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Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (n = 202), first-line validation cohort (n = 118), second-line cohort (n = 56), and surgery cohort (n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08–1.46) and IL-15 (HR = 2.23, 95% CI 1.48–3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds.

Background: To investigated the prognosis of the most prevalent cancers (breast-, gastrointestinal-, and lung cancer), according to cancer status (i.e., active-, non-active-, history of-, and no cancer), following first-time of acute coronary syndrome (ACS). Methods: Danish nationwide registers were used to identify patients with first-time ACS from 2000−2018. Patients were stratified according to cancer type and status. Hazard ratios (HR) estimated by adjusted Cox regression models for 1year all-cause mortality reported. Further absolute risks of 1year cardiovascular versus non-cardiovascular death and 30-day cumulative incidence of coronary angiograms (CAG) was estimated, using the Aalen-Johansen non-parametric method, with competing risk of death. Results: We identified 150,478 (95.7%) with no cancer, 2,370 (1.5%) with history of cancer, 2,712 (1.7%) with non-active cancer and 1,704 (1.1%) with active cancer. Cancer patients were older with more comorbidities than patients with no cancer. When compared with no cancer, we found HRs (95% confidence intervals) of 1.71 (1.44−2.02), 2.47 (2.23−2.73) and 4.22 (3.87−4.60) correspondingly for active breast-, gastrointestinal-, and lung cancer. Increased HRs were also found for non-active cancers, but not for history of cancer. Cardiovascular disease was the leading cause of death in all patients. Among patients with active breast-, gastrointestinal-, and lung cancer 43%, 43%, and 31% underwent CAG, correspondingly, compared with 77% of patients without cancer. Conclusions: Active- and non-active cancers were associated with an increased 1-year all-cause mortality compared with patients with history of cancer and no cancer. Cardiovascular disease was the leading cause of death; notably CAG was less frequently performed in cancer patients.

Sebastian Kinnberg Nielsen,1 Nina Nouhravesh,1 Mads Hashiba Jensen,1 Rawia Farah Gedde Jensen,1 Mads Falk Klein,2 Zaigham Saghir,3,4 Dorte Nielsen,5 Morten Schou,1 Morten Lamberts1 1Department of Cardiology, Herlev-Gentofte University Hospital, Copenhagen, Denmark; 2Department of Surgery, Herlev-Gentofte University Hospital, Copenhagen, Denmark; 3Department of Respiratory Medicine, Herlev-Gentofte University Hospital, Copenhagen, Denmark; 4Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 5Department of Oncology, Herlev-Gentofte University Hospital, Copenhagen, DenmarkCorrespondence: Sebastian Kinnberg Nielsen, Department of Cardiology, Herlev-Gentofte University Hospital, Gentofte Hospitalsvej 1, Opgang 6, 3. sal 2900, Hellerup, Copenhagen, Denmark, Tel +45 40479556, Email Sebastian.Kinnberg.Nielsen03@regionh.dkBackground/Aim: The Danish National Patient Registry (DNPR) provides unique epidemiological insight, but often lacks granular data. We propose a procedure-based definition of cancer status in patients with breast-, lung- and colorectal cancer, which can be applied to administrative health databases. New definitions of cancer status are needed as mortality and morbidity are closely linked to cancer status, yet most studies only use duration since cancer diagnosis as a severity marker. The aim of the study was to validate a new pragmatic definition.Methods: Medical journals of 600 patients, with breast-, lung- and colorectal cancer from the Department of Oncology at Herlev-Gentofte Hospital were retrospectively reviewed. We defined active cancer as a cancer diagnosis, not followed by a potentially curative procedure within 6 months of the diagnosis. The remaining patients were characterized as having non-active cancer. This dichotomization was then compared to a cancer status assessment based on treatment received and paraclinical test such as their first post-procedural control scan. Based on this comparison, we calculated the positive predictive value (PPV) of our definitions of active and non-active cancer.Results: The calculated PPVs for active breast-, lung- and colorectal cancer were 87% (CI 95%: 0.74– 0.99), 91% (CI 95%: 0.87– 0.96) and 82% (CI 95%: 0.73– 0.91). The PPVs for non-active breast-, lung- and colorectal cancer were 95% (CI 95%: 0.92– 0.99), 91% (CI 95%: 0.82– 0.99) and 73% (CI 95%: 0.66– 0.81), respectively.Conclusion: We found an overall high PPV for both active and non-active cancer across all three types of cancer.Keywords: active cancer, non-active cancer, DNPR, validation, epidemiology

