations of RCC patients with rather short follow-up periods. In this study, we aimed to clarify the distribution and prognostic role of ABO blood groups upon 15 years of median follow-up in non-metastatic RCC patients. Materials and methods We evaluated the distribution and prognostic significance of ABO blood group system in two independent cohorts (n = 405 and n = 1473) of non-metastatic RCC patients, who underwent curative (partial or total) nephrectomy between 1998 and 2012 at two tertiary academic centers. Cancer-specific survival, metastasis-free survival, as well as overall survival (OS) were assessed using the Kaplan-Meier method, univariable- and multivariable Cox regression models were applied, respectively. Results In the two cohorts, blood groups were not associated with any clinical endpoints (for cohort 2: Cancer-specific survival (HR = 1.233; 95%CI 0.998–1.523, P = 0.052), metastasis-free survival (HR = 1.161; 95%CI 0.952–1.416, P = 0.142) and OS (HR = 1.037; 95%CI 0.890–1.208, P = 0.641), respectively). Compared to 250.298 healthy blood-donors of the Styrian state, the distribution of blood groups was (624 (42.4%) versus 106.861 (42.7%) in group A, 191 (13%) vs. 34.164 (13.7%) in group B, 575 (39%) versus 93.579 (37.4%) in group O and 83 (5.6%) vs. 15.694 (6.3%), P = 0.467). Conclusion In this large study with the longest period of follow-up reported to date, the ABO blood group system could not be validated as a prognostic factor in predicting important clinical endpoints in non-metastatic RCC patients.

// Jakob Michael Riedl 1 , Florian Posch 1 , Florian Moik 1 , Angelika Bezan 1 , Joanna Szkandera 1 , Maria Anna Smolle 1 , Anne-Katrin Kasparek 1 , Martin Pichler 1, 3 , Herbert Stoger 1 , Michael Stotz 1 and Armin Gerger 1, 2 1 Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria 2 Center for Biomarker Research in Medicine, 8010 Graz, Austria 3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA Correspondence to: Michael Stotz, email: michael.stotz@medunigraz.at Keywords: biomarker, inflammation, metastatic, colorectal cancer, palliative chemotherapy Received: July 05, 2017 Accepted: August 08, 2017 Published: October 04, 2017 ABSTRACT Introduction: Inflammatory biomarkers are useful prognostic tools in cancer patients. However, the prognostic and predictive value of inflammatory biomarkers beyond the 1 st -line setting in metastatic colorectal cancer (mCRC) is unclear. Results: In multivariate analysis 1 standard deviation increase in neutrophil-lymphocyte-ratio (NLR) was associated with an 8.5% absolute lower objective-response-rate (ORR) in 1 st -line (p

This study aimed to quantify the benefit of adjuvant radiotherapy (AXRT) for local control, distant metastasis, and long-term survival outcomes in patients with localized soft tissue sarcoma (STS). This single-center retrospective observational study enrolled 433 STS patients who underwent surgery with curative intent. An inverse probability of treatment-weighted (IPTW) analysis was implemented to account rigorously for imbalances in prognostic variables between the adjuvant treatment groups. During a median follow-up period of 5.5 years, the study observed 38 local recurrences (9%), 73 occurrences of distant metastasis (17%), 63 STS-related deaths (15%), and 57 deaths from other causes (13%). As expected, patients receiving AXRT (n = 258, 60%) were more likely to have high-grade G3 tumors (p

