A review of mitotane in the management of adrenocortical cancer.

IMPORTANCE: Mitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma. OBSERVATIONS: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret. CONCLUSIONS AND RELEVANCE: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.

Clinical utility of plasma cell-free DNA in pancreatic neuroendocrine neoplasms.

In advanced pancreatic neuroendocrine neoplasms (PanNEN), there are little data detailing the frequency of genetic alterations identified in cell free DNA (cfDNA), plasma-tissue concordance of detected alterations, and clinical utility of cfDNA. Patients with metastatic PanNENs underwent cfDNA collection in routine practice. Next-generation sequencing (NGS) of cfDNA and matched tissue when available was performed. Clinical actionability of variants was annotated by OncoKB. Thirty-two cfDNA samples were analyzed from 25 patients, the majority who had well-differentiated intermediate grade disease (13/25; 52%). Genomic alterations were detected in 68% of patients and in 66% of all cfDNA samples. The most frequently altered genes were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%), and ATRX (12%). Twenty-three out of 25 (92%) patients underwent tumor tissue NGS. Tissue-plasma concordance for select genes was as follows:DAXX (95.7%), ARID1A (91.1%), ATRX (87%), TSC2 (82.6%), MEN1 (69.6%). Potentially actionable alterations were identified in cfDNA of 8 patients, including TSC2 (4; level 3b), ATM (1; level 3b), ARID1A (2; level 4), and KRAS (1; level 4). An ETV6:NTRK fusion detected in tumor tissue was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second-generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN-associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

Sequencing of Somatostatin-Receptor-Based Therapies in Neuroendocrine Tumor Patients.

Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to somatostatin receptors and are used for palliation of hormonal syndromes and control of tumor growth. The long-acting SSAs octreotide long-acting release and lanreotide are commonly used in the first-line metastatic setting because of their tolerable side effect profile. Radiolabeled SSAs are used both for imaging and for treatment of NETs. 177Lu-DOTATATE is a ß-emitting radiolabeled SSA that has been proven to significantly improve progression-free survival among patients with progressive midgut NETs and is approved for treatment of metastatic gastroenteropancreatic NETs. A key question in management of patients with gastroenteropancreatic and lung NETs is the sequencing of 177Lu-DOTATATE in relation to other systemic treatments (such as everolimus) or liver-directed therapies. This question is particularly complicated given the heterogeneity of NETs and the near absence of randomized trials comparing active treatment options. This state-of-the-art review examines the evidence supporting use of somatostatin-receptor-targeted treatments within the larger landscape of NET therapy and offers insights regarding optimal patient selection, assessment of benefit versus risk, and treatment sequencing.

Actualización diagnóstica y terapéutica de los tumores neuroendocrinos bien diferenciados / Updates on well-differentiated neuroendocrine tumors

Los tumores neuroendocrinos bien diferenciados (TNE) son neoplasias malignas poco frecuentes que incluyen tanto los carcinoides como los tumores neuroendocrinos pancreáticos (TNEP). Estos tumores se asocian en general con metástasis en el momento del diagnóstico. Si bien la supervivencia prolongada es frecuente, la supervivencia global se reduce de manera acentuada cuando los pacientes presentan síntomas, así como cuando el tumor progresa pese a la terapia con análogos de la somatostatina. Aunque estos fármacos pueden contribuir a tratar la sintomatología y ralentizar el crecimiento tumoral, en especial en neoplasias de bajo grado, no se ha demostrado que el tratamiento a largo plazo sea eficaz en estos pacientes. Recientemente, los ensayos preclínicos y dos estudios de fase III han brindado avances promisorios, sobre todo en el tratamiento de los TNEP. La aparición de terapias dirigidas contra el factor de crecimiento vascular endotelial (VEGF), los inhibidores de la diana de la rapamicina (mTOR) y el tratamiento con receptores de péptidos radiomarcados se ha asociado con eficacia moderada, pero pueden vincularse con toxicidad relevante. En esta revisión, discutiremos los ensayos recientes y las terapias actuales de los TNE bien diferenciados.(AU)

Actualización diagnóstica y terapéutica de los tumores neuroendocrinos bien diferenciados / Updates on well-differentiated neuroendocrine tumors

Los tumores neuroendocrinos bien diferenciados (TNE) son neoplasias malignas poco frecuentes que incluyen tanto los carcinoides como los tumores neuroendocrinos pancreáticos (TNEP). Estos tumores se asocian en general con metástasis en el momento del diagnóstico. Si bien la supervivencia prolongada es frecuente, la supervivencia global se reduce de manera acentuada cuando los pacientes presentan síntomas, así como cuando el tumor progresa pese a la terapia con análogos de la somatostatina. Aunque estos fármacos pueden contribuir a tratar la sintomatología y ralentizar el crecimiento tumoral, en especial en neoplasias de bajo grado, no se ha demostrado que el tratamiento a largo plazo sea eficaz en estos pacientes. Recientemente, los ensayos preclínicos y dos estudios de fase III han brindado avances promisorios, sobre todo en el tratamiento de los TNEP. La aparición de terapias dirigidas contra el factor de crecimiento vascular endotelial (VEGF), los inhibidores de la diana de la rapamicina (mTOR) y el tratamiento con receptores de péptidos radiomarcados se ha asociado con eficacia moderada, pero pueden vincularse con toxicidad relevante. En esta revisión, discutiremos los ensayos recientes y las terapias actuales de los TNE bien diferenciados.