Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach. MATERIALS AND METHODS: We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records. RESULTS: Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment). CONCLUSIONS: Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.

A prognostic systemic inflammation score (SIS) in patients with advanced intrahepatic cholangiocarcinoma.

PURPOSE: Systemic-inflammatory response parameters (SIR) are known prognostic markers in different tumour entities, but have not been evaluated in patients with iCCA treated with systemic chemotherapy. Therefore, we evaluated the impact of different SIR markers on the clinical course of patients with advanced iCCA treated at our center. METHODS: SIR markers were retrospectively evaluated in 219 patients with iCCA at the West-German-Cancer-Center Essen from 2014 to 2019. Markers included neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), CRP, and the modified Glasgow-Prognostic-Score (mGPS), which were correlated with clinico-pathological findings, response to chemotherapy (ORR), progression-free (PFS) and overall survival (OS) using Kaplan-Meier analyses, and Cox proportional models. RESULTS: Median overall survival (OS) of the entire cohort was 14.8 months (95% CI 11.2-24.4). Median disease-free survival (DFS) in 81 patients undergoing resection was 12.3 months (95% CI 9.7-23.1). The median OS from start of palliative CTX (OSpall) was 10.9 months (95% 9.4-14.6). A combined Systemic Inflammatory Score (SIS) comprising all evaluated SIR markers correlated significantly with ORR, PFS, and OSpall. Patients with a high SIS (≥ 2) vs. SIS 0 had a significantly inferior OSpall (HR 8.7 95% CI 3.71-20.38, p < 0.001). Multivariate analysis including known prognostic markers (ECOG, CA19-9, LDH, and N- and M-status) identified the SIS as an independent prognostic factor. CONCLUSIONS: Inflammatory markers associate with inferior survival outcomes in patients with iCCA. A simple SIS may guide treatment decisions in patients treated with systemic chemotherapy.

Multimodal survival prediction in advanced pancreatic cancer using machine learning.

BACKGROUND: Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care. METHODS: In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups. RESULTS: Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59). CONCLUSIONS: The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.

Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

[Conventional epiphyseal chondrosarcoma of childhood and adolescence: a case report]. / Konventionelles epiphysäres Chondrosarkom des Kindes- und Jugendalters: ein Fallbericht.

INTRODUCTION: Conventional chondrosarcoma is the second most common primary malignant bone tumor and usually occurs at older adult ages. It is rare in childhood and adolescence. CASE HISTORY: This case report presents the treatment course of a 13-year-old boy with a symptomatic chondrogenic tumor of the right distal femur. Histopathologically, an epiphyseal intermediate-grade chondrosarcoma (G2) was diagnosed. DISCUSSION: Based on the following case, potential radiological and histopathological differential diagnoses, such as chondroblastoma or chondroblastic osteosarcoma, are discussed against the background of current standards in orthopedic oncology.

DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbor somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behavior and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥50%) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (P < 0.0001) and lymph node metastases (P < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behavior. DLL3 expression in ≥50% of tumor cells virtually excludes MTC without stromal desmoplasia. DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

Complexity of PEComas : Diagnostic approach, molecular background, clinical management.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences.

[Complexity of PEComas : Diagnostic approach, molecular background, clinical management (German version)]. / Komplexität von PEComen : Diagnose, Molekulargenetik, klinisches Management.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences.

[Round-cell sarcomas]. / Rundzellige Sarkome.

Round-cell sarcomas represent highly malignant tumors that occur predominantly in children, adolescents, and young adults. Round-cell sarcomas are caused by recurrent translocations that involve certain transcription factors. Ewing's sarcoma, Ewing-like sarcomas (e.g. CIC-DUX positive or BCOR positive sarcomas), desmoplastic small round-cell tumors (DSRCTs), and alveolar rhabdomyosarcomas (ARMs) are typical examples of this particular group of sarcomas. These entities differ in their tumor genetics, which is correlated with immunohistochemical expression profiles and with clinical phenotypes. Classification should be based on molecular findings. Immunohistochemistry may serve as a surrogate marker.

