German Cancer Research Center

Liebers N., Boumendil A., Finel H., Edelmann D., Kobbe G., Baermann B., Serroukh Y., Blaise D., Beelen D.W., Solano C., Itälä-Remes M., van Meerten T., Choi G., Schmidt S.A., Kröger N., et. al.

Abstract Brexucabtagene autoleucel (brexu-cel) and allogeneic hematopoietic cell transplantation (alloHCT) are effective treatments for relapsed or refractory mantle cell lymphoma (r/r MCL), but the optimal choice remains unclear. We conducted an analysis of 64 patients aged ≥50 years with r/r MCL treated with brexu-cel in the ZUMA-2 study, matching them 1:1 by propensity score to 64 (of 272) patients with r/r MCL who underwent alloHCT using data from the European Society for Blood and Marrow Transplantation registry. The median follow-up time was 36.5 months for the brexu-cel cohort and 34.1 months for the matched alloHCT cohort. Patients who received brexu-cel had a significantly higher overall survival [(OS) 81.3% vs. 59.2%; HR, 0.39; P = 0.004] and lower nonrelapse mortality (3.6% vs. 21.2%; P = 0.015) 1 year after treatment. Chronic GVHD occurred within the first year in 26.9% of patients who underwent alloHCT. However, long-term progression-free survival (PFS) and OS remain comparable. Despite the limitations of this nonrandomized study, the findings indicate a superior safety profile for brexu-cel in r/r MCL. Significance: Patients aged ≥50 years with r/r MCL had superior OS and lower nonrelapse mortality 1 year after receiving brexu-cel compared with alloHCT. However, the long-term PFS and OS are similar for both treatments. Individual risk–benefit evaluation is essential to guide optimal treatment decisions.

Chang C.Y., Jung J., Moulopoulos L.A., Wennmann M.

Farazi M., Yang X., Gehl C.J., Barnett G.C., Burnet N.G., Chang-Claude J., Parker C.C., Dunning A.M., Azria D., Choudhury A., Rancati T., De Ruysscher D., Seibold P., Sperk E., Talbot C.J., et. al.

Abstract Background: Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively affects survivors. Few risk factors are known beyond the radiation dose and volume of bladder exposed. A polygenic risk score (PRS) could identify susceptible patients. Methods: A PRS was built using genome-wide association results from the Radiogenomics Consortium (N = 3,988) and then tested in the prospective REQUITE and URWCI studies (N = 2,034). The primary outcome was time to patient–reported gross [grade ≥2, (≥G2)] hematuria, analyzed using Cox proportional hazards regression. Secondary outcomes were ≥G2 urinary retention and frequency. The PRS was externally validated for clinically diagnosed irradiation cystitis in the UK Biobank (N = 8,430). A gene-burden test evaluated rare coding variants. Results: A 115-variant PRS was associated with a significantly increased risk of ≥G2 hematuria [hazard ratio (HR) per SD = 1.22; P = 0.009] as well as urinary retention (HR per SD = 1.18; P = 0.016) and frequency (HR per SD = 1.14; P = 0.036). When binarized, men in the upper decile (PRShigh) had a >2-fold increased risk of hematuria after adjusting for clinical risk factors [HR = 2.12; P = 0.002; Harrel’s concordance index = 0.71 (95% confidence interval, 0.65–0.76)]. A similar effect size was seen in the UK Biobank for clinically diagnosed irradiation cystitis [odds ratio (OR) = 2.15; P = 0.026]. The burden test identified BOD1L1 as a putative novel radiosensitivity gene. Conclusions: This PRS identifies susceptible patients and could guide the selection of those needing reoptimized treatment plans that spare the bladder beyond currently recommended constraints. Impact: PRS-guided treatment planning in radiation oncology could lower the incidence of clinically relevant bladder toxicity and reduce the impact of this outcome on prostate cancer survivors.

Alduhayh S., Laskar R.S., Jiang X., Zhu Z., Vincent E.E., Constantinescu A., Buchanan D.D., Grant R.C., Phipps A.I., Brenner H., Huang W., Kweon S., Li L., Pearlman R., Castellví-Bel S., et. al.

