PURPOSE:Angiogenesis plays an essential role in neuroendocrine tumors (NETs). This study evaluates efficacy and safety of axitinib in extrapancreatic (ep)-NETs. PATIENTS AND METHODS:AXINET was an international, randomized, double-blind, placebo-controlled, phase II/III trial including patients age 18 years and older, with unresectable/metastatic G1-2 epNETs and up to two previous treatment lines. Patients were randomly assigned (1:1) to axitinib 5 mg or placebo, both orally twice a day, in combination with intramuscular octreotide long-acting release 30 mg once every 28 days until disease progression or unacceptable toxicity. Randomization was stratified by primary tumor site, Ki-67 index (≤5% or >5%), and time from diagnosis (> or ≤12 months). The primary end point was investigator-assessed progression-free survival (PFS). Efficacy was also assessed by a blinded independent central review (BICR). RESULTS:From October 2011 to May 2019, 256 patients were assigned to axitinib (n = 126) or placebo (n = 130). Investigator-assessed median PFS was 17.2 months (95% CI, 13.6 to 24.7) versus 13.1 months (95% CI, 10.9 to 18.6) in the axitinib and placebo groups, respectively (hazard ratio [HR], 0.86 [95% CI, 0.65 to 1.15]). The median BICR PFS was 16.6 months (95% CI, 13.5 to 24.2) versus 9.9 months (95% CI, 8.2 to 13.9) in the axitinib and placebo groups, respectively (HR, 0.71 [95% CI, 0.54 to 0.94], P = .017). Objective response rate (ORR) was significantly greater for axitinib per investigator assessment (17.5% v 4.6%; P = .001) and BICR (12.8% v 3.2%; P = .005). Most common grade ≥3 toxicities were hypertension (24.0% v 9.2%) and diarrhea (13.6% v 1.5%). CONCLUSION:Axitinib significantly increased PFS per BICR assessment and ORR both per investigator and BICR assessment compared with placebo, although the primary study end point was not met. Toxicity profile was manageable with no new safety concerns.

PTEN hamartoma tumour syndrome (PHTS) is a diverse multi-system disorder predisposing to a high hereditary risk of breast, thyroid, endometrial, and a moderate risk of renal, and colorectal cancer and skin melanoma. Besides the risk of cancer, PHTS is also associated with benign tumours such as skin and connective tissue tumours, vascular malformations and neurodevelopmental disorders, including autism spectrum disorders. New evidence on cancer risks and the effectiveness of surveillance has been published since the last iteration of the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) guidelines from 2020, necessitating the update presented here A comprehensive literature review was undertaken, and guidelines were revised by clinicians with PHTS expertise from relevant medical disciplines, together with PHTS patients and their representatives. Revised recommendations were put forward for surveillance for breast, thyroid, endometrial, renal, and colorectal cancer and skin melanoma. The proposed cancer surveillance recommendations for PHTS require significant patient commitment as well as a coordinated multidisciplinary medical approach. There is a need for prospective evaluation of the effectiveness of these recommendations in the PHTS population.

BACKGROUND:Early detection is critical in pancreatic ductal adenocarcinoma (PDAC)-one of the most lethal malignancies due to its typically late diagnosis. METHODS:In this study, we aimed to validate an epidemiological risk score (ERS) designed to identify individuals at increased risk of developing PDAC prior to the use of imaging or other diagnostic procedures. The ERS was constructed through a meta-analysis of 24 well-established epidemiological risk factors. We applied this score to a prospective cohort of 178 high-risk individuals with a family history of PDAC within the IMAGene project (ClinicalTrials.gov registration code: NCT06334458). To evaluate the predictive value of the ERS, all participants underwent whole-body or abdominal magnetic resonance imaging (MRI) and the findings were classified according to the Oncologically Relevant Findings Reporting and Data System criteria to identify and categorize lesions based on their malignant potential. External validation was conducted by using a subset of the UK Biobank (UKB) cohort (≈300 000 individuals), among whom 1648 were diagnosed with PDAC. RESULTS:Higher ERS values were associated with the presence of potentially malignant lesions on MRI. Both pancreatic and extra-pancreatic malignant lesions were more frequent among individuals with higher ERS scores (P = .01 and P = .02 respectively) compared with controls. External validation in PDAC cases within the UKB cohort confirmed these associations. CONCLUSION:Our findings support the integration of the ERS as a feasible, low-cost tool for PDAC risk stratification, with the potential to facilitate earlier detection and improve clinical outcomes.

