@misc{HempelGaumannVelosodeOliveiraetal.2022, author = {Hempel, L. and Gaumann, A. and Veloso de Oliveira, J. and Philipp, P. and Hempel, D. and Robert, Sebastian and Ebner, F.}, title = {Zielgerichtete Therapien f{\"u}r das Endometriumkarzinom im Real-World-Setting}, series = {Geburtshilfe und Frauenheilkunde}, volume = {82}, journal = {Geburtshilfe und Frauenheilkunde}, number = {10}, publisher = {Georg Thieme Verlag}, doi = {10.1055/s-0042-1756859}, year = {2022}, abstract = {Mit wachsenden Erkenntnissen zu grundlegenden molekularen Mechanismen werden zunehmend Zielstrukturen f{\"u}r neuartige personalisierte Therapien f{\"u}r das Endometriumkarzinoms (EC) identifiziert. Diese Therapien haben das Potenzial, das Langzeit{\"u}berleben von Krebspatientinnen mit geeigneten Biomarkern zu verbessern. In der vorliegenden Studie wurde bei 11 Patientinnen mit EC, ein Panel Hybrid Capture-basiertes Next Generation Sequencing (FoundationOne CDx, Penzberg, Deutschland) durchgef{\"u}hrt. Bei allen untersuchten Patientinnen wurden genetische Ver{\"a}nderungen festgestellt, die potenzielle Ziele f{\"u}r personalisierte Therapien darstellen. Signifikante Ver{\"a}nderungen wurden bei 7 (63,6\%) Patientinnen in TP53, bei 4 (36,4\%) in PIK2CA, bei 3 (27,3\%) in ERBB2, bei 3 (27,3\%) in ARIDA1A, bei 2 (18,2\%) in NF1, bei 2 (18,2\%) in PTEN und bei einer Patientin in PIK3R1, festgestellt. TMB konnte bei 10 von 11 Patientinnen analysiert werden und war bei 5 (45,5\%) niedrig, bei 3 (27,3\%) intermediate und bei 2 Patientinnen (18,2\%) hoch. Die Mikrosatelliten waren bei 2 Patientinnen (18,2 \%) instabil (MSI) und bei 7 Patientinnen (63,6 \%) stabil (MSS). Außerdem wurden die Ergebnisse der Immunhistochemie (IHC) mit den NGS-Daten vergleichen. Drei Patientinnen waren in der IHC Her2 positiv, obwohl keine ERBB2-Amplifikation nachweisbar war. Im Gegensatz dazu identifizierte die NGS-Analyse eine Patientin, die in der IHC negativ f{\"u}r Her2 war jedoch eine ERBB2-Amplifikationen aufwies und sich somit f{\"u}r Her2/neu-gerichtete Therapien qualifizierte. Diese Daten unterstreichen die Bedeutung der Identifizierung molekularer Muster, da 100 \% der analysierten Patientinnen potenziell therapierelevante Alterationen aufwiesen. Alle Patientinnen mit EC sollten eine NGS-Analyse, sowie eine Untersuchung auf Her2/neu und PD-L1 mittels IHC erhalten.}, language = {de} } @article{HempelLapaGaumannetal.2022, author = {Hempel, L.C. and Lapa, C. and Gaumann, A. and Veloso de Oliveira, J. and Scheiber, J. and Philipp, P. and Oyarzun, C. and Wesarg, S. and Robert, Sebastian and Hempel, D.}, title = {36P A point mutation replacing cysteine with arginine at position 382 (C382R) in the transmembrane domain of FGFR2 leads to response to FGF2-inhibitor pemigatinib in chemo-refractory intrahepatic cholangiocarcinoma}, series = {Annals of Oncology}, volume = {33}, journal = {Annals of Oncology}, doi = {https://doi.org/10.1016/j.annonc.2022.01.045}, pages = {S17 -- S17}, year = {2022}, abstract = {Background To date, targeted tyrosine kinase inhibitors have been approved for FGFR2 and FGFR3 fusions (pemigatinib and erdafitinib, respectively), but the importance of FGFR2 mutations for transformation activity and as a druggable gene variant with response to different FGFR inhibitors is poorly understood. FGFR2 inhibitors present a mainstay of treatment for locally advanced or metastatic intrahepatic cholangiocellular carcinoma (iCCA). Methods A 74-year-old male was diagnosed with iCCA in liver segments seven and eight with infiltration of the hepatic veins and inferior vena cava revealed a C382R mutation of the intramembrane domain of FGRR2 receptor. We performed an in-silico study to understand the potential mode-of-action of the mutant FGFR2 targets. Based on experimentally determined structures we then used a structure generated by AlphaFold2 as the variation in question is located at a position not determined well in the experiments. This revealed that the C382R mutation is located in the trans-membranal domain at a position crucial for signal transduction, both for activation and inhibition of downstream-signaling. The Molecular Tumor Board decided to start the treatment with 13.5 mg pemigatinib once daily for 14 days, followed by 7 days of free therapy interval resulting in a sustained partial response. The patient continues to be treated of 13.5 mg as described above. Results In our case report, we were able to show that the patient in whom an C382R mutation was detected responded to the therapy with pemigatinib. This shows that real-world scenarios differ from the data of the approval studies, thereby illustrating how complex data on patients with FGFR mutations is. One of the main problems of large approval studies is that the functionality of the respective alterations is often disregarded. Conclusions Our results suggest that respective mutation may be successfully targeted by FGFR-selective tyrosine-kinase inhibitors, demonstrating the importance of the functional characterization of mutations. no conflicts of interest.}, language = {en} }