Abstract Background: The tumor immunosurveillance theory supports that allergic conditions could decrease cancer risk. However, observational evidence yielded inconsistent results for the association between allergic diseases and colorectal cancer risk. We used Mendelian randomization (MR) to examine potential causal associations of allergies with the risk of overall and early-onset colorectal cancer. Methods: Genome-wide association study summary statistical data were used to identify genetic variants associated with allergic diseases (Nvariants = 65) and individual allergic conditions (asthma, hay fever/allergic rhinitis, and eczema). Using two-sample MR, we examined these variants in relation to incident overall (Ncases = 52,775 cases) and early-onset colorectal cancer (Ncases = 6,176). The mediating role of white blood cells was examined using multivariable MR. Results: In inverse-variance–weighted models, genetic liability to allergic diseases was inversely associated with overall {OR per log (odds) = 0.90 [95% confidence interval (CI), 0.85–0.96]; P < 0.01} and early-onset colorectal cancer [OR = 0.83 (95% CI, 0.73–0.95); P = 0.01]. Similar inverse associations were found for hay fever/allergic rhinitis or eczema, whereas no evidence of association was found between liability to asthma-related phenotypes and colorectal cancer risk. Multivariable MR adjustment for eosinophils weakened the inverse associations for liability to allergic diseases for overall [OR = 0.96 (95% CI, 0.89–1.03); P = 0.26] and early-onset colorectal cancer [OR = 0.86 (95% CI, 0.73–1.01); P = 0.06]. Conclusions: Our study supports a potential causal association between liability to allergic diseases, specifically hay fever/allergic rhinitis or eczema, and colorectal cancer, possibly at least in part mediated via eosinophil counts. Impact: Our results provide evidence that allergic responses may also have a role in immunosurveillance against colorectal cancer.

Moser I., Engelhardt M., Grittner U., Ferreira F.M., Denker M., Reinsch J., Fischer L., Link T., Heppner F.L., Capper D., Vajkoczy P., Picht T., Rosenstock T.

Background/Objectives: Non-invasive motor mapping with navigated transcranial magnetic stimulation (nTMS) is an established diagnostic tool to identify spatial relationships between functional and tumor areas and to characterize motor excitability. Recently, nTMS has been used to analyze the impact of different brain tumor entities on motor excitability. However, entity-specific excitability patterns are not sufficiently validated yet. Methods: We retrospectively analyzed nTMS motor mapping data of 800 motor-eloquent brain tumor patients in this observational study. The motor excitability profile consisted of four nTMS parameters (resting motor threshold (RMT), cortical motor area, amplitude and latency) measured on both hemispheres. The relationship between motor excitability parameters and tumor entity, glioma subtype and motor status were assessed using multiple regressions analyses. Regression models included patient- and tumor-specific factors. Results: Gliomas had more frequent pathologic RMT ratios (OR 1.76, 95%CI: 1.06–2.89, p = 0.030) compared to benign entities. In the subgroup of gliomas, pathologic RMT ratios were more associated with the isocitrate dehydrogenase (IDH)-wildtype status (OR 0.43, 95%CI: 0.23–0.79, p = 0.006) and less so with higher WHO grades (OR 1.61, 95%CI: 0.96–2.71, p = 0.074). This was true for both IDH-mutant astrocytomas (OR 0.43, 95%CI: 0.20–0.91, p = 0.027) and IDH-mutant oligodendrogliomas (OR 0.43, 95%CI: 0.20–0.93, p = 0.031). Motor area enlargement on the tumor hemisphere was more frequently observed in lower WHO-graded gliomas (OR 0.87, 95%CI: 0.78–0.97, p = 0.019). Interestingly, a larger cortical motor area was additionally found for oligodendrogliomas on the healthy hemisphere (OR 1.18, 95%CI: 1.01–1.39, p = 0.041). Motor deficits were related with higher RMT (OR 1.12, 95%CI: 1.05–1.21, p = 0.001), reduced amplitude (OR 0.78, 95%CI: 0.64–0.96, p = 0.019) and prolonged latency (OR 1.12, 95%CI: 1.02–1.24, p = 0.025) in the tumor hemisphere. Conclusions: Neuroplastic phenomena such as adjustment of the motor excitability level and an enlargement of the nTMS-positive motor area were more frequently observed in benign tumors and in IDH-mutated gliomas. Consequently, patients experienced motor deficits less often, suggesting a differentiated susceptibility to resection-related paresis. Future studies will analyze which stimulation paradigms are most effective in stimulating and optimizing neuroplasticity processes to improve the functional outcomes (and thus the quality of life) for patients.