Biliary tract cancer (BTC) is characterized by a desmoplastic extracellular matrix (ECM). We tested the diagnostic and prognostic use of seven circulating biomarkers of ECM remodeling: pro-peptides of type III collagen (PRO-C3), VI (PRO-C6) and XI (PRO-C11), matrix metalloprotease (MMP) degraded type III collagen (C3M) and type IV collagen (C4M) fragments, granzyme B degraded type IV collagen fragments (C4G) and MMP degraded and citrullinated vimentin (VICM) a marker of macrophage activation. The study included 269 patients with all stages of BTC and 49 patients with benign biliary tract diseases. Serum samples from BTC patients were collected before surgery, or before first- or second-line chemotherapy. C3M, C4M, PRO-C3, PRO-C6, PRO-C11 and VICM levels were elevated in patients with BTC compared to patients with benign disease. Receiver operating characteristics curve analyses identified PRO-C3 (area under curve [AUC] = 0.87) as the ECM marker with the best diagnostic performance. The ECM biomarkers correlated with inflammation biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6] and YKL-40) but not with CA19-9. To investigate prognostic performance, patients were split into three cohorts (first-line, second-line and surgery). Elevated ECM biomarker levels were associated with short overall survival (OS), but only pretreatment PRO-C3 and PRO-C6 were associated with OS in both the first-line and second-line settings when adjusting for CA19-9, performance status and stage in a multivariate Cox-regression analyses. Our results indicate that collagen remodeling is increased in patients with BTC and associated with survival. The collagen pro-peptides (PRO-C3 and PRO-C6) could be used as novel biomarkers in these patients.

Background Sparse evidence exists regarding the feasibility and patients' experiences of exercise programs among older cancer populations. Objective The aim of this study was to explore the experiences of older patients with advanced cancer who participated in a 12-week supervised and multimodal exercise program in a hospital setting. Methods Individual interviews were conducted with 18 participants (≥65 years) with advanced cancer who completed the intervention program regardless of compliance rate. In addition, written evaluation questionnaires were collected. Data were analyzed using thematic analysis. Results Three main themes were identified: (1) Motivated to strengthen body and mind, with the subthemes "Doing what only I can do"and "Reaching goals with support from healthcare professionals and peers"; (2) Exercise as an integrated part of the treatment course; and (3) Overcoming undeniable physical limitations. Conclusions The participants experienced several benefits from participation, including physical improvements, increased energy, reduction of symptoms, and improved social engagement. Goal setting, being positively pushed and cheered on, and integration of fun games increased motivation. In contrast, being pushed beyond physical limitations and experiencing severe symptoms were experienced as barriers toward exercising. Adherence to the exercise program was facilitated by coordinating a tailored program with medical appointments and receiving comprehensive support and guidance. Implications for Practice Multimodal exercise programs seem to be beneficial for older patients with advanced cancer and should be coordinated with oncological treatment in combination with targeted support and advice on symptom management.

Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC).Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%.Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events.The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual.

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197, SCOPUS: ar.j, info:eu-repo/semantics/published

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.

BACKGROUND Communication between patients and healthcare professionals becomes increasingly important as patients with cancer are primarily treated in outpatient settings, where the time to communicate is brief. There is a need to understand patients' experiences of communication to ensure person-centered communication during treatment. OBJECTIVE The aim of this study was to explore how patients experience communication with healthcare professionals during their course of treatment in an oncology outpatient clinic to elucidate how their needs for support are met. METHODS Data were generated through semistructured qualitative interviews in patients with cancer who received treatment in an oncology outpatient clinic (n = 18). Interpretive description methodology and symbolic interactionism inspired the analytical approach. RESULTS Three overarching communication categories were generated, namely, verbal practices, relational practices, and nonverbal practices, which reflect distinct characteristics and the quality of the communication. Communication was characterized as being informative, cheerful, and routinized, which the patients found supportive and, contrarily, superficial, task focused, lacking continuity in care, and missing existential dimensions. CONCLUSION The communication practice in the oncology outpatient clinic especially supported patients in managing their treatment and side effects. However, psychological, social, and existential concerns were rarely addressed, requiring the patient to self-manage these issues in everyday life while living with cancer. IMPLICATIONS FOR PRACTICE Patients are socialized by verbal and nonverbal communication practices in the outpatient clinic, which influences their expectations of what to talk about during their treatment. Methods are needed to support person-centered communication in outpatient settings, so patient care needs are met more broadly.

