What do German Molecular Tumor Boards recommend in patients with PIK3CA mutated tumors? - Launch and first results from the German TEAM-D Transsectoral Molecular Tumor Board exchange platform Deutschland (TEAM-D).

BACKGROUND AND RATIONALE: Comprehensive molecular tumor profiling is widely used in the management of patients with cancer. Molecular tumor boards devise treatment strategies based on testing results. In this setting, the Transsectoral Molecular Tumor Board exchange platform Deutschland (TEAM-D) aims to drive peer-to-peer exchange to connect experts in the field. METHODS: During the first virtual TEAM-D meeting, participants from 16 German universities and 5 nonacademic institutions discussed five cases with PIK3CA hotspot mutations. Furthermore, an illustrative case vignette was presented. RESULTS: Overall, German caregivers show restraint in administering off-label PIK3CA inhibitor and favor clinical trials in this setting. CONCLUSIONS: In the setting of precision oncology, TEAM-D enables virtual case discussion across the different sectors of the German healthcare system. Based on the example of PIK3CA hotspot mutations, TEAM-D demonstrated the value of integrating knowledge from different healthcare professionals.

CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial.

The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 .

Successful treatment of doxorubicin-induced cardiomyopathy with low-dose sacubitril/valsartan: a case report.

Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a challenging and life-threatening complication of many chemotherapeutic regimens. CTRCD prevention, diagnosis, and therapy require both careful interdisciplinary assessment and management. For patients with CTRCD, current guidelines of the European Society of Cardiology (ESC) recommend an angiotensin-converting-enzyme inhibitor in combination with a beta-blocker. Recent studies indicate a beneficial effect of sacubitril/valsartan in this patient population. Case summary: A 68-year-old female patient with a pleural epithelioid angiosarcoma developed heart failure with reduced ejection fraction and elevated serum biomarkers following doxorubicin treatment. After implementation of a recommended cardioprotective medical therapy including torasemide, ramipril, carvedilol, and spironolactone, the patient suffered two cardiac decompensations within 4 weeks after initiation of a paclitaxel regimen and pleural radiation therapy due to pain exacerbation. Despite a continuous application of the cardioprotective medical treatment regimen, no improvement of left-ventricular ejection fraction (LVEF) was detected in a 4-month follow up. Interestingly, after omitting ramipril and implementing low-dose sacubitril/valsartan (26/24 mg), we observed a decrease in serum biomarkers within 3 months as well as a significant improvement of LVEF within 6 months. After nearly 10 months of disease stabilization under paclitaxel, the patient suffered progressive cancer disease and deceased 1 week later after the initiation of a therapeutic attempt with pazopanib. Discussion: This case report highlights the importance of interdisciplinary care in cancer patients as well as the promising role of (low-dose) sacubitril/valsartan in patients with CTRCD even in the setting of delayed initiation.

Prevalence of corneal findings and their interrelation with hematological findings in monoclonal gammopathy.

PURPOSE: To determine prevalence of paraproteinemic keratopathy (PPK) among patients with monoclonal gammopathy (MG). To evaluate interrelation between corneal and hematological parameters in patients with PPK. METHODS: Fifty-one patients with monoclonal gammopathy of undetermined significance (n = 19), smoldering multiple myeloma (n = 5) or multiple myeloma (n = 27) were prospectively included in this study. Best-corrected visual acuity, slit-lamp biomicroscopy, Scheimpflug tomography, in-vivo confocal laser scanning microscopy, optical coherence tomography and complete hematological workup were assessed. RESULTS: We identified n = 19 patients with bilateral corneal opacities compatible with PPK. PPK was newly diagnosed in 13 (29%) of 45 patients with a primary hematological diagnosis and in n = 6 patients without previous hematological diagnosis. The most common form was a discreet stromal flake-like PPK (n = 14 of 19). The median level of M-protein (p = 0.59), IgA (p = 0.53), IgG (p = 0.79) and IgM (p = 0.59) did not differ significantly between the patients with and without PPK. The median level of the FLC κ in serum of patients with kappa-restricted plasma cell dyscrasia was 209 mg/l in patients with PPK compared to 38.1 mg/l in patients without PPK (p = 0.18). Median level of FLC lambda in serum of patients with lambda-restricted plasma cell dyscrasia was lower in patients with PPK compared to patients without PPK (p = 0.02). CONCLUSION: The PPK was mostly discreet, but its prevalence (29%) was higher than expected. Median level of the monoclonal paraprotein was not significantly higher in patients with PPK compared to patients without PPK. Our results suggest a lack of correlation between morphology and severity of the ocular findings and severity of the monoclonal gammopathy. TRIAL REGISTRATION: German Clinical Trial Register: DRKS00023893.

Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity.

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.

Impact of cardiac amyloidosis on outcomes of patients hospitalized with heart failure.

BACKGROUND: Amyloidosis is a multi-systemic disease potentially leading to failure of affected organs. We aimed to investigate prevalence and prognostic implications of cardiac amyloidosis of any etiology on outcomes of hospitalized patients with heart failure (HF) in Germany. METHODS: We analyzed data of the German nationwide inpatient sample (2005-2018) of patients hospitalized for HF (including myocarditis with HF and heart transplantation with HF). HF patients with amyloidosis (defined as cardiac amyloidosis [CA]) were compared with those HF patients without amyloidosis and impact of CA on outcomes was assessed. RESULTS: During this fourteen-year observational period 5,478,835 hospitalizations for HF were analyzed. Amyloidosis was coded in 5,407 HF patients (0.1%). CA prevalence was 1.87 hospitalizations per 100,000 German population. CA patients were younger (75.0[IQR 67.0-80.0]vs.79.0[72.0-85.0]years, p < 0.001), predominantly male (68.9%) and had a higher prevalence of cancer (14.8% vs. 3.6%, p < 0.001). Adverse in-hospital events including necessity of transfusions of blood constituents (7.1% vs. 5.4%, p < 0.001) and cardio-pulmonary resuscitation (CPR, 2.7% vs. 1.4%; p < 0.001) were more frequent in CA. CA was independently associated with acute kidney failure (OR 1.40 [95%CI 1.28-1.52], p < 0.001), CPR (OR 1.58 [95%CI 1.34-1.86], p < 0.001), intracerebral bleeding (OR 3.13 [95%CI 1.68-5.83], p < 0.001) and in-hospital mortality between the 5 and 8th decade of life, but in-hospital mortality was strongly influenced by cancer. CONCLUSIONS: CA was identified as an independent risk factor for complications and in-hospital mortality in HF patients, whereby it has to be mentioned that amyloidosis subtypes could not differentiated in the present study. Physicians should be aware of this issue concerning treatments and monitoring of CA-patients.

cbpManager: a web application to streamline the integration of clinical and genomic data in cBioPortal to support the Molecular Tumor Board.

BACKGROUND: Extensive sequencing of tumor tissues has greatly improved our understanding of cancer biology over the past years. The integration of genomic and clinical data is increasingly used to select personalized therapies in dedicated tumor boards (Molecular Tumor Boards) or to identify patients for basket studies. Genomic alterations and clinical information can be stored, integrated and visualized in the open-access resource cBioPortal for Cancer Genomics. cBioPortal can be run as a local instance enabling storage and analysis of patient data in single institutions, in the respect of data privacy. However, uploading clinical input data and genetic aberrations requires the elaboration of multiple data files and specific data formats, which makes it difficult to integrate this system into clinical practice. To solve this problem, we developed cbpManager. RESULTS: cbpManager is an R package providing a web-based interactive graphical user interface intended to facilitate the maintenance of mutations data and clinical data, including patient and sample information, as well as timeline data. cbpManager enables a large spectrum of researchers and physicians, regardless of their informatics skills to intuitively create data files ready for upload in cBioPortal for Cancer Genomics on a daily basis or in batch. Due to its modular structure based on R Shiny, further data formats such as copy number and fusion data can be covered in future versions. Further, we provide cbpManager as a containerized solution, enabling a straightforward large-scale deployment in clinical systems and secure access in combination with ShinyProxy. cbpManager is freely available via the Bioconductor project at https://bioconductor.org/packages/cbpManager/ under the AGPL-3 license. It is already used at six University Hospitals in Germany (Mainz, Gießen, Lübeck, Halle, Freiburg, and Marburg). CONCLUSION: In summary, our package cbpManager is currently a unique software solution in the workflow with cBioPortal for Cancer Genomics, to assist the user in the interactive generation and management of study files suited for the later upload in cBioPortal.