Background Venous thromoboembolism (VTE) is a frequent and burdensome complication of metastatic colorectal cancer (CRC). However, the epidemiology of VTE in patients with localized CRC after surgery in curative intent is incompletely understood. In this single-center observational cohort study, we investigate patterns of VTE risk in localized CRC, and define its relationship with baseline risk factors, adjuvant chemotherapy and CRC recurrence. Methods Five-hundred-sixteen patients with stage II/III CRC were included retrospectively at the time of surgery, and followed until the occurrence of VTE, CRC recurrence, or death (median age = 65.1 years, stage II and III: n = 151 (29.5%), n = 361 (70.5%); adjCTX: n = 339 (65.7%)). Results During a median follow-up of 2.7 years, 15 VTEs (2.7%) and 116 recurrences (22.5%) occurred, and 46 patients (8.9%) died. Six-month, 1-year, and 5-year VTE risks were 1.6%, 2.0% and 3.2%, respectively. In competing risk time-to-VTE regression, adjCTX was not associated with an increased risk of VTE (Subdistribution hazard ratio = 0.98, 95% CI:0.33–2.88, p = 0.97). The occurrence of disease recurrence strongly increased the risk of VTE (Multi-state model: Transition hazard ratio (THR) = 13.03, 95% CI:4.39–38.74, p

Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3&ndash, 95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible.

BACKGROUND/AIM To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT). PATIENTS AND METHODS Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed. RESULTS Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022). CONCLUSION Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.

BACKGROUND: We are entering exciting times in precision oncology, with next-generation sequencing enabling the individualized screening of multiple patient- and tumor-specific genomic and transcriptomic changes. As new molecular information flows into the clinic, the pursuit of innovative targeted therapies and defining the actionable genome are at the forefront. The amount of molecular information, much of it of unknown clinical relevance, has rendered the interpretation of detected aberrations a daunting task for clinical geneticists and oncologists alike. In this regard, several clinical decision support platforms have emerged on the market and need to be validated before implementation in routine clinical care of advanced cancer patients. METHODS: Here, we present a retrospective, descriptive study in adult patients with solid tumors using plasma DNA for the identification of actionable targets. We generated genomic profiles of 48 selected patients with advanced breast (BC), colorectal (CRC) and non-small cell lung cancer (NSCLC; samples selected had tumor fraction under 5%) using shallow whole-genome sequencing in parallel to the AVENIO ctDNA Expanded Panel, which covers 77 genes spanning 192kb. Somatic copy number alterations (SCNAs) and somatic variants were annotated for pathogenicity and subsequently matched to therapies using the following clinical decision support platforms: NAVIFY Mutation Profiler (NMP, Roche), CureMatch BIONOV (CureMatch) and QCI Interpret (QCI-I, Qiagen). We assessed the various features of each tool, correlated genomic features with actionable targets, compared genomic characteristics between tumor entities and evaluated the alignment of treatment recommendations. RESULTS: Tumor fraction in plasma DNA was highest in patients with BC (24.95% [range 10.52-48.93]) compared to CRC (14.94% [range 4.07-54.69]) and NSCLC (4.46% [range 1.63-45.42]) patients, whereas fraction genome altered was highest in CRC (median FGA = 0.289). Of the total reported aberrations per patient, both CureMatch and NMP identified the highest median percent actionability in CRC patients, whereas NSCLC had the highest actionability according to QCI-I. The total number of matching clinical trials was highest in CRC patients across platforms. CureMatch, a pathway-based analysis, suggested ranked combination therapies to target the entire molecular profile. CONCLUSIONS: This study seeks to provide insight into alternative treatment options and available clinical trials which were possibly previously overlooked due to incomplete molecular knowledge of the patient's tumor. These analyses may prove extremely valuable for increasing oncologists' confidence in and efficiency of employing molecular cancer diagnostics in a routine setting, in turn increasing clinicians' ability to use genomics-guided personalized cancer therapy when deciding on treatments in the future. Citation Format: Samantha O. Perakis, Sabrina Weber, Ricarda Graf, Qing Zhou, Jakob M. Riedl, Nadia Dandachi, Marija Balic, Armin Gerger, Ed Schuuring, Harry J. Groen, Jochen B. Geigl, Michael R. Speicher, Ellen Heitzer. Identification of actionable targets in advanced cancer patients from circulating tumor DNA using clinical decision support platforms [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1315.