4171 Background: The Phase 3 COMPETE trial demonstrated a significant treatment effect in favor of 177 Lu-edotreotide over everolimus in patients with Grade 1/2, well-differentiated, gastroenteropancreatic neuroendocrine tumors; 177 Lu-edotreotide significantly improved progression-free survival (primary endpoint) and objective response rate (secondary endpoint) compared to everolimus. Nowadays, treatment choice also considers the impact of therapy on patients’ quality of life (QoL); here, we present QoL results from the COMPETE trial. Methods: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and EORTC QLQ-gastrointestinal neuroendocrine tumors (GI.NET) were completed by patients at baseline, each month during the first year, and every 3 months thereafter until disease progression or end of study. Mean change from baseline, duration of maximum health-related quality of life (HRQoL) improvement (until deterioration), and time to deterioration were calculated. Between-group comparisons were conducted using repeated measure analysis with factors for treatment, randomization stratification factors, visit, baseline value, and treatment-by-visit interaction; all HRQoL analyses were prespecified and exploratory. Results: Based on repeated measure analysis, mean change from baseline was in favor of 177 Lu-edotreotide: overall mean change (95% confidence interval [CI]) in global health score was 0.9 (-2.7, 4.4) in the 177 Lu-edotreotide arm vs -9.9 (-13.9, -6.0) in the everolimus arm (nominal p<0.0001) (positive change corresponds to improvement). Time to deterioration in global health status/QoL was longer in the 177 Lu-edotreotide arm vs the everolimus arm (Table 1). Similar trends were observed in the EORTC QLQ-C30 and EORTC QLQ-GI.NET subdomains. In the 177 Lu-edotreotide arm, 90/207 (43.5%) participants had a clinically meaningful improvement (≥10 points) in global HRQoL score, vs 31/102 (30.4%) participants in the everolimus arm. Among these participants, the median duration of improvement was 22.0 (95%CI: 10.1, not evaluable [NE]) vs 10.2 (95%CI: 3.3, NE) months in the 177 Lu-edotreotide and everolimus arm, respectively. Conclusions: Consistent with the overall COMPETE outcomes, this analysis demonstrated clinically meaningful and durable HRQoL benefits for 177 Lu-edotreotide compared with everolimus. Clinical trial information: NCT03049189 . Time to deterioration in global health status/QoL (≥10 points). Parameter / Statistics 177 Lu-edotreotide(N=207) Everolimus(N=102) Patients with ≥10 points deterioration, n (%) 114 (55.1) 78 (76.5) Median, months (95% CI) a 10.251 (7.359, 15.901) 2.267 (2.004, 3.253) Nominal stratified p-value b <0.0001 Stratified hazard ratio (95% CI) 0.392 (0.292, 0.527) a Estimated via Kaplan-Meier method. b Derived from a two-sided test between the two groups.

Background: Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), is actually used to prevent organ transplant rejection and treat metastatic breast, renal, and neuroendocrine cancers. Despite significant pharmacokinetic variability among patients, routine therapeutic drug monitoring (TDM) is not commonly used in oncology. Methods: The aim of this multicenter, prospective observational cohort study is to assess the prevalence of everolimus minimum concentration at a steady state (Cminss) falling outside the therapeutic range (10-26.3 ng/mL) during a routine TDM programme. Sixty patients with metastatic breast, neuroendocrine, or renal cancers, either starting or continuing everolimus treatment according to hospital protocols, are to be included between 1st of January 2024 and 31st of December 2025 (patients undergoing clinical trials are excluded). We hypothesize that 30-50% of our patients and their blood samples will not achieve the target optimal plasma concentrations. Blood samples are collected every 4-6 weeks to monitor drug levels. The secondary goal is to explore correlation between out-of-range everolimus levels and factors such as demographic and anthropometric data, treatment specifics, lab results, genetic polymorphisms, and the presence of toxicity. Conclusions: This study could offer valuable insights into optimizing dosing strategies and may contribute to future research on personalizing everolimus and other anticancer treatments. This personalized approach seeks to tailor therapy not only to the tumour's molecular profile but also to the individual characteristics of each patient, improving both drug selection and dosing precision.

PURPOSE:Multikinase inhibitors have shown efficacy in endocrine neoplasms, and synergism with immune checkpoint inhibitors has been noted in other tumors. PATIENTS AND METHODS:This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1. RESULTS:From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8-42.8] in ATC (N = 14); 8.3% (95% CI, 1.0-27.0) in ACC (N = 24); 15.4% (95% CI, 1.9-45.5) in PPGL (N = 13), and 16.7% (95% CI, 4.7-37.4) in GEP-NET (N = 24). Lung well-differentiated neuroendocrine tumors and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed. CONCLUSIONS:Cabozantinib and atezolizumab were safely administered and showed promising ORR, and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.