Outla Z., Oyman-Eyrilmez G., Korelova K., Prechova M., Frick L., Sarnova L., Bisht P., Novotna P., Kosla J., Bortel P., Borutzki Y., Bileck A., Gerner C., Rahbari M., Rahbari N., et. al.

The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.

Outla Z., Oyman-Eyrilmez G., Korelova K., Prechova M., Frick L., Sarnova L., Bisht P., Novotna P., Kosla J., Bortel P., Borutzki Y., Bileck A., Gerner C., Rahbari M., Rahbari N., et. al.

The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.

Seidmann L., Wingerter A., Oliver Metzig M., Bornas A., El Malki K., Ustjanzew A., Ortmüller F., Kamyshanskiy Y., Kindler T., Laible M., Mohr X., Henninger N., Russo A., Beck O., Alt F., et. al.

Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies.

Michel L.L., Schwarz D., Romar P., Feisst M., Hamberger D., Priester A., Kurre E., Klein E., Müller J., Schinköthe T., Weiler M., Smetanay K., Fremd C., Heublein S., Thewes V., et. al.

ImportanceChemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting adverse effect of taxane-based chemotherapies. Currently, there is no established strategy for prevention or treatment.ObjectiveTo compare the effectiveness of 1-sided hand cooling and compression for preventing CIPN in patients with primary breast cancer receiving taxane-based chemotherapy.Design, Setting, and ParticipantsThe POLAR randomized clinical trial was conducted at the National Center for Tumor Diseases Heidelberg between November 2019 and January 2022. Female patients with breast cancer who received weekly nab-paclitaxel–based or paclitaxel-based neoadjuvant or adjuvant chemotherapy were enrolled. Patients with prior chemotherapy, preexisting neuropathy, or neuropathy-related comorbidities were excluded.InterventionsPatients were randomized 1:1 to cooling or compression of the dominant hand. No intervention was performed on the other hand. Cooling was performed with a frozen glove and compression was applied by 2 surgical gloves (1 size smaller than the tight-fitting size) 30 minutes before, after, and during taxane administration.Main Outcomes and MeasuresThe primary end point was the efficacy to prevent grade 2 or higher sensory CIPN evaluated by Common Terminology Criteria for Adverse Events, version 5.0. Further CIPN assessment included the clinical version of the Total Neuropathy Score and QLQ CIPN20. CIPN rates were compared between intervention groups. Nail toxic effects, quality of life, CIPN-associated dose reductions, treatment discontinuations, and risk factors were evaluated. Follow-up examinations were performed 1 week, 1 month, and 6 to 8 months after the last taxane dose.ResultsA total of 122 female patients with primary breast cancer (mean [SD] age, 50 [12] years) were randomized to either cooling or compression of the dominant hand. Twenty-one individuals withdrew from the study, so 101 patients were included in the final analysis (n = 52 and n = 49 for cooling and compression, respectively). Both interventions significantly reduced the incidence of grade 2 or higher CIPN (cooling: 15 participants experiencing high-grade CIPN in the cooling arm [29%] vs 26 in the control arm [50%]; P = .002; effect size, 21.15% [95% CI, 5.98%-35.55%]; compression: 12 participants experiencing CIPN in the intervention arm [24%] vs 19 in the control arm [38%]; P = .008; effect size, 14.29% [95% CI, 2.02%-27.24%]). CIPN was the main reason for treatment discontinuations in 16 of 24 participants (67%). The predominant risk factors were the cumulative taxane dosage and the neurotoxic agent. Participants experiencing grade 2 or higher CIPN showed a reduced global health status during and 6 to 8 months after taxane therapy.Conclusions and RelevanceIn this randomized clinical trial, cooling and compression were highly effective and significantly reduced the risk of high-grade CIPN.Trial RegistrationClinicalTrials.gov Identifier: NCT06541769

Delaidelli A., Burwag F., Ben-Neriah S., Suk Y., Shyp T., Kosteniuk S., Dunham C., Cheng S., Okonechnikov K., Schrimpf D., von Deimling A., Ellezam B., Perreault S., Singh S., Hawkins C., et. al.

