Publications by authors named "Ulrich Keilholz"

198 Publications

Can routine register data be used to identify vulnerable lung cancer patients of suboptimal care in a German comprehensive cancer centre?

Eur J Cancer Care (Engl) 2021 Jan 15:e13398. Epub 2021 Jan 15.

Charité Comprehensive Cancer Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objectives: Several patient factors have been described to influence access to optimal cancer care like socioeconomic factors or place of residence. In this study, we investigate whether data routinely collected in a clinical cancer registry can be used to identify populations of lung cancer patients with increased risk of not receiving optimal cancer care.

Methods: We analysed data of 837 lung cancer patients extracted from the clinical cancer registry of a German university hospital. We compared patient populations by two indicators of optimal care, namely implementation of tumour board meeting recommendations as well as the timeliness of care.

Results: There was a high rate of implementation of tumour board meeting recommendations of 94.4%. Reasons for non-implementation were mainly a patient's own wish or a worsening of the health situation. Of all patient parameters, only tumour stage was associated with the two optimal care indicators.

Conclusion: Using routine data from a clinical cancer registry, we were not able to identify patient populations at risk of not getting optimal care and the implementation of guideline-conform care appeared to be very high in this setting. However, limitations were the ambiguity of optimal care indicators and availability of parameters predictive for patients' vulnerability.
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http://dx.doi.org/10.1111/ecc.13398DOI Listing
January 2021

Primary Extracellular Matrix Enables Long-Term Cultivation of Human Tumor Oral Mucosa Models.

Front Bioeng Biotechnol 2020 4;8:579896. Epub 2020 Dec 4.

Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Berlin, Germany.

3D tumor models clearly outperform 2D cell cultures in recapitulating tissue architecture and drug response. However, their potential in understanding treatment efficacy and resistance development should be better exploited if also long-term effects of treatment could be assessed . The main disadvantages of the matrices commonly used for culture are their limited cultivation time and the low comparability with patient-specific matrix properties. Extended cultivation periods are feasible when primary human cells produce the extracellular matrix . Herein, we adapted the hyalograft-3D approach from reconstructed human skin to normal and tumor oral mucosa models and compared the results to bovine collagen-based models. The hyalograft models showed similar morphology and cell proliferation after 7 weeks compared to collagen-based models after 2 weeks of cultivation. Tumor thickness and VEGF expression increased in hyalograft-based tumor models, whereas expression of laminin-332, tenascin C, and hypoxia-inducible factor 1α was lower than in collagen-based models. Taken together, the produced extracellular matrix better confined tumor invasion in the first part of the cultivation period, with continuous tumor proliferation and increasing invasion later on. This proof-of-concept study showed the successful transfer of the hyalograft approach to tumor oral mucosa models and lays the foundation for the assessment of long-term drug treatment effects. Moreover, the use of an animal-derived extracellular matrix is avoided.
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http://dx.doi.org/10.3389/fbioe.2020.579896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746540PMC
December 2020

Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer.

Oncotarget 2020 Oct 13;11(41):3688-3697. Epub 2020 Oct 13.

Charité Comprehensive Cancer Center, Berlin, Germany.

Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.
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http://dx.doi.org/10.18632/oncotarget.27763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566806PMC
October 2020

[Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma].

Aktuelle Urol 2020 Dec 7;51(6):572-581. Epub 2020 Oct 7.

Medizinische Hochschule Hannover, Urology, Hannover.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.
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http://dx.doi.org/10.1055/a-1252-1780DOI Listing
December 2020

Information, communication, and cancer patients' trust in the physician: what challenges do we have to face in an era of precision cancer medicine?

Support Care Cancer 2021 Apr 3;29(4):2171-2178. Epub 2020 Sep 3.

Charité - Universitätsmedizin Berlin, Charité Comprehensive Cancer Center, Berlin, Germany.

Purpose: Despite promising achievements in precision cancer medicine (PCM), participating patients are still faced with manifold uncertainties, especially regarding a potential treatment benefit of molecular diagnostics (MD). Hence, MD poses considerable challenges for patient information and communication. To meet these challenges, healthcare professionals need to gain deeper insight into patients' subjective experiences. Therefore, this qualitative study examined information aspects of MD programs in cancer patients.

