Pancreatic Neuroendocrine Carcinoma Research Articles

Consensus on the Clinical Diagnosis and Treatment of Grade 3 Pancreatic Neuroendocrine Tumors

The World Health Organization (WHO) 2017 classifications for neuroendocrine neoplasms (NENs) subdivided grade 3 pancreatic neoplasms (pNENs) into G3 well-differentiated pancreatic neuroendocrine tumors (G3 pNETs) and poorly-differentiated pancreatic neuroendocrine carcinomas (pNECs), according to the mitotic count, Ki-67 index and cell differentiation. As a new category, G3 pNETs remains a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice. Therefore, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

Broncho biliary fistula following interventional radiology for hepatic metastases.

Bronchobiliary fistulas are defined as an abnormal communication between the biliary system and the bronchial tree. They are extremely rare complications of radiofrequency or microwave ablation. A 39-year-old woman with a history of neuroendocrine pancreatic carcinoma suffering from liver metastasis was treated with microwave ablation (MWA). In this case report, we present a case of intractable biliptysis from a bronchobiliary fistula secondary to an MWA. The patient was diagnosed by endoscopic retrograde cholangiopancreatograph and hepatobiliary scintigraphy. Treatment involved a right hemihepatectomy, a redo-hepaticojejunostomy, and the surgical placement of a transhepatic drain. After 6 weeks of drain placement, this could be removed. The fistula was thus successfully treated.

Primary Resistance to RET Inhibition in a RET Fusion-Positive Pancreatic Neuroendocrine Carcinoma.

We present a 54-year-old White male with a diagnosis of stage IV pancreatic neuroendocrine carcinoma. Next-generation sequencing of the tumor/blood identified a complex tumor genome, which included a rearranged during transfection (RET) gene fusion. The patient initially received cytotoxic chemotherapy with a significant radiographic response. After 4 cycles of chemotherapy, the patient was transitioned to a clinical trial using selpercatinib, a RET inhibitor, as maintenance therapy. Unfortunately, our patient developed progression of disease at the first treatment monitoring scan. Our patient suffered primary resistance to RET-targeted therapy. Proposed mechanisms of resistance include intrinsic resistance of the nuclear receptor co-activator 4-RET fusion to RET inhibition, the RET fusion representing a passenger alteration to another tumorigenic driver pathway and/or decreased efficacy of RET inhibition after platinum-based chemotherapy. Our patient's clinical course highlights the fact that "actionable" genomic alterations do not always equate to patient benefit.

Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

Surgery for advanced pancreatic neuroendocrine neoplasms: recommendations based on a consensus meeting of the European Society of Endocrine Surgeons (ESES).

This European Society of Endocrine Surgeons (ESES) guideline provides evidence-based recommendations based on the surgical management for locally advanced pancreatic neuroendocrine neoplasms, indications for neoadjuvant therapy, primary tumor resections in the setting of metastatic disease and surgical indications for Grade 3 pancreatic neuroendocrine tumours and pancreatic neuroendocrine carcinoma.

Sequential Irreversible Electroporation for Locally Advanced Pancreatic Cancer.

Pancreatic cancer is a lethal disease, with locally advanced pancreatic cancer (LAPC) having a dismal prognosis. For patients with LAPC, gemcitabine-based regimens, with or without radiation, have long been the standard of care. Irreversible electroporation (IRE), a non-thermal ablative technique, may potentially prolong the survival of patients with LAPC. In this article, the authors present a case of LAPC of the uncinate process (biopsy proven pancreatic neuroendocrine carcinoma) with duodenal invasion. The patient had a combination of chemotherapy and radiation therapy but was found to have stable disease. He then underwent intra-operative IRE with cholecystectomy, Roux-en-Y gastrojejunostomy and hepaticojejunostomy. He subsequently underwent percutaneous IRE 13 months post open IRE. The patient also completed peptide receptor radionuclide therapy and has been started on Lanreotide. Following combination therapy, the pancreatic tumor showed significant reduction in size, with patient survival at 53 months post-diagnosis at the time of writing.

Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model.

The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900-2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

A case of pancreatic neuroendocrine carcinoma was diagnosed based on the dramatic changes observed in imaging over a two-month period

Pancreatic Neuroendocrine Carcinoma (PanNEC) is a rare type of cancer with rapid progression and a poor prognosis. In this report, we present a case of PanNEC that was diagnosed after a dramatic change in its imaging features. A 73-year-old woman with upper abdominal pain was referred to our hospital for evaluation of a 28 mm cystic mass found on abdominal computed tomography. The tumor was also visualized as a cyst on endoscopic ultrasound and did not enhance, but it compressed the main pancreatic duct. Two months later, the tumor had increased in size (50 mm) and transformed into a solid lesion. Pathological findings from a specimen obtained by EUS-FNA revealed that the tumor was PanNEC with a Ki-67 index of >80%. The patient’s survival time was only 4 months after the onset. In considering a case of an uncommon pancreatic mass, it’s important to bear in mind the possibility that it could be PanNEC.

Gene expression profiling of pancreatic neuroendocrine carcinoma and mixed neuroendocrine-non-neuroendocrine neoplasm

Pancreatic neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) are rare pancreatic malignant tumors, and comprehensive gene analyses are scarce. In this study, six NECs and six MiNENs were collected, immunohistochemistry for synaptophysin, chromogranin A, INSM1, Ki-67, and Rb was conducted, and KRAS mutational status was examined. Among these cases, comprehensive gene expression analysis of oncogene pathways using nCounter® were performed with six NECs and four MiNENs, and those data were compared with that of three pancreatic ductal adenocarcinomas (PDACs), with that of three normal pancreatic ducts, and with each other. By dividing NEC and MiNEN cases into KRAS-mutated group and KRAS-wild group, the difference of clinicopathological data and gene expression profiling data were examined between the two groups. Compared to the data of normal pancreatic epithelium, all 13 cancer-related pathways were upregulated in PDAC, MiNEN, and NEC group with more upregulation in this order. Compared to the data of PDAC, genes of DNA Damage repair pathway was most upregulated both in NECs and MiNENs. Regarding the difference between KRAS-mutated and KRAS-wild groups, several genes were differentially expressed between the two, where MMP7 was the upregulated gene with highest p-value and NKD1 was the downregulated gene with highest p-value in KRAS-mutated group. From the extent of upregulation of 13 pathways, MiNEN was considered more progressed stage than PDAC, and NEC was considered more progressed than MiNEN. From the comparison of KRAS-mutated and KRAS-wild NECs and MiNENs, several differentially expressed genes were identified in this study.

High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast.

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK6/7 in cells. These results suggested that FAK6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.

Primary tumor resection enhances the survival of pancreatic neuroendocrine carcinoma patients with liver metastasis under the definition of 2019 WHO classification.

With the update and release of the newest version of WHO classification (2019) for neuroendocrine neoplasm, the clinical features, risk factors of prognosis and the effect of surgical treatment on newly classified pancreatic neuroendocrine carcinoma (pNEC) patients with liver metastasis were not deeply analyzed. In the present study, we tried to reveal the clinical features, and prognostic factors of pNEC patients with liver metastasis with the newest definition of WHO 2019, and explore whether primary tumor resection (PTR), chemotherapy and radiotherapy affect overall survival (OS) and cancer-specific survival (CSS) in those patients. We collected data from pNEC patients with liver metastasis from the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed between 2010 and 2019. We strictly selected pNEC patients according to the 2019 WHO classification criteria. The univariate and multivariate Cox regression analysis were used to determine independent predictors of the survival of these patients. The forest plots map was drawn by R-4.2.2 software to display the results of the multivariate analysis visually. Kaplan-Meier method was used to estimate the OS and CSS. Based on the multivariate analysis outcomes, we established the predictable nomogram model to predict the prognosis of pNEC patients with liver metastasis. The calibration plots were shown to prove the predictive value of the nomogram predictable model. We identified 205 eligible pNEC patients with liver metastasis. According to the multivariable Cox regression analysis in this study, we found that PTR, chemotherapy, primary tumor size and diagnosis to treatment time were independent prognostic factors for both OS and CSS. Kaplan-Meier survival curves demonstrated that PTR and chemotherapy were correlated with increased survival for pNEC patients with liver metastasis. The accuracy of the nomogram model was visually proved by the calibration plot with acceptable predictive performance. Four independent predictors of prognosis in pNEC patients with liver metastasis were identified in this study, including PTR, chemotherapy, tumor size and diagnosis to treatment time. PTR and chemotherapy for pNEC with liver metastasis could lead to a better prognosis, which may provide inspiration for practical clinical guidelines.