PD-L1 expression is a predictive biomarker for anti-PD-L1 immunotherapy in triple negative breast cancer (TNBC). In the neoadjuvant setting, immunohistochemical (IHC) evaluation of PD-L1 expression can only be performed on small tissue biopsies. In our study we investigated heterogeneity of PD-L1 expression in TNBC, and how reliably PD-L1 expression in small tissue samples reflects PD-L1 expression in larger tumor sections in TNBC. Tissue microarrays (TMAs) were constructed from surgical specimens of 110 patients with TNBC. TMAs contained 4 cores (1 mm in diameter) per patient. To evaluate PD-L1 expression, TMAs were stained with PD-L1 IHC 22C3 PharmDx. Single-core PD-L1 expression was compared to overall PD-L1 expression of each patient’s tumor, to ascertain how often small samples of tumor tissue show the same PD-L1 expression as larger tumor samples. Our study found substantial heterogeneity of PD-L1 expression between different TMA cores from the same patient. Heterogeneity was greater in immune cells (ICs) than in tumor cells, in large part due to the uneven distribution of ICs in the tumor. For IC PD-L1 expression, we found that sensitivity can be as low as 0.81 for detecting PD-L1 expression at the 1% threshold most commonly used in breast cancer. Negative predictive value for ICs was 0.7. There is substantial heterogeneity of PD-L1 expression between small tissue samples from the same TNBC tumor, especially for IC expression. This poses challenges for evaluation of PD-L1 expression in the neoadjuvant setting. Negative biopsies should prompt further investigation, and multiple biopsies might be necessary.

Secreted phospholipase A2 group IIa (sPLA2-IIa) has been shown to promote tumor genesis and cell proliferation. The properties of this group of enzymes are utilized in liposomal drug delivery of chemotherapy. sPLA2-IIa is also under investigation as a possible treatment target in itself, and as a prognostic marker. The expression of sPLA2-IIa in breast cancer has not been examined extensively, and never using immunohistochemistry. We sought to investigate the expression of sPLA2-IIa in a cohort of advanced breast cancer patients with correlation to known clinicopathologic risk factors and survival. Material from 525 breast cancer patients (426 primary tumors and 99 metastases or local recurrences) was examined for sPLA2-IIa expression using immunohistochemistry. Out of these, 262 showed expression of sPLA2-IIa. We found that there was no correlation to clinicopathologic characteristics, and no impact of sPLA2-IIa expression on prognosis. However, we found that a large proportion of patients in our study had high levels of sPLA2-IIa expression, and that sPLA2-IIa was equally expressed in primary tumors and metastases. These findings may be significant in the future development of liposomal drug delivery or targeted sPLA2-IIa treatment.

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Inflammation is an enabling characteristic of the hallmarks of cancer. There has therefore been increasing interest in the clinical value of circulating inflammatory biomarkers in cancer. In this review, we summarize results on C-reactive protein (CRP), alone or as part of the Glasgow Prognostic Score (GPS, composed of CRP and serum albumin), as a biomarker of prognosis or prediction and monitoring of therapeutic response in patients with breast cancer. A systematic literature search was performed in Medline and Embase from 1990 to August 2021. The association of serum CRP and overall survival and disease/progression-free survival was summarized in meta-analyses using a random effects model. The results from a total of 35 included studies (20,936 patients) were divided according to three identified patient settings (metastatic, non-metastatic, and general setting). Most of the studies examined prognostic utility. Several larger studies observed associations between high serum CRP and poor survival, but the meta-analyses suggested a limited value in a non-metastatic and general breast cancer setting (populations with unknown or varied disease stage). In metastatic patients, however, more consistent findings supported an association between serum CRP and prognosis (hazard ratio for overall survival: 1.87 (95% CI 1.31-2.67). Only five studies examined a role in prediction or monitoring of therapeutic response. One study reported a significant association between serum CRP levels and response to chemotherapy. Findings regarding serum CRP as a biomarker in breast cancer appear inconsistent, particularly in non-metastatic and general breast cancer, where the prognostic value could not be confirmed. In patients with metastatic breast cancer we suggest that high serum CRP is an indicator of poor prognosis. Too few studies assessed the role of serum CRP in prediction or monitoring of treatment response to allow conclusions.