[Systemic therapy of sarcomas : New biomarkers and therapeutic strategies]. / Systemische Therapie von Sarkomen : Neue Biomarker und Therapiestrategien.

Diagnostics and treatment of mesenchymal tumors (i.e. soft tissue sarcomas, gastrointestinal stromal tumors, and bone sarcomas) have changed dramatically in the past few years. Molecular and immunohistochemical biomarkers contribute significantly to improved diagnostics. They also play an increasing role in terms of clinical treatment decisions.Grading and tumor type-specific outcome data provide the basis for adjuvant chemotherapy of localized sarcomas. Recurrent gene fusions become more important as predictive biomarkers for targeted therapies in the context of systemic treatments. Immuno-oncology-based approaches are currently being studied in clinical trials, and the first responses of selected patients have been demonstrated. However, the role of predictive biomarkers in this field, such as PD-L1, still needs to be elucidated. Comprehensive genetic analyses of metastatic sarcomas will continue to identify additional therapeutic targets and the corresponding biomarkers.

[Epithelioid, biphasic and mixed tumors of soft tissue]. / Epitheloide, biphasische und Mischtumoren des Weichgewebes.

Epithelioid soft tissue tumors consist exclusively of epithelioid tumor cells. Biphasic tumors are composed of both a spindle-cell and an epithelioid component. The rare mixed tumors of soft tissue show a broader variety of cellular and stromal differentiation but also include at least one, possibly several, epithelioid portions.The close morphological similarity of some of these entities with each other, as well as with the more frequent soft tissue metastases of carcinomas, carcinosarcomas, and melanomas, to malignant mesothelioma and certain lymphomas, can often make the correct diagnosis extremely difficult. Recent advances in the detection of certain molecular alterations (mostly chromosomal translocations) have contributed to changes in tumor classification but also to improved pathological diagnostics (e.g. through the development of potent diagnostic antibodies) and biological understanding.The present overview should help the pathologist in the diagnosis of these rare tumors through the classical approach of morphological pattern recognition. The most important entities are discussed and illustrated in more detail, with the incorporation of the latest immunohistochemical and molecular aspects and the differential diagnosis of similar tumors.

[Predictive value of PD-L1 diagnostics]. / Der prädiktive Wert der PD-L1-Diagnostik.

Immuno-oncology related treatments have become standard of care for many tumor entities. Numerous additional indications are currently under investigation in ongoing clinical trials. Predictive biomarkers include microsatellite instability as well as tumor mutational burden. However, PD-L1 testing by immunohistochemistry (IHC) is already widely established as a biomarker in clinical routine for certain treatment decisions in non-small cell lung cancer, head and neck cancer and in urothelial carcinomas. More applications of that kind are expected to follow. Moreover, PD-L1 testing can provide clinicians with valuable information even if the test is not mandatory (i. e., complementary diagnostics). PD-L1 staining requires a highly specific staining over a broad dynamic range. Sensitive and specific primary antibodies and suitable staining protocols are prerequisite. Selection of appropriate patients' materials, validation and contiguous quality assurance need to meet the highest standards. There are different scoring algorithms for PD-L1 stainings which are specific to tumor entities and certain clinical decisions. The tumor proportion score (TPS) is a PD-L1 measurement which is applied, for example, to lung cancer, head and neck cancer and melanomas. Within this approach, only membranous staining of tumor cells is regarded as a significant staining. In contrast, the combined positivity score (CPS) and inflammatory cell (IC) scoring include or are restricted to PD-L1 expression in certain inflammatory cells, respectively. CPS and IC scoring are standard measurements of PD-L1 in urothelial carcinoma.

[FGFR3 overexpression is a relevant alteration in colorectal cancer]. / FGFR3-Überexpression ist eine relevante Alteration in kolorektalen Karzinomen.

