Clinically actionable genomic and transcriptomic landscape of advanced neuroendocrine neoplasms.
Epithelial neuroendocrine neoplasms (NENs) are a rare and heterogeneous group of malignancies with limited treatment options. Comprehensive molecular characterization may reveal novel therapeutic opportunities for these clinically challenging tumors.
Within a nationwide precision oncology program, we performed whole-genome/exome and transcriptome sequencing in 168 patients with a diagnosis of advanced NEN from diverse anatomic origins, followed by evaluation of real-world outcomes associated with molecularly guided interventions.
Our analysis revealed substantial molecular heterogeneity across advanced NENs, including distinct genetic profiles between low-grade and high-grade tumors, as well as alterations specific to particular tissues of origin. Candidate therapeutic targets included elevated tumor mutational burden induced by temozolomide exposure, rare actionable kinase mutations, overexpression of targetable antigens, and signatures of homologous recombination deficiency, providing a rationale for immune checkpoint blockade, kinase inhibitors, antibody-drug conjugates, poly(ADP-ribose) polymerase (PARP) inhibitors, and platinum-based therapies, respectively. Overall, 144 patients (85.7%) received molecularly guided treatment recommendations, of which 85 were implemented in 57 patients (39.6%). Among 68 evaluable therapy outcomes, 47 (69.1%) demonstrated clinical benefit (objective response, n = 25; disease stabilization, n = 22). At the patient level, 34 of the 57 treated (59.6%) experienced clinical benefit from at least one therapy (objective response, n = 18; disease stabilization, n = 16).
Comprehensive genomic and transcriptomic profiling identified distinct molecular alteration patterns and therapeutic vulnerabilities among different classes of epithelial NENs from various tissues, warranting further investigation in anatomic-site-specific studies. Our outcome data underscore the clinical utility of broad molecular profiling in patients with advanced NENs lacking further standard treatment options.
Funding for the study was institutional.
Within a nationwide precision oncology program, we performed whole-genome/exome and transcriptome sequencing in 168 patients with a diagnosis of advanced NEN from diverse anatomic origins, followed by evaluation of real-world outcomes associated with molecularly guided interventions.
Our analysis revealed substantial molecular heterogeneity across advanced NENs, including distinct genetic profiles between low-grade and high-grade tumors, as well as alterations specific to particular tissues of origin. Candidate therapeutic targets included elevated tumor mutational burden induced by temozolomide exposure, rare actionable kinase mutations, overexpression of targetable antigens, and signatures of homologous recombination deficiency, providing a rationale for immune checkpoint blockade, kinase inhibitors, antibody-drug conjugates, poly(ADP-ribose) polymerase (PARP) inhibitors, and platinum-based therapies, respectively. Overall, 144 patients (85.7%) received molecularly guided treatment recommendations, of which 85 were implemented in 57 patients (39.6%). Among 68 evaluable therapy outcomes, 47 (69.1%) demonstrated clinical benefit (objective response, n = 25; disease stabilization, n = 22). At the patient level, 34 of the 57 treated (59.6%) experienced clinical benefit from at least one therapy (objective response, n = 18; disease stabilization, n = 16).
Comprehensive genomic and transcriptomic profiling identified distinct molecular alteration patterns and therapeutic vulnerabilities among different classes of epithelial NENs from various tissues, warranting further investigation in anatomic-site-specific studies. Our outcome data underscore the clinical utility of broad molecular profiling in patients with advanced NENs lacking further standard treatment options.
Funding for the study was institutional.
Authors
Kreutzfeldt Kreutzfeldt, Apostolidis Apostolidis, Oleś Oleś, Krieghoff-Henning Krieghoff-Henning, Heilig Heilig, Heining Heining, Mock Mock, Teleanu Teleanu, Hutter Hutter, Gieldon Gieldon, Klink Klink, Beck Beck, Richter Richter, Baude-Müller Baude-Müller, Reisinger Reisinger, Hammer Hammer, Kamkar Kamkar, Pfütze Pfütze, Geörg Geörg, Lamping Lamping, Rieke Rieke, Uhrig Uhrig, Jann Jann, Pape Pape, Allgäuer Allgäuer, Stenzinger Stenzinger, Winkler Winkler, Wiedenmann Wiedenmann, Jäger Jäger, Brors Brors, Hübschmann Hübschmann, Schröck Schröck, Keilholz Keilholz, Pavel Pavel, Horak Horak, Glimm Glimm, Fröhling Fröhling
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