The role of mean platelet volume (MPV) as a predictor of outcomes in various cancer entities including colorectal cancer (CRC) has already been analyzed. However, data on the prognostic and predictive value of MPV in CRC over multiple lines of systemic therapy are missing. In this retrospective single-center cohort study, 690 patients with UICC stage II, III or IV CRC receiving adjuvant and/or palliative chemotherapy were included. Primary endpoints in the adjuvant, palliative and best supportive care (BSC) setting were 3-year recurrence-free survival (RFS), 6-months progression-free survival (PFS), and 6-months overall survival (OS), respectively. Kaplan–Meier estimators, log-rank tests, and uni- and multivariable Cox models were used to analyze RFS, PFS and OS. A cut-off defining patients with low MPV was chosen empirically at the 25th percentile of the MPV distribution in the respective treatment setting. Three-year RFS was 76%. Median 6-month PFS estimates in 1st, 2nd and 3rd line therapy were 59, 37 and 27%, respectively. Median 6-month OS in BSC was 31%. Small platelets as indicated by low MPV did not predict for shorter RFS. In the first 3 palliative treatment lines a consistent association between low MPV and decreased 6-month PFS was not observed. In the BSC setting, patients with low MPV had numerically but not significantly shorter OS. Higher MPV levels did not consistently predict for ORR or DCR across the first 3 palliative treatment lines. Small platelets are not predicting CRC outcomes, and thus are hardly useful for influencing clinical decision making.

Background/aim Colorectal cancer (CRC) is the third most common cancer worldwide. The prognosis between left- and right-sided CRC differs, partly due to baseline differences as vascular supply. The purpose of the present study was to investigate whether there are genetic differences between left- and right-sided CRC. Patients and methods Eighty-seven patients with CRC (mean age: 61 years) were retrospectively included in the study. Blood samples were used for genetic analysis, by applying the sequencing research panel Ion AmpliSeq Colon and Lung Cancer Research Panel V2. Statistical analyses included Chi-square tests, Kaplan-Meier survival curves, and univariate/multivariate Cox-regression analyses. Results By testing the sequence of 22 genes included in the panel, a significant difference was detected between left- and right-sided CRC regarding the expression of BRAF and DDR2 genes, with mutations occurring more often in the right-sided CRC. In the multivariate setting, left-sided CRC only turned out as a significant positive prognostic parameter regarding progression-free survival, irrespective of the type of chemotherapy or BRAF and NRAS mutations. Conclusion Tumour location was the only parameter proven to be an independent prognostic factor for CRC in the present study.

IntroductionMetastasectomy is hypothesised to improve OS in metastatic STS, but evidence in favour of this approach derives from non-controlled single-arm cohorts affected by selection bias. The objective was to quantify the effect of metastasectomy vs. non-surgical management on overall survival (OS) in patients with metachronous metastases from extremity- and trunk soft tissue sarcoma (STS).Materials and methodsFrom a population of 1578 STS patients, 135 patients who underwent surgery for localised STS at two European centres between 1998 and 2015 and developed metachronous STS metastases were included. Propensity score analyses with inverse-probability-of-treatment-weights (IPTW) and landmark analyses were performed to control for selection and immortal time bias, respectively.ResultsOS was significantly longer in the 68 patients undergoing metastasectomy than in the 67 patients who were treated non-invasively for their metastasis (10-year OS: 23% vs. 4%; hazard ratio (HR) = 0.34, 95% CI: 0.22–0.53, p ConclusionIn this observational bi-centre study, metastasectomy was associated with prolonged survival in patients with metachronous STS metastases. In the absence of randomized studies, our results indicate that metastasectomy should be considered as an important treatment option for metachronous STS metastases.

Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: [1] Early TLS, composed of dense lymphocytic aggregates without FDCs, [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.