Methods: In two German Comprehensive Cancer Centers, 30 cancer patients undergoing MD participated in semi-structured interviews on information transfer and information needs regarding MD. Additionally, patients provided sociodemographic and medical data and indicated their subjective level of information (visual analogue scale, VAS, 0-10).

Results: On average patients had high levels of information (mean = 7, median = 8); nevertheless 20% (n = 6) showed an information level below 5 points. Qualitative analysis revealed that patients show limited understanding of the complex background of MD and have uncertainties regarding their personal benefit. Further, patients described unmet information needs. Existential threat in awaiting the results was experienced as burdensome. To withstand the strains of their situation, patients emphasized the importance of trusting their physician.

Conclusion: The challenges in PCM consist in providing unambiguous information, especially concerning treatment benefit, and providing guidance and support. Therefore, psycho-oncology needs to develop guidelines for adequate patient communication in order to help healthcare providers and cancer patients to handle these challenges in the developing field of PCM.
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http://dx.doi.org/10.1007/s00520-020-05692-7DOI Listing
April 2021

Multiplexed Quantification of Four Neuroblastoma DNA Targets in a Single Droplet Digital PCR Reaction.

J Mol Diagn 2020 Aug 26. Epub 2020 Aug 26.

Department of Pediatric Hematology and Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Neuroblastoma Research Group, Experimental and Clinical Research Center, Berlin, Germany.

The detection and characterization of cell-free DNA (cfDNA) in peripheral blood from neuroblastoma patients may serve as a minimally invasive approach to liquid biopsy. Major challenges in the analysis of cfDNA purified from blood samples are small sample volumes and low cfDNA concentrations. Droplet digital PCR (ddPCR) is a technology suitable for analyzing low levels of cfDNA. Reported here are two quadruplexed ddPCR assay protocols that reliably quantify MYCN and ALK copy numbers in a single reaction together with the two reference genes, NAGK and AFF3, and accurately estimate ALK (exon 23 position 3522, C>A) and ALK (exon 25 position 3824, G>A) mutant allele fractions using cfDNA as input. The separation of positive and negative droplets was optimized for detecting two targets in each ddPCR fluorescence channel by the adjustment of the probe and primer concentrations of each target molecule. The quadruplexed assays were validated using a panel of 10 neuroblastoma cell lines and paired blood plasma and primary neuroblastoma samples from nine patients. Accuracy and sensitivity thresholds in quadruplexed assays corresponded well with those from the respective duplexed assays. Presented are two robust quadruplexed ddPCR protocols applicable in the routine clinical setting and that require only minimal plasma volumes for the assessment of MYCN and ALK oncogene status.
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http://dx.doi.org/10.1016/j.jmoldx.2020.07.006DOI Listing
August 2020

A multilayered epithelial mucosa model of head neck squamous cell carcinoma for analysis of tumor-microenvironment interactions and drug development.

Biomaterials 2020 11 6;258:120277. Epub 2020 Aug 6.

Freie Universität Berlin, Institute of Pharmacy (Pharmacology & Toxicology), Königin-Luise-Str. 2+4, 14195, Berlin, Germany. Electronic address:

Pharmacotherapy of head and neck squamous cell carcinoma (HNSCC) often fails due to the development of chemoresistance and severe systemic side effects of current regimens limiting dose escalation. Preclinical models comprising all major elements of treatment resistance are urgently needed for the development of new strategies to overcome these limitations. For model establishment, we used tumor cells from patient-derived HNSCC xenografts or cell lines (SCC-25, UM-SCC-22B) and characterized the model phenotype. Docetaxel and cetuximab were selected for comparative analysis of drug-related effects at topical and systemic administration. Cetuximab cell binding was mapped by cluster-based fluorescence lifetime imaging microscopy.The tumor oral mucosa (TOM) models displayed unstructured, hyper-proliferative, and pleomorphic cell layers, reflecting well the original tumor morphology and grading. Dose- and time-dependent effects of docetaxel on tumor size, apoptosis, hypoxia, and interleukin-6 release were observed. Although the spectrum of effects was comparable, significantly lower doses were required to achieve similar docetaxel-induced changes at topical compared to systemic application. Despite displaying anti-proliferative effects in monolayer cultures, cetuximab treatment showed only minor effects in TOM models. This was not due to inefficient cetuximab uptake or target cell binding but likely mediated by microenvironmental components.We developed multi-layered HNSCC models, closely reflecting tumor morphology and displaying complex interactions between the tumor and its microenvironment. Topical application of docetaxel emerged as promising option for HNSCC treatment. Aside from the development of novel strategies for topical drug delivery, our tumor model might help to better understand key regulators of drug-tumor-interactions.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120277DOI Listing
November 2020

Analysis of cancer-related mutations in extracellular vesicles RNA by Droplet Digital™ PCR.