545 Background: The treatment options for patients with biliary tract cancer (BTC) are limited. The aim of this study was to evaluate the clinical benefit of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with BTC. Methods: In this phase 2 study with a Simon’s 2-stage optimal design, patients with BTC refractory to at least one line of prior chemotherapy were randomized 1:1 to receive SBRT of 15 Gy combined with nivolumab or nivolumab/ipilimumab stratified by performance status. Signed informed consent was obtained from all patients. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of patients with stable disease, partial response (PR), or complete response according to RECIST 1.1. Decision on expansion independently for both arms was pending on CBR from the first stage. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between September 2018 and January 2022, 61 patients (19 SBRT/nivolumab and 42 SBRT/nivolumab/ipilimumab) received at least one treatment. Forty-eight patients (79%) had cholangiocarcinoma (intrahepatic 41, perihilar 2, distal 4, unspecified 1) and 13 patients (21%) had gallbladder cancer. No responses were observed in SBRT/nivolumab arm and this cohort was closed for inclusion after first stage based on CBR of 11% (95% confidence interval (CI) 1-33). SBRT/nivolumab/ipilimumab resulted in CBR of 31% (95% CI 18-47) and an overall response rate of 11.9% (95% CI 4.0-25.6). Of the five patients that achieved a PR, the median duration of response was 4.4 months (95% CI 0.0-9.2). A median PFS of 1.7 months (95% CI 1.6-1.7) and 1.7 months (95% CI 1.6-1.8), and a median OS of 4.7 months (95% CI 3.2-6.2) and 5.0 months (95% CI 2.1-7.9) were observed for patients receiving SBRT/nivolumab and SBRT/nivolumab/ipilimumab, respectively. Treatment-related adverse events grade 3 or higher occurred in 3 (16%) patients in the SBRT/nivolumab arm and 13 (31%) patients in the SBRT/nivolumab/ipilimumab arm. One patient died due to hepatitis in the combination arm. Conclusions: The combination of SBRT/nivolumab/ipilimumab demonstrated anti-tumor activity and acceptable toxicities in patients with advanced BTC. Further studies are warranted. Clinical trial information: NCT02866383 .

Background: Older patients with cancer are at risk of physical decline and impaired quality of life during oncological treatment. Exercise training has the potential to reduce these challenges. The study aim was to investigate the feasibility and effect of a multimodal exercise intervention in older patients with advanced cancer (stages III/IV). Patients and Methods: Eighty-four older adults (≥65 years) with advanced pancreatic, biliary tract, or non-small cell lung cancer who received systemic oncological treatment were randomized 1:1 to an intervention group or a control group. The intervention was a 12-week multimodal exercise-based program including supervised exercise twice weekly followed by a protein supplement, a home-based walking program, and nurse-led support and counseling. The primary endpoint was change in physical function (30-second chair stand test) at 13 weeks. Results: Median age of the participants was 72 years (interquartile range [IQR] 68–75). Median adherence to the exercise sessions was 69% (IQR 21–88) and 75% (IQR 33–100) for the walking program. At 13 weeks, there was a significant difference in change scores of 2.4 repetitions in the chair stand test, favoring the intervention group (p

Background: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. Methods: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. Findings: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5–36·4). 12 (11%, 95% CI 6–18) patients had an objective response, including 11 (15%, 8–25) of 75 patients with PD-L1-positive tumours and one (3%; 0–17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3–4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. Interpretation: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit–risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. Funding: Merck Sharp & Dohme.

PURPOSE To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC). METHODS Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383 ). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits. RESULTS Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival. CONCLUSION Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.