Background/Aim: Growing evidence suggests that human cancers are stem cell diseases and recent data support the existence of cancer stem cells (CSCs) in a variety of malignancies, including colon cancer. These CSCs were shown to be capable of initiating tumor development and progression. Several studies have suggested CD133, CD26 and CD44 as markers of tumor-initiating cells of colon cancer. The purpose of the present study was to assess the impact of single-nucleotide polymorphisms (SNPs) in stem cell-related genes on clinical outcome in a large cohort of colon cancer patients with clinical stage II and III. Patients and Methods: Data from 599 consecutive patients with colon cancer stage II and III, treated between 1995 and 2011 at a single centre, were retrospectively evaluated. Genomic DNA was extracted from paraffin-embedded normal tissue distant from the tumor to obtain germline DNA. Allelic distribution of polymorphisms was tested for deviation from Hardy-Weinberg equilibrium using x(2)-test. The association of polymorphisms with time to recurrence (TTR) and overall survival (OS) was analyzed using Kaplan-Meier curves and compared by the log-rank test. Case-wise deletion for missing polymorphisms was used in univariable and multivariable analyses. Results: CD44 rs187115 showed a statistically significant association with TTR; patients carrying at least one G allele had a significant reduced risk of recurrence compared to patients with the homozygous A/A variant (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.48-0.94, p=0.019). CD44 rs13347 showed a statistically significant association with OS. Patients carrying at least one T allele in rs13347 had a significantly reduced risk of death compared to patients with the homozygous C/C variant (HR=0.61, 95% CI=0.41-0.92, p=0.019). None of the other investigated polymorphisms (CD44 rs187116, CD44 rs7116432, CD44 rs353639, DPP4 rs2268889, DPP4 rs3788979, DPP4 rs7608798 and CD133 rs2240688) were associated with either TTR or OS. Conclusion: Germline variants rs13347 and rs187115 in the stem cell gene CD44 are prognostically relevant in stage II and III colon cancer patients.

Background The Lung Immune Prognostic Index (LIPI), consisting of an elevated derived neutrophil-lymphocyte ratio (dNLR, 1 point for dNLR > 3 units) and an elevated lactate dehydrogenase level (LDH, 1 point for LDH > upper limit of normal) has recently been proposed as a biomarker for predicting immune checkpoint inhibitor (ICI) therapy outcomes in advanced non-small cell lung cancer (NSCLC). We sought to validate the LIPI in an external cohort, and quantify the evolution of the LIPI over time during ICI therapy. Methods dNLR levels, LDH levels and ICI treatment outcomes including disease control rate (DCR), 1-year progression-free survival (PFS), and 1-year overall survival (OS) were ascertained from 87 patients with advanced NSCLC who were treated with ICIs at a single academic center in Austria (Table). Results DCR estimates were 59%, 43%, and 32% in patients with good (0 points, n = 22), intermediate (1 point, n = 40), and poor (2 points, n = 25) LIPI risk (p = 0.171). One-year PFS estimates were 36%, 27%, and 10% (log-rank p = 0.015), and corresponding 1-year OS estimates were 53%, 52%, and 20% (log-rank p = 0.003), respectively. During ICI treatment, 1,227 LIPI measurements were available. In linear mixed modeling, the LIPI remained stable over time in the 29 patients without disease progression (average change/month=0.0 points, 95%CI: -0.1-0.0, p = 0.161), but increased over time in the 56 patients who developed disease progression (average change/month=0.02 points, 95%CI: 0.0-0.03, p = 0.004). Conclusions This study externally validated an elevated LIPI as a biomarker for poor ICI treatment outcomes in patients with advanced NSCLC. The LIPI increases before disease progression (Table). Continuous data are reported as medians [25th-75th percentile], and count data as absolute frequencies (%). Table . 1263P Baseline characteristics of the study population Variable Median IQR or absolute count % dNLR (units) 2.7 [1.8-4.1] LDH (U/L) 267 [199-346] Age (years) 67 [59-74] Female sex 41 (47%) ECOG performance status (points) 0 [0-1] Never smoker 19 (22%) Tumor histology / ---Squamous NSCLC 19 (22%) ---Adenocarcinoma 59 (68%) ---Other 9 (10%) PD-L1 expression (%) 50 [1-80] Treatment line of IO agent / ---1st line 36 (41%) ---2nd line 43 (49%) ---3rd, 4th, or 5th line 8 (10%) IO agent / ---Nivolumab 49 (56%) ---Pembrolizumab 35 (40%) ---Atezolizumab 3 (3%) Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