Biotechniques 2020 08 25;69(2):99-107. Epub 2020 Jun 25.

Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin & Berlin Institute of Health, Charité Comprehensive Cancer Center, Berlin, Germany.

Extracellular vesicles (EVs) are taking their place as potential biomarkers in the field of liquid biopsy. In this study, EVs were isolated from plasma samples of 31 patients with colorectal cancer and melanoma via differential centrifugation and Droplet Digital™ PCR (Bio-Rad, CA, USA) was used to profile V600E/K, G12A/C/D/V and  G13D mutations from EV-derived cDNA. The concordance rates with corresponding tissue were 54% and 44% in the colorectal cancer and melanoma cohort, respectively. Two patients displayed mutations in EVs not previously detected in tissue as evidence for emerging molecular resistance to anti-EGFR and BRAF/MEK inhibitor therapy prior to radiological evidence of tumor progression. We concluded that EV-derived nucleic acids may provide clinically relevant diagnostic information and mirror evolution of the disease.
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http://dx.doi.org/10.2144/btn-2020-0028DOI Listing
August 2020

Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts.

J Clin Oncol 2020 08 12;38(22):2543-2551. Epub 2020 Jun 12.

Princess Máxima Center, Utrecht, the Netherlands.

Purpose: Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma.

Patients And Methods: The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data.

Results: For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data.

Conclusion: The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.
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http://dx.doi.org/10.1200/JCO.19.03034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392743PMC
August 2020

Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'.

Eur J Cancer 2020 08 7;135:1-7. Epub 2020 Jun 7.

University Comprehensive Cancer Center Hamburg, Department of Oncology, Hematology with Section Bone Marrow Transplantation and Pneumology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address:

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.
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http://dx.doi.org/10.1016/j.ejca.2020.04.019DOI Listing
August 2020

Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC.

Int J Cancer 2020 Oct 18;147(8):2293-2302. Epub 2020 Jun 18.

Department of Hematology and Oncology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Hindenburgdamm 30, Berlin, 12203, Germany.

Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately reanalyzed. APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV-negative HNSCC samples. An APOBEC-enriched, HPV-negative subgroup was identified, that showed higher T-cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune-evasion pathways were also enriched in these tumors. Analysis of single-cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.
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http://dx.doi.org/10.1002/ijc.33123DOI Listing
October 2020

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node-positive melanoma without the need for completion lymph node dissection.

Eur J Cancer 2020 07 23;134:9-18. Epub 2020 May 23.

Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, Rotterdam, the Netherlands.

Purpose: Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM).

Methods: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation.

Results: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance.

Conclusions: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.
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http://dx.doi.org/10.1016/j.ejca.2020.04.022DOI Listing
July 2020

Automated Real-Time Tumor Pharmacokinetic Profiling in 3D Models: A Novel Approach for Personalized Medicine.

Pharmaceutics 2020 Apr 30;12(5). Epub 2020 Apr 30.

Freie Universität Berlin, Institute of Pharmacy (Pharmaceutical and Medicinal Chemistry), 14195 Berlin, Germany.

Cancer treatment often lacks individual dose adaptation, contributing to insufficient efficacy and severe side effects. Thus, personalized approaches are highly desired. Although various analytical techniques are established to determine drug levels in preclinical models, they are limited in the automated real-time acquisition of pharmacokinetic profiles. Therefore, an online UHPLC-MS/MS system for quantitation of drug concentrations within 3D tumor oral mucosa models was generated. The integration of sampling ports into the 3D tumor models and their culture inside the autosampler allowed for real-time pharmacokinetic profiling without additional sample preparation. Docetaxel quantitation was validated according to EMA guidelines. The tumor models recapitulated the morphology of head-and-neck cancer and the dose-dependent tumor reduction following docetaxel treatment. The administration of four different docetaxel concentrations resulted in comparable courses of concentration versus time curves for 96 h. In conclusion, this proof-of-concept study demonstrated the feasibility of real-time monitoring of drug levels in 3D tumor models without any sample preparation. The inclusion of patient-derived tumor cells into our models may further optimize the pharmacotherapy of cancer patients by efficiently delivering personalized data of the target tissue.
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http://dx.doi.org/10.3390/pharmaceutics12050413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284432PMC
April 2020

Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis.