Abstract Background While international consensus and the 2021 WHO classification recognize multiple molecular medulloblastoma subgroups, these are difficult to identify in clinical practice utilizing routine approaches. As a result, biology-driven risk stratification and therapy assignment for medulloblastoma remains a major clinical challenge. Here, we report mass spectrometry-based analysis of clinical samples for medulloblastoma subgroup discovery, highlighting a MYC-driven prognostic signature and MYC immunohistochemistry (IHC) as a clinically tractable method for improved risk stratification. Methods We analyzed 56 formalin fixed paraffin embedded (FFPE) medulloblastoma samples by data independent acquisition mass spectrometry identifying a MYC proteome signature in therapy resistant Group 3 medulloblastoma. We validated MYC IHC prognostic and predictive value across two Group 3/4 medulloblastoma clinical cohorts (n=362) treated with standard therapies. Results After exclusion of WNT tumors, MYC IHC was an independent predictor of therapy resistance and death [HRs 23.6 and 3.23; 95% confidence interval (CI) 1.04-536.18 and 1.84-5.66; P = .047 and < .001]. Notably, only ~50% of the MYC IHC positive tumors harbored MYC amplification. Accordingly, cross-validated survival models incorporating MYC IHC outperformed current risk stratification schemes including MYC amplification, and reclassified ~20% of patients into a more appropriate very high-risk category. Conclusion This study provides a high-resolution proteomic dataset that can be used as a reference for future biomarker discovery. Biology-driven clinical trials should consider MYC IHC status in their design. Integration of MYC IHC in classification algorithms for non-WNT tumors could be rapidly adopted on a global scale, independently of advanced but technically challenging molecular profiling techniques.

Kampers L.F., Metselaar D.S., Vinci M., Scirocchi F., Veldhuijzen van Zanten S., Eyrich M., Biassoni V., Hulleman E., Karremann M., Stücker W., Van Gool S.W.

Malignant glioma is a highly aggressive, therapeutically non-responsive, and deadly disease with a unique tumor microenvironment (TME). Of the 14 currently recognized and described cancer hallmarks, five are especially implicated in malignant glioma and targetable with repurposed drugs: cancer stem-like cells, in general, and glioma stem-like cells in particular (GSCs), vascularization and hypoxia, metabolic reprogramming, tumor-promoting inflammation and sustained proliferative signaling. Each hallmark drives malignant glioma development, both individually and through interactions with other hallmarks, in which the TME plays a critical role. To combat the aggressive malignant glioma spatio-temporal heterogeneity driven by TME interactions, and to overcome its therapeutic challenges, a combined treatment strategy including anticancer therapies, repurposed drugs and multimodal immunotherapy should be the aim for future treatment approaches.

Moreno Velásquez I., Peters S.A., Dragano N., Greiser K.H., Dörr M., Fischer B., Berger K., Hannemann A., Schnabel R.B., Nauck M., Göttlicher S., Rospleszcz S., Willich S.N., Krist L., Schulze M.B., et. al.

Background Using data from the largest German cohort study, we aimed to investigate sex differences in the relationship of socioeconomic position (SEP) with cardiovascular disease (CVD), CVD risk factors, and estimated CVD risk. Methods and Results A total of 204 780 (50.5% women) participants from the baseline examination of the population‐based NAKO (German National Cohort) were included. Logistic, multinomial, and linear regression models were used to estimate sex‐specific odds ratios (ORs) and β coefficients with 95% CIs of CVD, CVD risk factors, and very high‐risk score (Systemic Coronary Risk Estimation‐2) for CVD associated with SEP. Women‐to‐men ratios of ORs (RORs) with 95% CIs were estimated. In women compared with men, low versus high SEP (educational attainment and relative income) was more strongly associated with myocardial infarction, hypertension, obesity, overweight, elevated blood pressure, antihypertensive medication, and current alcohol consumption, but less strongly with current and former smoking. In women with the lowest versus highest educational level, the OR for a very high 10‐year CVD risk was 3.61 (95% CI, 2.88–4.53) compared with 1.72 (95% CI, 1.51–1.96) in men. The women‐to‐men ROR was 2.33 (95% CI, 1.78–3.05). For the comparison of low versus high relative income, the odds of having a very high 10‐year CVD risk was 2.55 (95% CI, 2.04–3.18) in women and 2.25 (95% CI, 2.08–2.42) in men (women‐to‐men ROR, 1.31 [95% CI, 1.05–1.63]). Conclusions In women and men, there was an inverse relationship between indicators of SEP and the likelihood of having several CVD risk factors and a very high 10‐year CVD risk. This association was stronger in women, suggesting that CVD risk is more strongly influenced by SEP in women compared with men.