BACKGROUND: The identification of predictive biomarkers is the basis of individualized cancer treatment. To this end, non-invasive molecular profiling of circulating tumor DNA (ctDNA) from peripheral blood could eliminate ineffective therapy attempts. In this prospective, non-randomized, open two-stage clinical phase II study (EudraCT number: 2014-005341-44), the success of a targeted therapy selected by molecular tumor profiling was evaluated. Patients with locally advanced or metastasized carcinoma were recruited at the Division of Oncology at the Medical University of Graz. The primary endpoint was set as a 1.2-fold increase of PFS compared to the last evidence-based drug therapy. METHODS: Whole-genome sequencing (0.1x coverage) and a cancer hotspot panel of clinically relevant genes were performed on plasma DNA to identify clinically relevant somatic copy number alterations (SCNAs) and mutations. To match the genetic profile to targeted treatments, publicly available databases such as “My Cancer Genome” were used. Annotated results were discussed at a molecular tumor board including oncologists, pathologists and a clinical geneticist. Additionally, selected molecular profiles were analyzed retrospectively via CureMatch PreciGENE™ to validate our results and to test the algorithm for its potential to identify combinatorial therapy options. RESULTS: In accordance with the study protocol, an interim analysis was performed after 24 patients. Median age was 56 years (range 38-74). Colorectal cancer (n=7) comprised the majority of the tumor entities evaluated whereas pancreas (n=4), cholangiocarcinoma (n=2), cardiac (n=2), CUP (n=2), renal (n=1), gallbladder (n=1), breast (n=1), laryngeal (n=1), gastric (n=1), esophageal (n=1) and bladder (n=1) comprised the remaining number of cases in this pan-cancer cohort. Informative results could be achieved in 18 patients (75%), meaning that either an SCNA or mutation was detected and that tumor-specific DNA content was above 5% (median tumor fraction 22.7%, range 5.2-40.3). Of these, 8 patients had a molecular target associated with a current existing drug. Furthermore, PreciGENE™ analysis was able to identify either a 2-drug or 3-drug combination option in each of the tested cases, including a case for which no therapy was previously identified. CONCLUSIONS: Statistical analysis of the molecular tumor board decisions and patient outcomes is now ongoing. However, early evidence demonstrated that only a low number of patients benefited from this approach. Retrospective analysis of select cases via the CureMatch PreciGENE™ platform was able to suggest combination therapies overlooked by standard database matching of actionable targets with existing therapies, suggesting the power of a machine learning approach to finding evidence-based therapies and potentially improving patient outcomes. Citation Format: Samantha O. Perakis, Peter Ulz, Jakob M. Riedl, Lukas Scheipner, Karl Kashofer, Gerald Hoefler, Jochen B. Geigl, Michael R. Speicher, Ellen Heitzer, Armin Gerger. Molecular-biological tumor profiling for drug treatment selection in patients with advanced and refractory carcinoma: A prospective, two-stage Phase II individualized cancer treatment study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT130.