Int J Cancer 2020 Oct 24;147(8):2303-2315. Epub 2020 Apr 24.

Charité Comprehensive Cancer Center, Berlin, Germany.

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC.
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http://dx.doi.org/10.1002/ijc.33003DOI Listing
October 2020

Mutations Predict Sensitivity to Adjuvant Gemcitabine in Patients with Pancreatic Ductal Adenocarcinoma: Next-Generation Sequencing Results from the CONKO-001 Trial.

Clin Cancer Res 2020 Jul 31;26(14):3732-3739. Epub 2020 Mar 31.

Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Purpose: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data.

Experimental Design: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA.

Results: The most common mutations in the CONKO cohort were (75%), (60%), (10%), (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, = 0.005). With respect to gemcitabine treatment, mutations were a positive predictive factor for gemcitabine efficacy [mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; < 0.001); wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; = 0.483)] with a significant test for interaction ( = 0.003). In the TCGA dataset, mutations were associated with shortened DFS.

Conclusions: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3034DOI Listing
July 2020

Cancer testis antigen Cyclin A1 harbors several HLA-A*02:01-restricted T cell epitopes, which are presented and recognized in vivo.

Cancer Immunol Immunother 2020 Jul 10;69(7):1217-1227. Epub 2020 Mar 10.

Department of Hematology and Oncology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany.

Cyclin A1 is a promising antigen for T cell therapy being selectively expressed in high-grade ovarian cancer (OC) and acute myeloid leukemia (AML) stem cells. For adoptive T cell therapy, a single epitope has to be selected, with high affinity to MHC class I and adequate processing and presentation by malignant cells to trigger full activation of specific T cells. In silico prediction with three algorithms indicated 13 peptides of Cyclin A1 9 to 11 amino acids of length to have high affinity to HLA-A*02:01. Ten of them proved to be affine in an HLA stabilization assay using TAP-deficient T2 cells. Their immunogenicity was assessed by repetitive stimulation of CD8 T cells from two healthy donors with single-peptide-pulsed dendritic cells or monocytes. Intracellular cytokine staining quantified the enrichment of peptide-specific functional T cells. Seven peptides were immunogenic, three of them against both donors. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA-A*02:01-positive AML cell line THP-1. Immunopeptidome analysis based on direct isolation of HLA-presented peptides by mass spectrometry of primary AML and OC samples identified four naturally presented epitopes of Cyclin A1. The immunopeptidome of HeLa cells transfected with Cyclin A1 and HLA-A*02:01 revealed six Cyclin A1-derived HLA ligands. Epitope p410-420 showed high affinity to HLA-A*02:01 and immunogenicity in both donors. It proved to be naturally presented on primary AML blast and provoked spontaneous functional response of T cells from treatment naïve OC and, therefore, warrants further development for clinical application.
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http://dx.doi.org/10.1007/s00262-020-02519-6DOI Listing
July 2020

Support of a molecular tumour board by an evidence-based decision management system for precision oncology.

Eur J Cancer 2020 03 23;127:41-51. Epub 2020 Jan 23.

Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany; Department of Hematology and Oncology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178, Berlin, Germany. Electronic address:

Background: Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow for the interpretation of molecular analyses.

Methods: A specialized physician screened results from molecular analyses for potential biomarkers, irrespective of the diagnostic modality. Best available evidence was retrieved and categorized through establishment of an in-house database and interrogation of publicly available databases. Annotated biomarkers were ranked using predefined evidence levels and subsequently discussed at a molecular tumour board (MTB), which generated treatment recommendations. Subsequent translation into patient treatment and clinical outcomes were followed up.