BACKGROUND Metastatic colorectal cancer (mCRC) is a complex and heterogeneous disease with few standard and targeted treatment options. Next-generation sequencing of tumor tissue was performed to identify cancer driver mutations to discover possible personalized treatment options, as targeted treatment possibilities are limited for this patient population. Results of genomic sequencing in patients with treatment-refractory mCRC are described in this retrospective analysis. MATERIAL AND METHODS Clinico-pathological characteristics and genomic sequence results of consecutive patients with refractory mCRC, referred to the Experimental Cancer Therapy Unit (ECTU) at Department of Oncology, Herlev & Gentofte Hospital in the period from 1 October 2015 to 14 December 2018 were reviewed in this retrospective analysis. Tumor tissue from the patients was analyzed by next-generation sequencing using the Oncomine Comprehensive primer panel to detect actionable variants of cancer driver mutations and microsatellite instability status. From August 2018 tumor mutational burden was also analyzed. RESULTS A total of 80 patients with treatment-refractory mCRC and in a fairly good performance were referred to the ECTU during this period. Genomic sequencing of tumor tissue was performed for all 80 patients and a cancer driver mutation was identified in 90% (n = 72) of the patients. A total of 31.3% (n = 25) of the patients received therapy either as targetable therapy outside an available trial (n = 2), FDA approved therapy (n = 2), or treatment in phase 1 or 2 trials, independent of the genomic signature 26.3% (n = 21). CONCLUSION Most mCRC patients refractory to standard anti-neoplastic therapies, presented with a cancer driver mutation, however, only a few of these mutations gave rise to matched therapies as only 2.5% of the patients from this period received targeted therapy.

Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil...

Introduction Immune checkpoint inhibitors, targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways have shown remarkable potential in several types of cancer. In this review we summarize published and ongoing studies on checkpoint inhibitors in pancreatic cancer (PC). Methods We conducted a systematic literature search using Medline and Embase up to November 2018; additional data from a search on clinicaltrials.gov were included. Endpoints of interest encompassed overall survival (OS), progression free survival (PFS) and response rates. Results Full-length articles constituted a minority of included records. Furthermore, few patients were enrolled, and only few phase II studies were identified. Disappointing limited activity was demonstrated with single-agent checkpoint inhibitors in PC. A small number of studies on combination therapy showed promise with regards to response. But overall, PC patients treated with checkpoint inhibitors were not shown to elicit improvement in response rates or overall survival. Conclusion Checkpoint inhibition monotherapy has failed to elicit efficacy in patients with pancreatic cancer. Combination regimens including chemotherapy have shown initial promise, but these results need to be verified. Numerous studies on checkpoint inhibition in PC are ongoing.

PURPOSE: Older patients with cancer are underrepresented in exercise-based trials. To engage older patients in physical activity (PA), it is necessary to consider age-related decline in health, comorbidities and practicalities. The study aim was to explore attitudes towards PA and exercise among older patients with cancer to inform future exercise-based interventions.METHOD: Individual interviews (N = 23) were conducted in patients ≥ 65 years with advanced lung, biliary tract and pancreatic cancer receiving palliative oncological treatment. Patients were recruited with a purposive sampling strategy. A semi-structured interview guide focusing on attitudes towards PA and exercise, including barriers, facilitators and motivators, was used. Data on the informants' medical history, demographics and PA level was collected.RESULTS: Identified themes were: 1) a general positive perception of physical activity is expressed 2) comorbidities and external circumstances prevent physical activity, 3) fatigue overshadows life, 4) social support is key to short and long-term motivation, 5) fixed conditions keep one focused, 6) familiarity raises confidence and motivation.CONCLUSIONS: Even though perceptions of PA were positive among older patients with cancer, most struggled to stay physically active during oncological treatment. Several factors related to cancer and aging were identified as barriers; most profoundly was the overwhelming feeling of fatigue. Improving physical and mental well-being, fixed conditions (e.g. group-based exercise and supervision) and social support were identified as motivators and facilitators. Preferences for PA varied, but activities that were familiar increased motivation. Exercise programs for older patients with cancer must be adjustable to each patient's limitations, needs and personal resources.

Purpose Effective communication in cancer care and treatment is linked to better health outcomes, improved treatment adherence, and improved quality of life for cancer patients. While the characteristics of effective communication have been identified, there is sparse knowledge about the current conditions for providing effective communication especially within the outpatient clinical context, where the majority of cancer patients are currently being treated. This study aimed to explore communication practices between nurses and patients undergoing chemotherapy in an outpatient clinic to gain insight into how patients are supported in this setting. Methods Data were collected through 70 h of participant observations of nurse-patient interactions supplemented with ad hoc interviews with nurses in an oncology outpatient clinic. The methodology and data analysis are guided by interpretive description, thematic analysis and symbolic interactionism. Results Three themes were generated that characterised communication in the outpatient clinic: Treatment-centred communication, efficient communication and spatially-bound communication. While there was good opportunity for patients to learn about treatment and side effects during cancer treatment, psychosocial concerns were rarely addressed. Conclusions The outpatient setting influences the type and quality of communication between nurses and patients. Improvement of communication should include not only verbal and written information, but focus on the importance of nonverbal communication in the oncology outpatient clinic. Furthermore, there is a need to make environmental adjustments that can facilitate the opportunity for patients to express their needs and for nurses to respond to them.

Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 μg/kg up to 400 μg/kg) or intravenously (dosing at 75 μg/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNFα and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.

Background With the improvements in treatment of patients with metastatic HER2-positive breast cancer (BC) the development of CNS metastases has become a major limitation of life expectancy and quality of life for many patients. Meningeal carcinomatosis represents approximately 10-20% of CNS metastases. The prognosis of meningeal carcinomatosis remains extremely poor. In the present study, we analysed the prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid (CSF) of meningeal carcinomatosis. Methods Between June 1985 and August 1992 sixty-nine CSF samples were collected at Herlev Hospital from trastuzumab naïve BC patients suspected of meningeal carcinomatosis. The cohort was composed of BC patients from two previous studies. Meningeal carcinomatosis was confirmed by tumour cells in CSF (or autopsy/scans). The samples were centrifuged, frozen and kept at -80oC. The concentrations of YKL-40, IL-6 and HER2 in CSF were measured by commercial ELISA (Quidel and R&D) or Luminez (HER2 in second study). Overall survival in meningeal carcinomatosis was analysed with Kaplan-Meier curves and log rank tests using the median CSF value of HER2, YKL40 and IL-6 as cut off. Results 20 patients (29%) had meningeal carcinomatosis (18 patients had tumour cells in CFS, one was diagnosed by autopsy and one by CT scan; 13 of these patients participated in the first study and 7 in the second).10 patients had concomitant brain metastasis. The median survival was 35 days (4-305 days). The median [IQR] CSF concentration of YKL-40 was 284 ng/ml (187-597), IL-6 was15.9 pg/ml (6.5-51.0) and HER2 was 1.5 (0.36-8.70) in the patients with meningeal carcinomatosis. The survival was significantly shorter in patients with high levels of YKL-40 (p=0.03) and IL-6 (p= Conclusion In this cohort high levels of YKL-40 and IL-6 in CSF were associated with short survival in patients with BC and meningeal carcinomatosis. This was not found for HER2 in CSF or concomitant brain metastasis. Citation Format: Ryberg M, Johansen JS, Grantzau TL, Dehlendorff C, Nielsen DL. The prognostic value of HER2, YKL-40 and IL-6 in cerebrospinal fluid in trastuzumab naïve breast cancer patients diagnosed with meningeal carcinomatosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-06.

Effects of exercise in patients with breast cancer have been thoroughly investigated. The aim was to explore differences in effects regarding type, delivery mode and extensiveness (e.g. intensity; volume) of the interventions.We searched for randomised controlled trials including patients with breast cancer receiving systemic treatment, exercise-based interventions, and measures on patient reported- and objectively measured outcomes.Exercise showed significant and moderate effects on the primary outcomes quality of life and physical function, Standardised Mean Difference: 0.52 (95 % CI 0.38-0.65) and 0.52 (95 % CI 0.38-0.66), respectively. Type of exercise had little influence on the effects, however combined aerobic- and resistance exercise seemed superior for increasing physical function, compared to aerobic or resistance exercise. Supervised interventions were superior to partly and unsupervised. Extensiveness of the intervention only influenced physical function.Supervised interventions, more than type or extensiveness of interventions, seem to increase effects.

Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI’s, combinations of CPI’s and combinations of CPI’s with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15–20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

Simple Summary Around 15% of breast cancer patients are diagnosed as triple-negative (TNBC), which have significantly lower 5-year survival rates (77%) than other types of breast cancer (93%). Our study aimed at developing an image analysis-based biomarker to assess how the immune system interacts with the tumor and investigate the potential added value of stromal tumor-infiltrating lymphocytes (sTIL) for the prognosis of overall survival compared to the manual approach. In a large retrospective cohort of 257 patients, we found that our fully automated hematoxylin and eosin (H&E) image analysis pipeline can quantify sTIL density showing both high concordance with manual scoring and association with the prognosis of patients with TNBC. It also overcomes natural limitations of manual assessment that hinder clinical adoption of the immune biomarker. We conclude that sTIL scoring by automated image analysis has prognostic potential comparable to manual scoring and should be further investigated for future use in a clinical setting. Abstract Triple-negative breast cancer (TNBC) is an aggressive and difficult-to-treat cancer type that represents approximately 15% of all breast cancers. Recently, stromal tumor-infiltrating lymphocytes (sTIL) resurfaced as a strong prognostic biomarker for overall survival (OS) for TNBC patients. Manual assessment has innate limitations that hinder clinical adoption, and the International Immuno-Oncology Biomarker Working Group (TIL-WG) has therefore envisioned that computational assessment of sTIL could overcome these limitations and recommended that any algorithm should follow the manual guidelines where appropriate. However, no existing studies capture all the concepts of the guideline or have shown the same prognostic evidence as manual assessment. In this study, we present a fully automated digital image analysis pipeline and demonstrate that our hematoxylin and eosin (H&E)-based pipeline can provide a quantitative and interpretable score that correlates with the manual pathologist-derived sTIL status, and importantly, can stratify a retrospective cohort into two significant distinct prognostic groups. We found our score to be prognostic for OS (HR: 0.81 CI: 0.72–0.92 p = 0.001) independent of age, tumor size, nodal status, and tumor type in statistical modeling. While prior studies have followed fragments of the TIL-WG guideline, our approach is the first to follow all complex aspects, where appropriate, supporting the TIL-WG vision of computational assessment of sTIL in the future clinical setting.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals. Experimental Design: We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I–IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models. Results: Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89–0.96] in the discovery cohort and 0.92 (95% CI, 0.87–0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95–0.98) in the discovery cohort and 0.93 (95% CI, 0.90–0.96) in the replication cohort. All nine serum proteins of index I were found in index II. Conclusions: This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.

Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan–Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09–0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47–1.80) for high FOXP3 TILs (Pinteraction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine.

Background Cardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity. Subjects, Materials, and Methods Patients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention). Results A total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment. Conclusion 5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%–6% of the patients developed acute coronary syndromes during treatment with 5-FU. Implications for Practice Symptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%–19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.

Hepatic arterial infusion (HAI) of chemotherapy is an experimental treatment option for patients with colorectal cancer liver metastases (CRCLM). The current study aimed to investigate the predictive and prognostic value of cell free DNA (cfDNA) in patients with CRCLM receiving HAI with oxaliplatin and systemic capecitabine. Plasma samples from 62 patients were investigated who were included into a single arm phase II study investigating HAI treatment for patients with CRCLM. The clinical outcome of the trial has been presented previously. In brief, treatment consisted of intrahe-patic infusion of oxaliplatin 100 mg/m2 every second week with concomitant oral capecitabine 3,500 mg/m2 every second week for up to 12 cycles. Blood samples were drawn at baseline and follow-up and plasma was analyzed for cell free DNA using a direct fluorescent assay. The baseline level of plasma cfDNA was 0.92 ng/µl (95% CI 0.84-1.00). Patients with a baseline value of cfDNA above the 75th quartile had a median overall survival of 2.4 years (95% CI 0.7-2.8), compared with 3.9 years (95% CI 2.8-5.9) for patients below the 75th quartile (P=0.02). The baseline level of cfDNA was significantly lower (0.91 ng/µl, 95% CI 0.76-0.98) in patients who achieved an objective response compared to non-responders (1.79 ng/µl; 95% CI 0.99-2.57; P=0.02). The current study demonstrated a possible prognostic and predictive value of cfDNA for patients with CRCLM undergoing HAI with oxaliplatin and concomitant capecitabine.