Patients with soft tissue sarcoma (STS) being treated following the standardized guidelines can still not be guaranteed to remain free from local recurrence (LR). A complete tumour resection has been accepted as a major prognostic factor for LR. This retrospective study was designed to analyse the influence of two different classifications of resection margins (R-classification and UICC-classification) on LR in STS patients.Of 411 patients treated at our institution for STS, 265 were eligible for statistical analysis. Kaplan-Meier curves and Cox regression models were used to assess the impact of an R0 resection according to the R-classification (resection margin clear but allowing1 mm) and according to the UICC-classification (minimal resection margin ≥1 mm) on LR.Survival curves showed a lower LR rate for R0 resections in the UICC-classification, namely 1.3%, 12% and 12% as compared to 2.1%, 9.5% and 16.5% for the R-classification. In multivariate analysis calculated separately for each classification, R1 resection as defined by the R-classification (HR: 11.214; 95%CI: 2.394-52.517; p = 0.002) as well as by UICC-classification (HR: 15.634; 95%CI: 2.493-98.029; p = 0.003) remained significant.In our study, margin status according to both classifications represents an independent prognostic factor for LR in patients with STS following curative surgery. Local control rates were superior after a minimal resection margin of 1 mm (R0 by UICC-classification) compared to R0 resections after the R-classification.

e15621 Background: Second-line chemotherapy (2LCTX) is increasingly applied in patients (pts) with advanced biliary tract cancer (aBTC), although no randomized trial has so far demonstrated the benefit of this intervention over best supportive care (BSC) alone. In the absence of randomized data, we thus conducted a comparative effectiveness analysis of survival outcomes in aBTC pts treated with BSC±2LCTX. Methods: In this single-center cohort study, we retrospectively included 80 pts with metastatic, recurrent, or inoperable aBTC who completed 1st-line CTX at our department between 2003 and 2016. Thirty-eight of these pts (48%) received 2LCTX+BSC (Fluoropyrimidine (FP) mono: n = 26 (68%), FP-based combination CTX: n = 9 (24%), Others: n = 3 (8%)). Primary endpoint was 18-month overall survival (OS). An inverse-probability-of-treatment-weighted analysis (IPTW) was implemented to rigorously account for imbalances in prognostic variables between the two study groups. Results: During a median follow-up of 14.8 months, we observed 49 deaths. Six-month, 12-month, and 18-month OS estimates were 77%, 53% and 23% in the BSC+2LCTX group, and 29%, 21%, and 14% in patients in the BSC group, for a univariable hazard ratio (HR) for OS of 0.36 (95%CI: 0.20-0.64, p = 0.001). However, pts receiving 2LCTX+BSC had a significantly higher prevalence of favorable prognostic variables, such as a higher Karnofsky Index (p = 0.0001), lower serum bilirubin (p = 0.03), higher hemoglobin (p = 0.002), and higher serum albumin (p = 0.0007). After careful adjustment for these imbalances using IPTW, 2LCTX+BSC was not associated with an OS benefit over BSC alone (Adjusted HR = 0.62, 95%CI: 0.30-1.29, p = 0.201). In IPTW analysis, 6-, 12-, and 18-month OS were 51%, 33% and 14% in the BSC+2LCTX group, and 35%, 29%, and 19% in patients in the BSC group. The beneficial association of 2LCTX with OS was highly time-dependent, with IPTW HRs of 0.07 (p = 0.002), 0.42 (p = 0.05), and 0.53 (p = 0.11) after 3, 6, and 12 months, respectively. Conclusions: Within the limitations of a non-randomized study, our data support the concept that 2LCTX is associated with a short-term OS benefit in pts with aBTC.