Results: One hundred patients were discussed in the MTB between January 2016 and May 2017. Molecular data were obtained for 70 of 100 patients (50 whole exome/RNA sequencing, 18 panel sequencing, 2 immunohistochemistry (IHC)/microsatellite instability analysis). The MTB generated a median of two treatment recommendations each for 63 patients. Thirty-nine patients were treated: 6 partial responses and 12 stable diseases were achieved as best responses. Genetic counselling for germline events was recommended for seven patients.

Conclusion: The development of an evidence-based workflow allowed for the clinical interpretation of complex molecular data and facilitated the translation of personalized treatment strategies into routine clinical care. The high number of treatment recommendations in patients with comprehensive genomic data and promising responses in patients treated with combination therapy warrant larger clinical studies.
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http://dx.doi.org/10.1016/j.ejca.2019.12.017DOI Listing
March 2020

Cancer patients' expectations when undergoing extensive molecular diagnostics-A qualitative study.

Psychooncology 2020 02 2;29(2):423-429. Epub 2019 Dec 2.

Comprehensive Cancer Center München, Munich, Germany.

Objective: Precision cancer medicine (PCM) aims at identifying tumor-driving molecular characteristics to improve therapy. Despite early successes for some cancers, the approach faces manifold challenges. Patients undergoing extensive molecular diagnostics (MD) may hope for personal benefit, although chances are small. In order to offer suitable support to this group, health-care professionals need to gain insight into patients' experience. Thus, this study sought to explore the expectations of cancer patients undergoing MD of their tumor.

Methods: In two German Comprehensive Cancer Centers, 30 patients with advanced-stage cancer who had exhausted conventional treatment and had consented to extensive, research-oriented MD (whole-genome sequencing n = 24, panel sequencing n = 6) participated in semi-structured interviews. Following thematic content analysis by Kuckartz, the interview transcripts were coded for expectations of MD participation and topics closely related. Moreover, patients completed questionnaires on their sociodemographic characteristics, medical history, and psychosocial distress.

Results: Patients reported to be expecting (a) an improvement of their treatment, (b) a contribution to research, and/or (c) additional insight to their own cancer. Further, they described to feel individually appreciated and to have a reason to maintain hope for cure or recovery by participating in MD.

Conclusions: Molecular diagnostics participation led patients to feel treated in a more "personalized" way, allowing them a greater sense of control in their situation of severe illness. Oncologists and psycho-oncologists need to ensure comprehensive information and empathetic support for patients undergoing extensive MD to balance their expectations and actual chances of clinical benefit.
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http://dx.doi.org/10.1002/pon.5282DOI Listing
February 2020

Liquid biopsy assessment of synchronous malignancies: a case report and review of the literature.

ESMO Open 2019 16;4(4):e000528. Epub 2019 Aug 16.

Charite Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Assessment of patients with synchronous primary cancers and metastases is challenging, as it can be difficult to assign the metastases to the correct primary due to low differentiation, high similarity on histology or inaccessibility of tumour tissue. Systemic treatment for metastatic disease, however, needs to be directed at the leading histology or cover multiple tumour types with the same regimen. Considering the additional obstacles in cancer management, including tumour heterogeneity and clonal evolution, blood-based genomic profiling ('liquid biopsy') is suggested to be a useful tool to provide accessible tumour-derived biomarkers. We herein report a case of a patient with independent primary tumours of the colon and pancreas, as well as liver metastases. All lesions were resected and genotyped revealing mutations G12C and G12D in the primary tumours, respectively. The G12D mutation detected in the pancreatic tumour was retrieved in the metastasis, thus confirming the pancreatic cancer to be the origin of the liver lesions. The prevalence of the pancreatic tumour was additionally verified by the detection of the G12D variant in circulating cell-free DNA (cfDNA). This case demonstrates the utility of liquid biopsy to identify the predominant tumour burden in patients with multiple primary cancers, based on the detection of the tumour-associated gene mutation in the plasma. Serial monitoring through liquid biopsies might allow disease surveillance to guide cancer management. The review of the literature highlights the importance of liquid biopsies in personalised oncology, even though only one case report refers to the benefit of cfDNA analysis in a patient affected by synchronous primary tumours.
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http://dx.doi.org/10.1136/esmoopen-2019-000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735668PMC
August 2019

The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Evidence, Advantages, and Future Directions.