Background/Introduction Anthracycline-based chemotherapy has improved the prognosis in cancer and hematological malignancies but is associated with the development of heart failure (HF). Besides well-known cardiac risk factors and cumulative dose of anthracycline, recent research has suggested that genetic variations associated with cardiomyopathies may increase the risk of HF associated with anthracycline. However, the importance of familial predisposition for the risk of developing anthracycline associated cardiotoxicity is unknown. Purpose To evaluate the risk of anthracycline related HF in patients with vs. without a first-degree relative with HF. Methods In the nationwide Danish registries, patients treated with anthracycline from 2004–2016 were identified. Primary outcome was a subsequent diagnosis of HF. Follow-up was 10 years or December 31, 2017. Familial relations were identified in the Danish Family Registry, which hold all persons born since 1942. Exposure was a first-degree biological relative (parent or sibling) with a diagnosis of HF. Risk of HF was evaluated in a cumulative incidence function with death as competing event and in a Fine and Grey model adjusted for age, sex, prevalent ischemic heart disease, atrial fibrillation, hypertension and chronic obstructive pulmonary disease. Results A total of 11.651 patients (mean age 48.0 (SD±8.6), 12.2% male gender) were evaluated after exclusion of 46 with pre-anthracycline HF. Mean follow-up was 4.4 years (SD±2.9). In the group with a first-degree relative with HF (n=1.608) 35 patients (2.2%) was diagnosed with HF vs. 133 (1.3%) in the group without a first-degree relative with HF (n=10.043) corresponding to incidence rates per 1000 patient years of 5.2 (95% CI: 3.8–7.3) vs. 3.0 (95% CI: 2.5–3.5). The cumulative incidence of HF was higher in the first-degree relative HF group (Figure 1a), yielding an adjusted hazard ratio of 1.53 (95% CI: 1.05–2.24, p=0.03) for HF associated with anthracycline. All-cause mortality showed a trend towards higher risk in the later 5 years of follow-up in the first-degree relative HF group with a 10-year risk of 32.4% (95% CI: 28.4–36.5) vs. 26.1% (95% CI: 24.9–27.4) but no significant difference in the Kaplan-Meier estimate (p=0.08) (Figure 1b). Conclusion In this nationwide register-based study having a first-degree relative with HF was associated with a small but increased risk of anthracycline related HF, yielding attention towards the family predisposition, when estimating the risk of cancer therapy related cardiotoxicity. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Odense University Hospital

Background ATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody developed as a first in class tumor-localizing CTLA-4 antibody for improved efficacy and reduced toxicity. Methods The study (NCT03782467) is a first-in-human dose escalation study followed by an expansion part. In the dose escalation patients with refractory solid malignancies are enrolled and the expansion part will enroll patients with cutaneous or mucosal malignant melanoma. Patients receive ATOR-1015 intravenously Q2W as a single agent until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. Intra-patient dose escalation is allowed. The primary objective is to assess the safety and tolerability of ATOR-1015. Secondary objectives include pharmacokinetics, immunogenicity, pharmacodynamics, and clinical efficacy as assessed by iRECIST. Pharmacodynamic analyses include serum cytokines, immunophenotyping of peripheral blood mononuclear cells. Tumor biopsies before and after ATOR-1015 will be analyzed. Results As of June 26, 2020, 23 patients have been exposed to ATOR-1015. The median age of the patients is 54 years (range 40–72). Patients have received a median of 5 prior lines of therapy (range 1–16). Most common cancer type is colorectal cancer.Dose levels from 0.043 mg to 600 mg have been evaluated and declared safe. Dose escalation is ongoing, and currently two patients have been enrolled at 750 mg dose level. The median time on study was 8.4 weeks (range 0.1–34.3). Five patients are on study and 18 patients have discontinued. Reasons for discontinuation included clinical deterioration (n=10), disease progression (n=5), death due to disease progression (n=2), and investigator’s decision (n=1). Twelve of the 23 patients experienced a drug-related adverse event (AE). Two patients experienced a grade 3 drug-related AE, for all other patients AEs were grade 1 or 2. Infusion-related reactions (IRR) were reported in nine patients. Predominant symptoms of the IRR were chills, rash and pain. Potentially immune-related AEs grade 1 were reported in three patients: one patient had rash, one vitiligo, and one exanthema and eczema. No dose-limiting toxicities have occurred. Best response is stable disease. Pharmacokinetic data show dose proportional kinetics up to 600 mg. Preliminary biomarker analysis shows pharmacodynamic activity of ATOR-1015. Conclusions ATOR-1015 has been safe and well-tolerated up to 600 mg. Currently 750 mg is under evaluation. Best response is stable disease. Following the dose escalation phase, an expansion cohort for patients with advanced malignant melanoma will be initiated. Ethics Approval The study is approved by the Ethic Boards in Sweden and Denmark.