ETA2024 Poster Presentations Translational thyroid cancer research-1 (10 abstracts)
Impact of genomic biomarkers on treatment decisions and clinical outcomes in patients with radioiodine-refractory thyroid cancer and treatment with multi-tyrosine kinase inhibitors – a multi-center registry analysis
Josefine Achterfeld 1 , Viktoria Köhler 2 , Mihaela Chirica 3 , Deborah Goerdts 4 , Elke Berg 1 , Joerg Kumbrink 3 , Eva Hoster 5 , Felix Megerle 6 , Constantin Smaxwil 7 , Benjamin Sandner 8 , Christian H. Pfob 9 , Andreas Zielke 10 , Matthias Schott 11 , Martin Fassnacht 12 , Matthias Kroiß 13 & Christine Spitzweg 14
1LMU Hospital, Department of Internal Medicine Iv, Munich, Germany; 2University Hospital of Munich, LMU Munich, Department of Medicine I, Goethe University Hospital, Frankfurt, Germany, Department of Internal Medicine Iv, München, Germany; 3LMU Hospital, Department of Pathology, Munich, Germany; 4LMU Klinikum, Department of Internal Medicine Iv, Munich, Germany; 5Institute for Medical Information Processing, Biometry and Epidemiology, LMU Munich, Munich, Germany, LMU Hospital, Institute for Medical Information Processing, Biometry and Epidemiology, Munich, Germany; 6University Hospital Würzburg, Division of Endocrinology and Diabetes, Department of Medicine, University of Würzburg, Würzburg, Germany, Division of Endocrinology and Diabetes, Würzburg, Germany; 7Diakonieklinikum Stuttgart, Department of Endocrine Surgery, Diakonie-Klinikum Stuttgart, Stuttgart, Endokrine Chirurgie, Stuttgart, Germany; 8University of Leipzig, Department of Internal Medicine Iii, University Hospital of Leipzig, Leipzig, Department of Internal Medicine, Division of Endocrinology and Diabetes, Leipzig, Germany; 9University of Augsburg, Faculty of Medicine, Nuclear Medicine, Augsburg, Germany; 10Diakonie-Klinikum Stuttgart, Department of Endocrine Surgery, Diakonie-Klinikum Stuttgart, Stuttgart, Abteilung für Endokrine Chirurgie, Stuttgart, Germany; 11Division for Specific Endocrinology, University Hospital Duesseldorf, Medical Faculty, University of Duesseldorf, Düsseldorf, Germany; 12University Hospital Würzburg, Medizinische Klinik I, Division of Endocrinology and Diabetes, Würzburg, Germany; 13LMU Klinikum, Department of Medicine Iv, University Hospital, LMU Munich, Ziemssenstraße 1, 80336 München, Germany, Medizinische Klinik und Poliklinik Iv, München, Germany; 14University Hospital, LMU Munich, Department of Medicine Iv, Internal Medicine Iv, Munich, Germany
Background: In differentiated thyroid cancer (DTC) BRAF mutations are oncogenic drivers in ~60% of cases. This mutation confers downstream MEK-ERK activation resulting in radioiodine (RAI)-refractory disease. Dedifferentiation towards poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) comes with additional mutations in TP53 or the TERT promoter. Activating alterations of RAS and RET are the most frequent alternative oncogenic events. Next generation sequencing (NGS) plays a crucial role to identify these somatic alterations as basis for precision thyroid-oncology. Here, we aimed to determine the frequency and impact of genetic biomarkers on treatment decisions and outcomes in patients with RAI-refractory DTC in a real-world setting.
Patients Methods: In this interim analysis, 97 patients treated with multi-tyrosine kinase inhibitors (MKIs), or selective inhibitors from7 German referral centers were included. Tumor samples of all patients were tested for targetable mutations by NGS testing. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
Results: Ninety-seven patients were included with follicular (FTC) histology in 40 (41%), papillary (PTC) histology in 32 (33%), and PDTC in 25 (26%). Median patient age was 71 years (range 31 – 82 years), and NGS was performed most frequently early during treatment (median 2 treatment lines, range 0 – 5). Thirteen samples (n = 97, 13%) were tested positive for BRAFV600E, and one BRAFK601E variant (n = 97 1%) was found. Seven cases (n = 69, 10%) had activating RAS mutations (N-RAS [4/69; 6%]; H-RAS [2/69; 3%]; K-RAS [1/69, 1%]. Two NTRK (n = 69, 3%), 2 ALK (n = 42, 5%), and 3 RET fusions (n = 45, 7%) were detected. Remaining alterations included TP53 (13/50, 26%), PTEN (10/50, 20%), and TERT promoter (2/50, 4%). 42% had no druggable target. First line therapy was Lenvatinib in 70 patients (72%) and sorafenib in 14 patients (14%). Seven patients (7%) were treated with selective inhibitors (alectinib [2/7, 29%], larotrectinib [1/7, 14%], dabrafenib [2/7, 29%], and selpercatinib [2/7,29%]). Median PFS from time of initiation of systemic treatment with MKI was 119 months (95% confidence interval [CI], not reached [NR]) and median OS was 48 months (95% CI, 30.6 – 65.4). Median PFS and OS from time of initiation of systemic treatment with selective inhibitors was NR (95% CI, NR).
Conclusion: Our real-world clinical data indicate that BRAF mutations are relatively rare in patients with RAI-refractory DTC compared to published data, which may be explained by the histologic subtypes in our cohort. MKIs/selective inhibitors are effective treatment options in the majority of patients with RAI-refractory DTC, and we found median OS to be comparable with published data sets. To be able to target druggable mutations within an individualized therapy concept, we highly recommend timely molecular analysis of tumor tissue in patients with RAI-refractory DTC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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