Front Oncol 2019 21;9:668. Epub 2019 Aug 21.

Medical Oncology Department, Catalan Institute of Oncology, B-ARGO Group-Badalona, Barcelona, Spain.

The addition of cetuximab to platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]), followed by maintenance cetuximab until disease progression (EXTREME), resulted in the first regimen to yield significantly improved survival outcomes in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in over 30 years. Currently, the EXTREME regimen is a guideline-recommended treatment in the first-line R/M setting, and, therefore, it is used as a control arm in all new first-line, phase 3 immunotherapy trials. More recently, new checkpoint inhibitor approaches have emerged and are changing the treatment landscape for PD-L1-positive patients with R/M SCCHN. Additionally, alternative chemotherapy backbones in R/M SCCHN are continually investigated. Replacing 5-FU with a taxane in the EXTREME regimen seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel. These cetuximab-, platinum-, and taxane-based treatments have demonstrated promising survival results and cytoreductive properties in single-arm studies. Thus, these combination treatments may be of importance to patients with high tumor burden and dangerous site involvements (e.g., causing bleeding, suffocation, dysphagia, or ulceration), in whom symptom relief is a key treatment goal. TPExtreme is the first large, randomized trial comparing a cetuximab, platinum, and taxane combination regimen with EXTREME. Currently, the substitution of 5-FU with a taxane is a feasible and clinically beneficial option for patients with contraindications to 5-FU. The TPEx regimen appears to be a new option in first-line R/M SCCHN, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. For patients with R/M disease in whom further cisplatin- or carboplatin-based treatment is unsuitable, or whose disease has already progressed on first-line R/M therapy, treatment options such as cetuximab plus a taxane, which capitalize on the combinative ability of the 2 agents, can be considered. Notably, it is as of yet unknown what second-line treatments may be suitable to follow a checkpoint inhibitor-based first-line therapy.
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http://dx.doi.org/10.3389/fonc.2019.00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712586PMC
August 2019

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

Oral Oncol 2019 10 23;97:82-91. Epub 2019 Aug 23.

Department of Medicine, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany.

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis).

Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m/week).

Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%).

Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.
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http://dx.doi.org/10.1016/j.oraloncology.2019.08.004DOI Listing
October 2019

VIST - a Variant-Information Search Tool for precision oncology.

BMC Bioinformatics 2019 Aug 16;20(1):429. Epub 2019 Aug 16.

Knowledge Management in Bioinformatics, Department of Computer Science, Humboldt-Universität zu Berlin, Rudower Chaussee 25, Berlin, 12489, Germany.

Background: Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient's genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile.

Results: VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST's ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document's content.

Conclusion: Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/.
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http://dx.doi.org/10.1186/s12859-019-2958-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697931PMC
August 2019

Characterization of the tumor immune micromilieu and its interference with outcome after concurrent chemoradiation in patients with oropharyngeal carcinomas.

Oncoimmunology 2019;8(8):1614858. Epub 2019 May 25.

Department of Radiooncology and Radiotherapy, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Intra-tumoral CD8 + T-cell infiltration in squamous cell carcinoma of the head and neck (HNSCC) has previously been linked to the efficacy of cisplatin-based chemoradiation (CDDP-CRTX) and immune checkpoint inhibitor (ICI) monotherapy. Further detailed characterization of the tumor immune-micromilieu and its influence on outcome may guide the development of CRTX-ICI combinations.

Methods: Comprehensive immune transcriptome analysis was applied to a training set of tumor specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients treated with CDDP-CRTX in the ARO-0401 phase III study (n = 33). A composite immune signature risk score (ISRS) for survival prediction was developed, and subsequently validated in two independent OPSCC cohorts treated with either CDDP-CRTX (n = 36) or mitomycin-based CRTX (MMC-CRTX, n = 31). Further validation of the ISRS was performed in the OPSCC subset (n = 79) of the TCGA HNSCC cohort. Potential interference between immune signatures and HPV status was evaluated in multivariate Cox regression models.

