Hálfdánarson, Þorvarður R.

Abstract Insulin-producing pancreatic tumors are a common subtype of neuroendocrine tumor. Standard of care includes surgical resection of the pancreatic tumor and medical management with somatostatin analogs. For patients with metastatic disease, tumor control and hypoglycemic symptom relief can be achieved through surgical resection of the tumor, hepatic artery embolization, radiofrequency ablation, or radioembolization using radioactive isotopes as well as with systemic therapy such as somatostatin analogs and everolimus. We present the case of a 74-year-old male with metastatic insulin-producing pancreatic carcinoma. After a long history of successfully controlling his hypoglycemic episodes post-liver wedge resection, bland embolizations subsequently failed to maintain control of the frequency and severity of his hypoglycemic symptoms. Stereotactic body radiotherapy (SBRT) with protons was used to achieve symptomatic control and led to partial radiographic response with complete resolution of his hypoglycemic episodes. This case demonstrates the potential utility of proton SBRT in metastatic insulinomas.

PURPOSE Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression–based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF, in patients with CUP in the MOSAIC database to highlight potential treatment options. METHODS MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF. RESULTS CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS, IDH1/2, BRCA, and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)–approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients. CONCLUSION This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials.

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NEN are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in grading system changed the definition of grade 3 to include high grade well differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although, these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis and clinical behavior which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited which impact their management. In this review, we will summarize the current advances in the multidisciplinary approach for management of high grade GEP-NENs including G3-NETs and NECs.

AbstractBackgroundHead and neck cancers (HNC) present diagnostic challenges due to multifocal disease manifestations, posing difficulties in distinguishing between metastatic disease and second primary malignancies (SPM). This complexity underscores the need for advanced diagnostic approaches. Emerging technologies, such as next‐generation sequencing (NGS) and molecular classifier assays, show promise in providing precise insights into the diverse etiologies of HNC.MethodIn this article, we employed NGS and molecular classifier assays to delve into three distinct clinical cases. The objective was to showcase the instrumental role of these technologies in facilitating accurate diagnoses and differentiating between metastatic disease and SPM in HNC cases.ResultsThe results of this series highlight the effectiveness of NGS and molecular classifier assays in enhancing diagnostic accuracy for HNC and contributing to the precise differentiation of disease etiologies. The utilization of these advanced technologies proved instrumental in avoiding unnecessary interventions and paved the way for more targeted and effective treatment strategies.ConclusionOur findings underscore the necessity of incorporating advanced molecular testing technologies into the diagnostic and therapeutic approaches for HNC, thereby championing a more nuanced and effective approach to managing these complex cases.

PURPOSE Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]

3020 Background: Radioligand therapy (RLT) use has been increasing with the approval of 177Lu-Dotatate for metastatic neuroendocrine tumors (NET) & 177Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) & acute myeloid leukemia, (AML)] have been reported after 177Lutetium (177Lu) for NET with rates of 2-20% & median time from first 177Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH & tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post-177Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post-177Lu. Pt demographics, treatment history, labs & BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET & 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), & platinum agents in 10 (18%). The median number of 177Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) & were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177Lu underscores the impact of RLT on bone marrow progenitors.

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (Cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]