e15084 Background: The aim of this study is to quantify the value of the inflammatory biomarkers neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR), C-reactive protein (CRP) level and the advanced lung cancer inflammation index (ALI) as predictive and prognostic markers for treatment and survival outcomes over the first three chemotherapy lines in metastatic colorectal cancer (mCRC) patients. Methods: 258 patients with mCRC undergoing palliative chemo(immuno-)therapy were included in this retrospective study. Primary endpoints were 6-month progression free survival (PFS) and overall response rate (ORR) during 1st-line, 2nd-line, and 3rd-line treatment, and 6-month OS during best supportive care. Results: In multivariable analysis adjusting for polychemotherapy, 1 standard deviation (SD) increase in NLR was associated with a 8.5% absolute lower ORR in first line (95%CI: 11-7, p < 0.0001), 3% lower ORR in second line (4-2, p < 0.0001), and 3% lower ORR in third line (8-2, p = 0.24), respectively. The other inflammatory markers were not significantly associated with ORR. Regarding PFS, a higher NLR was consistently associated with higher risk of progression or death across all treatment lines, with rising hazard ratios (HR) over treatment lines (HR 1.30, p = 0.021 first line); (HR 1.37, p < 0.0001 second line); (HR 1.44 , p = 0.042 third line). The PLR was associated with 6 month PFS over all lines. (HR 1.43 (95%CI 1.09 – 1.88, p = 0.009 first line); (HR1.67 (95%CI 1.34 – 2.09, p < 0.0001 second line) and (HR 1.43 (95%CI 1.04 – 1.98, p = 0.029 in third line)) For CRP, the prognostic association was significant in the first two chemotherapy lines and in case of BSC. (HR 1.49 (95%CI 1.23 – 1.80, p < 0.0001 first line); (HR1.25 (95%CI 1.06 – 1.47, p = 0.007 second line); (HR 1.09 (95%CI 0.81 – 1.48, p = 0.552 third line and HR 1.43 (1.15 – 1-79, p = 0.002 in BSC)). More detailed results concerning the other biomarkers will be presented at the meeting. Conclusions: Our data demonstrate that inflammatory biomarkers are important and independent indicators of response to antineoplastic chemotherapy, relevant not only in first, but also in later treatment lines.

e15083 Background: The tumor immune infiltrate and organized lymphocytic aggregates within the tumor microenvironment, known as tertiary lymphoid structures (TLS), play a critical role in cancer. We hypothesize that the maturation stage of TLS harbors prognostic information on recurrence risk in patients (pts) with non-metastatic colorectal cancer (nmCRC). Methods: In a comprehensive immunofluorescence and clinical analysis of 111 pts with UICC stage II & III nmCRC (median age: 65 yrs; female: n = 53 (48%); stage III: n = 69 (62%)), we quantified the number and maturation status of tumor-associated TLS in baseline surgical specimens:[1] Early TLS (E-TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS (PFL-TLS, having FDCs but no germinal center (GC) reaction), and [3] Secondary follicle-like TLS (SFL-TLS, having an active GC reaction). The 3-year incidence of recurrence was the primary endpoint of this study, which occurred in 19 pts (3-year recurrence risk = 18.3%). Results: Most TLS formed in tissue adjacent to the tumor. The median number of TLS/mm of tumor perimeter was 1.0 [25th-75th percentile: 0.5-1.7]. The average proportions of different TLS maturation stages were 56% of E-TLS [40-78], 20% of PFL-TLS [6-37], and 16% of SFL-TLS [0-32]. A structural equation model was fitted to summarize the TLS counts and maturation stages into a TLS maturation immunoscore for predicting recurrence. 3-year recurrence risks were 31.7% (95%CI: 17.2-47.3), 15.9% (5.7-30.5), and 9.4% (2.4-22.4) in pts in the 1st, 2nd, and 3rd tertile of the score (Gray’s test p = 0.05). A higher score was significantly associated with a lower recurrence risk (Hazard ratio (HR) for 10 units increase = 0.76, 95%CI: 0.59-0.97, p = 0.03), and this association prevailed in multivariable analysis adjusting for age, ECOG performance status, stage, and adjuvant chemotherapy (Adjusted HR = 0.73, 0.54-0.99, p = 0.05). Conclusions: Tumors of nmCRC pts with a very low risk of recurrence are characterized by an increased fraction of mature TLS comprising FDCs and GCs. If confirmed prospectively, adjuvant chemotherapy may be avoided in nmCRC pts with a high TLS maturation score.