Results: Significant differences according to the 3-y OS status in the abundance of tumor-infiltrating T- and B-cells, and the expression levels of 51 immune-related genes were observed. A risk score based on 13 differentially expressed genes involved in cytokine signaling, T-cell effector functions and the TNFR pathway was established as robust predictive factor of OS. Its predictive power was superior to the 6-gene interferon-gamma signature of ICI efficacy and independent of the HPV status.

Conclusions: This study further elucidates the complex interaction of the tumor immune microenvironment with the efficacy of CDDP-CRTX in OPSCC. The results suggest immune markers for selection of patients treated with CRTX-ICI combinations.
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http://dx.doi.org/10.1080/2162402X.2019.1614858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682352PMC
May 2019

Comparative Analysis of Public Knowledge Bases for Precision Oncology.

JCO Precis Oncol 2019 24;3. Epub 2019 Jul 24.

Humboldt-Universität zu Berlin, Berlin, Germany.

Purpose: Precision oncology depends on the availability of up-to-date, comprehensive, and accurate information about associations between genetic variants and therapeutic options. Recently, a number of knowledge bases (KBs) have been developed that gather such information on the basis of expert curation of the scientific literature. We performed a quantitative and qualitative comparison of Clinical Interpretations of Variants in Cancer, OncoKB, Cancer Gene Census, Database of Curated Mutations, CGI Biomarkers (the cancer genome interpreter biomarker database), Tumor Alterations Relevant for Genomics-Driven Therapy, and the Precision Medicine Knowledge Base.

Methods: We downloaded each KB and restructured their content to describe variants, genes, drugs, and gene-drug associations in a common format. We normalized gene names to Entrez Gene IDs and drug names to ChEMBL and DrugBank IDs. For the analysis of clinically relevant gene-drug associations, we obtained lists of genes affected by genetic alterations and putative drug therapies for 113 patients with cancer whose cases were presented at the Molecular Tumor Board (MTB) of the Charité Comprehensive Cancer Center.

Results: Our analysis revealed that the KBs are largely overlapping but also that each source harbors a notable amount of unique information. Although some KBs cover more genes, others contain more data about gene-drug associations. Retrospective comparisons with findings of the Charitè MTB at the gene level showed that use of multiple KBs may considerably improve retrieval results. The relative importance of a KB in terms of cancer genes was assessed in more detail by logistic regression, which revealed that all but one source had a notable impact on result quality. We confirmed these findings using a second data set obtained from an independent MTB.

Conclusion: To date, none of the existing publicly available KBs on gene-drug associations in precision oncology fully subsumes the others, but all of them exhibit specific strengths and weaknesses. Consideration of multiple KBs, therefore, is essential to obtain comprehensive results.
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http://dx.doi.org/10.1200/PO.18.00371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446431PMC
July 2019

Detection of mutations in circulating cell-free DNA in relation to disease stage in colorectal cancer.

Cancer Med 2019 07 27;8(8):3761-3769. Epub 2019 May 27.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charité Comprehensive Cancer Center, Berlin, Germany.

Enthusiasm has emerged for the potential of liquid biopsies to provide easily accessible genetic biomarkers for early diagnosis and mutational cancer characterization. We here systematically investigated the suitability of circulating cell-free DNA (cfDNA) analysis for mutation detection in colorectal cancer (CRC) patients with respect to clinicopathological disease stage. Droplet Digital PCR (ddPCR) was performed to detect common point mutations in the KRAS and BRAF oncogenes in cfDNA from 65 patients and compared to mutations in tumor tissue. Stage of disease was classified according to UICC (Union for International Cancer Control) criteria. In tumor tissue, KRAS or BRAF mutations were present in 35 of 65 cases (44% UICC stage I, 50% stage II, 47% stage III, and 62% stage IV). Although cfDNA was detected in 100% of patients, ddPCR displayed the tumor tissue mutation in only 1 of 6 (17%) stage II patients, whereas 10 of 18 (56%) reported variants were verified in cfDNA samples of the stage IV cohort. No BRAF or KRAS mutation was detected in cfDNA from patients with wild-type tumor tissue. In one case of mutant stage II colon cancer (KRAS-G12C), the G12D variant was detected in cfDNA instead. Further workup revealed that circulating tumor-derived DNA and liver metastases originated from a synchronous KRAS-mutated cancer of the pancreas. Our results demonstrate that ddPCR-based analysis is highly specific and useful for mutation monitoring, but the sensitivity limits its usefulness for early cancer detection.
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http://dx.doi.org/10.1002/cam4.2219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639174PMC
July 2019

Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures.