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations.

INTRODUCTION: In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting. METHODS: We retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: ICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months. CONCLUSIONS: ICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma.

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient's liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.

Loss of LLGL1 Expression Correlates with Diffuse Gastric Cancer and Distant Peritoneal Metastases.

Background: Loss of LLGL1 has been associated with loss of cellular adhesion and dissemination of cells from colorectal cancer and malignant melanoma. Regulation and relevance of LLGL1 were analyzed in gastric cancer patients with lymphatic and distant dissemination. Furthermore, LLGL1 expression was analyzed in relation to the cellular adhesion protein E-cadherin. Methods: LLGL1 and E-cadherin transcription levels were evaluated in 56 gastric cancer patients and five gastric cancer cell lines. IHC staining for LLGL1 was performed on 39 gastric cancer specimens. LLGL1 was stably transfected into LLGL1 negative gastric cancer cell line SNU16 (del(17) (p11.2)) for functional in vitro assays and a xenograft bioassay. Results: Gastric cancer specimens and cell lines displayed LLGL1 and E-cadherin expression levels with variable intensity. In gastric mucosa, LLGL1 exhibited weak cytoplasmic and strong cortical staining. Loss of LLGL1 expression occurred in 65% of gastric cancers and significantly correlated with loss of E-cadherin expression (P=0.00009). Loss of LLGL1 expression was associated with the diffuse type of gastric cancer (P=0.029) with peritoneal carcinomatosis (M1; P=0.006) and with female gender (P=0.017). Stable reexpression of LLGL1 in SNU16 cells significantly increased both plastic surface adhesion and extracellular matrix proteins laminin and fibronectin, but had no impact on in vitro proliferation, apoptosis, or invasion or on in vivo proliferation or differentiation in our xenograft bioassay. Conclusion: LLGL1 is coexpressed with E-cadherin. Loss of expression of either protein is associated with diffuse gastric cancer and peritoneal metastases. LLGL1 does not impact on proliferation or epithelial-mesenchymal transition (EMT) rather increasing cellular adhesion.

The Hematologic Definition of Monoclonal Gammopathy of Undetermined Significance in Relation to Paraproteinemic Keratopathy (An American Ophthalmological Society Thesis).

PURPOSE: To determine if paraproteinemic keratopathy (PPK) in the setting of monoclonal gammopathy of undetermined significance (MGUS) causes distinct patterns of corneal opacification that can be distinguished from hereditary, immunologic, or inflammatory causes. METHODS: A retrospective, interventional study of patients showed distinct bilateral opacity patterns of the cornea at the eye clinics of Hanau, Mainz, Helsinki, Marburg, and Berlin between 1993 and 2015. Data on patient characteristics and clinical features on ophthalmic examination were collected, and serum protein profiles were evaluated. A literature review and analysis of all published studies of MGUS with PPK is also presented. RESULTS: The largest group of patients diagnosed with MGUS-induced PPK is analyzed in this study. We studied 22 eyes of 11 patients (6 male, aged 43 to 65, mean age 54; 5 female, aged 49 to 76, mean age 61) with distinct corneal opacities and visual impairment who were first suspected of having hereditary, inflammatory, or immunologic corneal entities. Subsequently, serum protein electrophoresis revealed MGUS to be the cause of the PPK. Literature review revealed 72 patients with bilateral PPK (34 male, mean age 57; 38 female, mean age 58) in 51 studies of MGUS published from 1934 to 2015 and disclosed six additional corneal opacity patterns. CONCLUSIONS: This thesis shows that MGUS is not always an asymptomatic disorder, in contrast to the hematologic definition, which has no hint of PPK. The MGUS-induced PPK can mimic many other diseases of the anterior layer of the eye. A new clinical classification for PPK in MGUS is proposed.

Erratum: The Hematologic Definition of Monoclonal Gammopathy of Undetermined Significance in Relation to Paraproteinemic Keratopathy (An American Ophthalmological Society Thesis).

[This corrects the article on p. T7 in vol. 114, PMID: 28050052.].