BACKGROUND:Estimating breast cancer risk involves quantifying genetic and non-genetic factors. This supports health interventions and risk communication to ensure adherence to screening recommendations. This study evaluated the change in risk estimation when incorporating breast density and polygenic risk score (PRS) into the baseline cancer risk assessment and compared the efficacy of 2 risk-assessment delivery models. METHODS:This 2-step study included 663 healthy women with a family history of breast cancer in which no pathogenic variants were identified. First, breast density and PRS were added to the baseline risk assessment for all participants. A randomized intervention study compared 2 delivery models (in-person vs pre-recorded video) for risk assessment in women at moderate or average risk. All tests were 2-sided. RESULTS:Breast density and PRS reclassified the risk group into 33% of the participants, with only 5% reclassified as high-risk. After disclosure of their estimated multifactorial risk, 65% of women aligned their risk perception with their estimated risk, compared to 47% at baseline (P < .05). No statistically significant differences were found in the primary endpoint cancer worry, mean = 10.2 (SD = 3.1) vs 10.1 (2.7), between delivery models. In-person delivery had slightly better psychological outcomes (excluding the primary outcome) and higher satisfaction, though few participants in the video group sought in-person clarification. CONCLUSIONS:Incorporating breast density and PRS into risk assessments led to substantial reclassification, with 1 in 5 women facing de-escalated surveillance. Personalized assessments improve objective perceptions alignment. A model using a pre-recorded video-based model matches in-person delivery for moderate and average-risk women and is scalable for population-level implementation.

Germline heterozygous pathogenic variants (PVs) in TP53 cause Li-Fraumeni syndrome (LFS), a condition associated with increased risk of multiple tumor types. As the associated cancer risks were refined over time, clinical criteria also evolved to optimize diagnostic yield. The implementation of multi-gene panel germline testing in different clinical settings has led to the identification of TP53 PV carriers outside the classic LFS-associated cancer phenotypes, leading to a broader cancer phenotypic redefinition and to the renaming of the condition as “heritable TP53-related cancer syndrome” (hTP53rc). Germline TP53 variant interpretation is challenging due to the diverse nature of TP53 PVs, variable penetrance of the syndrome, possible occurrence of TP53 somatic mosaicism, and TP53 involvement in clonal hematopoiesis of indeterminate potential (CHIP). Here we aim to assess the relevance and impact of these issues on the diagnostic routine, and to evaluate the sensitivity of the different LFS clinical criteria to identify hTP53rc. TP53 was analyzed in 6161 suspected hereditary cancer non-related patients categorized into three subgroups: (1) 495 patients fulfilling any LFS/Chompret clinical criteria; (2) 2481 patients diagnosed with early-onset breast/colorectal cancer; (3) 3185 patients without clinical criteria suggestive of hTP53rc. Ancillary tests were performed when TP53 PVs were identified in individuals not meeting LFS/Chompret criteria and/or when the variant was identified at low variant allele frequency (VAF). TP53 PVs were identified in blood DNA of 45 probands. Variant origin was elucidated in 39 of these: 72

Purpose: There is an increasing interest in the role of sex and gender in cancer pa-tients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET.Methods: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment.Results: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female pa-tients.Conclusions: Sex-related differences in toxicity with the MKI treatment require targeted in-formation and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Methods Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. Results The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood–cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15- TERT and 6p21- HLA . Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. Conclusions This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

