Context Pheochromocytomas/paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. Objective Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. Design Retrospective analysis of a multicenter cohort of PPGLs. Setting Six specialized Endocrine Tumor Centers in Germany, the Netherlands and Switzerland. Patients Patients with PPGLs participating in the ENSAT registry. Methods Clinical data were extracted from medical records and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. Main outcome measure Association of SSTR2 IHC positivity with genetic and clinic-pathological features of PPGLs. Results Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (p = 0.01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (p < 0.001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line “cold” somatostatin analogs 100% (n = 6, n = 3 SDHx). Conclusions SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.

Background Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3–5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. Objective The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. Patients and Methods We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. Results MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET- amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors ( p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET -amplified cases harbored potentially targetable oncogenic co-mutations in KRAS , BRAF, and EGFR. The most frequent co-occurring mutations in all MET -altered tumors were TP53 , KRAS , BRAF, and CDK4 . Conclusions We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-022-00918-6.

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