BACKGROUND: Fibroblast growth factor receptor (FGFR) signalling plays an important role in embryogenesis as well as in tumorigenesis. In current studies FGFR has proved to be a potential molecular target in a variety of solid tumours. In colorectal cancer (CRC) data on FGFR alterations is very sparse. However, there is a huge need for targeted therapies in this tumour entity with an incidence of 140,000 individuals (USA 2018) and a 5-year relative survival rate of only 14% in metastatic disease. OBJECTIVES: This article shall provide an overview of the FGFRs and the most frequent FGF ligand alterations in primary and metastatic CRC. RESULTS: In primary tumours and metastases various FGFR and FGF alterations can be observed. Primary tumours as well as metastases show FGFR alterations at the genomic (by fluorescence in situ hybridization) as well as on the ribonucleic acid (RNA) expression level (by RNA in situ hybridization). In both cohorts FGFR3 overexpression is the most frequent alteration and is associated with an unfavourable prognosis in metastases. CONCLUSIONS: FGFR3 overexpression defines a subgroup of metastatic colorectal cancers with an unfavourable prognosis. Since FGFR3 alterations can present a potential therapeutic target, patients with FGFR3 overexpression should be included into clinical studies with FGFR inhibitors.

The role of beta-catenin mutation and SOX9 expression in sex cord-stromal tumours of the testis.

The WHO classification of testis tumours includes the group of sex cord-stromal tumours. They are divided into several histological types, i.e. Leydig cell (LCT) and Sertoli cell tumours (SCT). Based on the physiological expression of ß-catenin in normal testis/Sertoli cells, it was previously shown that SCT can carry a ß-catenin mutation, causing a nuclear positivity for ß-catenin and cyclin D1. Furthermore, it could be shown that the stabilization of ß-catenin in Sertoli cells causes the loss of the Sertoli cell marker SOX9. We wanted to know whether the stabilization of ß-catenin in sex cord-stromal tumours influences SOX-9 expression and thus could be used in the diagnosis of sex cord-stromal tumours. Therefore, 53 cases of sex cord-stromal tumours and tumour-like lesions were investigated for their immunohistochemical expressions of ß-catenin, cyclin D1 and SOX9. In addition, mutation analyses of the ß-catenin gene (exon 3; CTNNB1) were performed. ß-catenin mutation in SCT results in nuclear ß-catenin and cyclin-D1 expressions on immunohistochemical analysis. The nuclear expression/stabilization of ß-catenin causes the loss of SOX9 in these tumours. In contrast, SOX9 is considerably expressed in non-mutated SCT as well as in Sertoli cells of non-neoplastic testes. In summary, immunohistochemical analyses of ß-catenin and SOX9 are useful to distinguish SCT from other sex cord-stromal tumours of the testis. Furthermore, the presence of SOX9 indicates that the cells of origin may be Sertoli cells.

[Predictive PD-L1 immunohistochemistry for non-small cell lung cancer : Current state of the art and experiences of the first German harmonization study]. / Prädiktive PD-L1-Immunhistochemie beim nichtkleinzelligen Bronchialkarzinom : Aktueller Stand und Erfahrungen der ersten deutschen Harmonisierungsstudie.

BACKGROUND: Antibodies against PD-1 and PD-L1 can cause strong and durable anti-tumor immune responses in non-small cell lung cancer (NSCLC). Immunohistochemistry for PD-L1 (PD-L1 IHC) was tested as a predictive biomarker. Several IHC assays and interpretation criteria were developed in parallel. AIM: The clinical significance of PD-L1 IHC in NSCLC and the optimum method for staining and interpretation of the results are the subject of ongoing studies. The diagnostic application of immunotherapy in NSCLC necessitates harmonization of PD-L1 IHC to obtain evidence for guidelines; therefore, a consensus opinion on a well-founded diagnostic mode of testing should be defined based on published studies and the results of the first German PD-L1 IHC harmonization study. METHODS: 1. Summary of the current data situation. 2. Evaluation of the first German PD-L1 IHC harmonization study (centralized, staining with PD-L1 IHC analogous to studies, 15 cases of NSCLC, 4 IHC study assays [28­8, 22C3, SP142 and SP263] and scoring by 9 pathologists). RESULTS: The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy. The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations. DISCUSSION: In principle, the use of PD-L1 IHC for assessment of the expression in tumor cells is a reliably determinable biomarker. Evaluation algorithms should be based on published clinical trials. For NSCLC approvals with obligatory PD-L1 IHC are to be expected but it remains to be seen to what extent PD-L1 IHC will be implemented in the clinical routine.