AbstractThe prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

1 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and limited therapeutic options. Immunotherapy and targeted therapy showed limited activity as single therapeutic strategies in ACC but synergism has been observed when combined in other genitourinary tumors such as Prostate and renal cell cancers. Therefore, we evaluated the activity and safety of cabozantinib plus atezolizumab in advanced/metastatic ACC. Methods: CABATEN was a prospective, multi-center, open-label, phase II study including patients with advanced and refractory endocrine and neuroendocrine tumors in 6 independent cohorts. Patients with locally advanced / metastatic ACC, ≥18 years old and ECOG 0-1 were included after progression to chemotherapy and/or mitotane. Prior treatment with cabozantinib or any immune checkpoint inhibitors was not allowed. Patients received atezolizumab 1200 mg IV Q3W plus cabozantinib 40 mg/day PO until progression or unacceptable toxicity. The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study empowered a Simon II stage design, requiring 1 response out of 9 patients at 1st stage to continue accrual in a 2nd stage, for a total of 24 patients. Three responses out of the 24 patients were required in the 2nd stage to consider the study positive for the cohort. Results: From October 2020 to November 2022, 24 patients with ACC were included, 54.2% were female and the median age was 51 years. Most (87.5%) were metastatic at inclusion, 45.8% were functioning, and 20.8% presented hypercortisolism. Most patients (54.2%) had ≥ 2 prior lines of systemic therapy for advanced disease (chemotherapy 91.7%, mitotane 45.8%). Cabozantinib was administered for a median of 3 months (95% CI: 2.7-6.1) and required reduction to 20 mg/day in 20.8% of patients. Atezolizumab was administered for a median of 4.5 cycles (95% CI: 4-8). Treatment was discontinued mainly due to disease progression (79.2%). Treatment discontinuation due to toxicity occurred in 9 (9.7%) patients. The ORR was 8.3% (95% CI: 1-27), including two partial responses that lasted for 5.4 and 17.4 months respectively. After a median follow-up of 10.7 months (range: 2.1-25.7), the median PFS was 2.9 months (95% CI: 2.8-5.7) and the median OS was 13.5 months (95% CI: 8.8-NR). Treatment-related adverse events (grade ≥3) were observed in 20.8% of the patients, consisting of hypertension (12.5%), and transaminase increase (8.3%). Conclusions: Cabozantinib plus atezolizumab showed modest activity in locally advanced/metastatic ACC. Safety profile was consistent with previous reports. The existence of long lasting responders makes it worthwhile to continue investigating predictive factors that help select patients for this combination. Clinical trial information: EudraCT:2019-002279-32 / NCT04400474 .

4128 Background: Early results with immune-checkpoint inhibitors (ICI) in NENs when used as single agents achieve limited response rates. Angiogenesis plays a key role in development and progression of NENs and synergism has been observed when antiangiogenics are combined with ICI in other tumors, whereas. We aimed to assess the efficacy and safety of cabozantinib (Cabo) plus atezolizumab (Atezo) in advanced and progressive NENs. Methods: CABATEN was a single-arm basket study using Atezo 1200 mg every 3 weeks plus Cabo 40 mg/day until progression or unacceptable toxicity in 6 NENs independent cohorts. We here focus in: well-differentiated lung neuroendocrine tumors (LungNET), pheochromocytoma paraganglioma (PPGL), well-differentiated gastroenteropancreatic (GEPNET) and grade 3 extrapulmonary neuroendocrine carcinomas (G3 EP-NEN). Primary endpoint was Overall Response Rate (ORR) by RECIST 1.1. The study had a Simon-II design. Here we present a subgroup analysis of efficacy for NENs (n=55), and for Cabo reduction using a relative dose intensity (RDI)<81% threshold and 3-month interval by Landmark analysis. Baseline characteristics were analyzed in subgroups with prolonged disease stability (PFS>12m or >15m) Results: Median (95%CI) age was 60 (56.0, 63.0) years and 62% were male. Cabo and Atezo treatment were administered for a median of 8.7m (95%CI: 6.2-11.9) and 9.0m (95%CI: 6.8-13.5) and interrupted due to AE’s in 80.0% and 40.0% of pts respectively. Cabo was reduced to 20 mg/day in 58,2% of patients. The 12-m PFS was 50% (95%CI: 29.6-84.4) RDI<81% vs 55.6% (95%CI: 39.7-77.9) RDI≥81% (p=0.9), 12-m OS was 86.7% (CI 95%: 71.1-100) RDI<81% vs 84.7% (CI 95%: 72.0-99.7) RDI≥81% (p=0.6), Cox. LungNET, PPGL, GEPNET and G3 EP-NEN presented a median PFS (m, 95% CI) of 8.4 [7.7-NR], 8.4 [5.7-NR], 13 [11.2-NR] and 2.7 [2.6-NR] respectively. PFS>12m subgroup had a trend towards better ECOG. PFS>15m GEP-NET presented a non-significant trend towards a lower Ki67 index and less previous treatment (no chemotherapy). ORR were 15.4% (95%CI:1.9-45.5) in PPGL and 16.7% (95%CI:4.7-37.4) in GEP-NET. LungNETs and G3 EP-NEN had no responses. Duration of response (DoR) were 12.2m (5.5-19.0) and 15.8m (10.6 - 20.2) in PPGL and GEP-NET cohorts, respectively. Conclusions: Cabo and Atezo showed limited activity but achieved prolonged disease control in a small group of patients with PPGL and GEPNET but not in LungNET and G3 EP-NEN, regardless of RDI of Cabo. Clinical trial information: 2019-002279-32.