PLoS Genet 2019 03 29;15(3):e1008076. Epub 2019 Mar 29.

cpo-Cellular Phenomics & Oncology Berlin-Buch GmbH, Berlin, Germany.

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel "sibling" 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients.
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http://dx.doi.org/10.1371/journal.pgen.1008076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457557PMC
March 2019

Somatic genome alterations in relation to age in lung adenocarcinoma.

Int J Cancer 2019 10 28;145(8):2091-2099. Epub 2019 Mar 28.

Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, W120NN, United Kingdom.

Lung adenocarcinoma (LUAD) is the most common cause of global cancer-related mortality and the major risk factor is smoking consumption. By analyzing 486 LUAD samples from The Cancer Genome Atlas, we detected a higher mutational burden among younger patients in the global cohort as well as in the TP53-mutated subcohort. The interaction effect of patient age and TP53 mutations significantly affected the mutational rate of younger TP53-mutated patients. Furthermore, we detected a significant enrichment of the smoking-related signature SI4 (SI4) among younger TP53-mutated patients, meanwhile the age-related Signature 1 (SI1) significantly increased in proportion to patient age. Although present and past smoking is reported in the TP53 wild-type patients, we observed a lower average number of somatic mutations, with no correlation with patient age. Overall, TP53 mutations were significantly higher in younger patients and mainly characterized by SI4 and Signature 24 (SI24). Therefore, TP53 seemed to acquire a particular sensitivity to smoking related C>A mutations in younger patients. We hypothesize that TP53 mutations at a younger age might be a crucial factor enhancing the sensitivity to smoking-related mutations leading to a burst of somatic alterations. The mutational profile of cancer cell might reflect the mutational processes operative in aging in a given tissue. Therefore, TP53-mutated and TP53 wild-type patient groups might represent phenotypes which endure aging-related mutational processes with different strength. Our study provides indications of age-dependent differences in mutational backgrounds that might be relevant for cancer prevention and age-adjusted treatment approaches.
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http://dx.doi.org/10.1002/ijc.32265DOI Listing
October 2019

Avelumab (anti-PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial.

J Immunother Cancer 2019 02 4;7(1):30. Epub 2019 Feb 4.

Brown University, Providence, USA.

Background: We evaluated the antitumor activity and safety of avelumab, a human anti-PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy.

Methods: In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety.

Results: Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5-13.9% and 1.8-16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0-not estimable) and 3.5 months (95% CI, 2.8-8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3-4.1) and 1.4 months (95% CI, 1.3-1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7-32.4%) and 7.9% (95% CI, 2.6-17.2%), and median OS was 11.1 months (95% CI, 8.9-13.7) and 6.6 months (95% CI, 5.4-9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4-20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-related death.

Conclusion: Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC.

Trial Registration: ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.
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http://dx.doi.org/10.1186/s40425-019-0508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362598PMC
February 2019

Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial.

J Immunother Cancer 2019 01 16;7(1):12. Epub 2019 Jan 16.

Genitourinary Malignancies Branch and Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease.

Patients And Methods: Patients received avelumab (10 mg/kg)-a human anti-PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.

Results: As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1-31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0-4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3-35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4-6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9-49.3]), PD-L1-positive tumors (42.1% [20.3-66.5]), or prior ipilimumab therapy (30.8% [14.3-51.8]). Thirty-nine patients (76.5%) had a treatment-related adverse event (TRAE), most commonly infusion-related reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-related deaths were reported.

Conclusion: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma.

Trial Registration: ClinicalTrials.gov identifier: NCT01772004 .
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http://dx.doi.org/10.1186/s40425-018-0459-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335739PMC
January 2019

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

Eur J Cancer 2019 01 18;107:142-152. Epub 2018 Dec 18.

Medical Oncology Department, Catalan Institute of Oncology, University of Barcelona, IDIBELL, Barcelona, Spain.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.

Patients And Methods: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS).

Results: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up.

Conclusion: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
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http://dx.doi.org/10.1016/j.ejca.2018.11.015DOI Listing
January 2019