[Sarcoma of the spleen with MDM2 expression]. / Sarkom der Milz mit MDM2-Expression.

Primary sarcomas and sarcoma metastases are a rarity in the spleen. We report on the case of a 69-year-old male patient presenting with unclear abdominal symptoms and computed tomography (CT) revealed a tumor mass in the spleen. Histologically the tumor mass predominantly showed features of a spindle cell sarcoma with lymphoid infiltrates. The expression and amplification of MDM2 could be demonstrated by means of immunohistochemistry and fluorescence in situ hybridization (FISH). Furthermore, staging examinations did not reveal indications of any other primary tumors. These preliminary findings were suggestive of a dedifferentiated liposarcoma; however, in the further diagnostic work-up the tumor showed strong expression of CD21 and CD23 and was ultimately diagnosed as a follicular dendritic cell sarcoma (FDCS). The case emphasizes that MDM2 expression represents a possible pitfall in the diagnosis of spindle cell tumors. The differential diagnostic distinction between FDCS and a dedifferentiated liposarcoma is discussed.

Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography.

BACKGROUND: The first evaluation of pelvic extended lymph node dissection (pLND) in oligometastatic prostate cancer (PCa) detected by (68)Ga-PSMA PET/CT. METHODS: Retrospective analysis of 35 PCa patients underwent (68)Ga-PSMA PET/CT affected by biochemical recurrence (BCR) after curative treatment (n = 23) or before primary therapy of high-risk PCa (n = 12). We performed pLND associated with pathologic imaging in 17 men with nodal oligometastatic PCa. RESULTS: Indicative lesions for PCa in PET/CT were detected in 91.4% (32 of 35) of patients. Nodal, bone, visceral (pulmonary), and within the prostate suspected disease were detected in 72% (23 of 32), 16% (5 of 32), 6% (2 of 32), and 47% (15 of 32) of patients, respectively. Median serum PSA in patients with pathological radiotracer uptake in recurrent and high-risk PCa patients was 2.9 ng/ml (range 0.18-30) and 19.5 ng/ml (range 6-90), respectively. The median number of removed lymph nodes with pLND in recurrent and high-risk PCa was 10 (range 4-17) and 12 (range 8-29) per patient and the median number of positive lymph nodes was 1 (range 1-2) and 3 (2-3) per patient, respectively. In total, two false positive and one false-negative lymph node were found. Diagnostic accuracies per nodal lesion in total of 213 removed nodes: sensitivity, 94%; specificity, 99%; positive predictive value (PPV), 89%, and negative predictive value (NPV), 99.5%. After pLND, 53% (9 of 17) of patients received androgen deprivation therapy and/or radiation therapy and hormonal therapy, while 47% (8 of 17) of patients remained free of any post-surgery therapy. Follow-up PSA remained less than 0.2 ng/ml in 82% (14 of 17) of patients. After pLND, immediate BCR (PSA never measured less than 0.2 ng/ml) in 18% (3 of 17) of patients was recorded. CONCLUSIONS: This represents the first study of pLND in the setting of nodal oligometastatic PCa detected by (68)Ga-PSMA PET/CT. The use of (68)Ga-PSMA PET/CT could be to improve the accuracy for the detection of nodal micrometastases. These promising findings need validation in larger studies.