Castoldi M., Roy S., Angendohr C., Pellegrino R., Vucur M., Singer M.T., Buettner V., Dille M.A., Wolf S.D., Heij L.R., Ghallab A., Albrecht W., Hengstler J.G., Flügen G., Knoefel W.T., et. al.

Highlights•miR-107 is globally downregulated in mouse liver cancers of different etiologies and represents a potential biomarker in human HCC.•Integration of in silico-prediction, miRNA and mRNA transcriptomics identified KIF23, a mitotic spindle-associated protein, as a specific target mediating the biological effects of miR-107.•The miR-107/KIF23 module promotes replicative fitness of liver cancer cells through an essential function in cytokinesis•Mice treated with a shRNA targeting Kif23 were completely protected from oncogene-induced liver cancer development.AbstractBackground & AimsIn hepatocellular carcinoma (HCC), there is a lack of successful translation of experimental targets identified in mouse models to human patients. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans.MethodsWe analyzed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays (TMA), were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection (HDTVi)-based preclinical HCC models in vivo.ResultsThe expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of human HCC patients. Overexpression of miR-107 or inhibition of its novel target Kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. HDTVi of vectors carrying either pre-miR-107 or anti-Kif23 shRNA inhibited the development of highly aggressive c-Myc-NRAS-induced liver cancers in mice.ConclusionsDisruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferation in vitro and prevented oncogene-induced liver cancer development in vivo, offering a novel potential avenue for the treatment of HCC in humans.Impact and implicationsOur study revealed the central role of the miR-107/KIF23 axis in controlling tumor cell fitness and HCC progression. The results demonstrate that the overexpression of miR-107 or silencing of its target, KIF23, markedly suppresses the proliferation, survival, and motility of human and mouse hepatoma cells. In this work, we demonstrate that the disruption of miR-107/Kif23 signaling effectively protects mice from an aggressive form of oncogene-induced liver cancer in vivo, implying that targeting miR-107/KIF23 might be a novel therapeutic approach for HCC in humans.Graphical abstract

Gambichler T., Girke S., Abu Rached N., Susok L., Becker J.C., Schulze H., Hirsch T., Kückelhaus M., Wellenbrock S.

Background: Merkel cell carcinoma (MCC) is a rare and frequently fatal form of skin cancer. Apart from Programmed Cell Death Protein 1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) signaling, there is a lack of knowledge regarding other immune checkpoint molecules. Recent studies have observed elevated glycoprotein CD200 (also known as OX-2) mRNA expression in in different types of tumors, with CD200R-expressing myeloid cells present in the tumor microenvironment. However, the potential role of the CD200/CD200 axis as an additional checkpoint modulator remains widely unexplored. The aim of this study was to determine the intratumoral protein expression of CD200 as well as CD200R in a larger cohort of MCC patients and to correlate the expression levels with patients’ outcomes. Methods: In this multicenter study, we investigated 68 patients with MCC (68 primary tumors and 15 corresponding metastases). Immunohistochemistry (IHC) was performed for CD200 as well as CD200R. Digital quantification and analysis of IHC were performed using QuPath-0.2.3. Results: CD200 and CD200R expression was observed in 100% of cases. Univariate analysis revealed that low CD200 expression in primary tumors (p = 0.0007, HR 9.35), male sex (p = 0.045, HR 2.41), and immunosuppression (p = 0.0031, HR 6.36) were significantly associated with MCC relapse. Low CD200 expression was also linked to prior immune checkpoint inhibitors (ICI) and/or chemotherapy treatment (p = 0.037). Multivariable analysis confirmed that low CD200 expression (p = 0.0012, HR 5.25) and immunosuppression (p = 0.0056, HR 4.11) were independent predictors of MCC relapse. Conclusions: Expression of CD200/CD200R proteins is very high in MCC and may thus be of diagnostic value. More importantly, low intratumoral CD200 protein expression in primary MCC represents a robust independent predictor of MCC relapse.

Chalitsios C.V., Markozannes G., Papagiannopoulos C., Aglago E.K., Berndt S.I., Buchanan D.D., Campbell P.T., Cao Y., Chan A.T., Dimou N., Drew D.A., French A.J., Georgeson P., Giannakis M., Gruber S.B., et. al.

Abstract Background: Waist circumference (WC) and its allometric counterpart, “a body shape index” (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease. Methods: Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively. Results: Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04–1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00–1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis. Conclusions: Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention. Impact: The proposed results have potential utility in colorectal cancer prevention.