Management of Localized Small- and Large-Cell Pancreatic Neuroendocrine Carcinoma in the National Cancer Database.

The role of curative-intent resection and perioperative chemotherapy for nonmetastatic pancreatic neuroendocrine carcinoma (PanNEC) remains unclear due to their biological aggressiveness and rarity. This study aimed to evaluate the association of resection and perioperative chemotherapy with overall survival for nonmetastatic PanNEC. Patients with localized (cT1-3, M0), small- and large-cell PanNEC were identified in the National Cancer Database from 2004 to 2017. The changing trends in terms of the annual proportions of resection and adjuvant chemotherapy were assessed. The survival of patients who received resection and those who received adjuvant chemotherapy were investigated using Kaplan-Meier estimates and Cox regression models. In total, 199 patients with localized small- and large-cell PanNEC were identified; 50.3% of those were resected, and 45.0% of the resected patients received adjuvant chemotherapy. Rate of resection and adjuvant treatment has trended upward since 2011. The resected group was younger, was more often treated at academic institutions, had more distal tumors, and had a lower number of small-cell PanNEC. The median overall survival was longer in the resected group compared to the unresected group (29.4 months vs 8.6 months, p < 0.001). Resection was associated with improved survival in a multivariable Cox regression model adjusting for preoperative factors (adjusted hazard ratio 0.58, 95% CI 0.37 to 0.92), while adjuvant therapy was not. This nationwide retrospective study suggests that resection is associated with improved survival in patients with localized PanNEC. The role of adjuvant chemotherapy needs more investigation.

Neoplastic Progression in Neuroendocrine Neoplasms of the Pancreas.

Pancreatic neuroendocrine neoplasms (PanNENs) represent a heterogeneous group of epithelial tumors of the pancreas showing neuroendocrine differentiation. These neoplasms are classified into well-differentiated pancreatic neuroendocrine tumors (PanNETs), which include G1, G2, and G3 tumors, and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs), which are G3 by definition. This classification mirrors clinical, histologic, and behavioral differences and is also supported by robust molecular evidence. To summarize and discuss the state of the art regarding neoplastic progression of PanNENs. A better comprehension of the mechanisms underpinning neoplastic evolution and progression of these neoplasms may open new horizons for expanding the biologic knowledge and ultimately for addressing new therapeutic strategies for patients with PanNEN. Literature review of published studies and the authors' own work. PanNETs can be seen as a unique category, where G1-G2 tumors may progress to G3 tumors mainly driven by DAXX/ATRX mutations and alternative lengthening of telomeres. Conversely, PanNECs display totally different histomolecular features more closely related to pancreatic ductal adenocarcinoma, including TP53 and Rb alterations. They seem to derive from a nonneuroendocrine cell of origin. Even the study of PanNEN precursor lesions corroborates the rationale of considering PanNETs and PanNECs as separate and distinct entities. Improving the knowledge regarding this dichotomous distinction, which guides tumor evolution and progression, will represent a critical basis for PanNEN precision oncology.

An miRNA Signature Predicts Grading of Pancreatic Neuroendocrine Neoplasms.

Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.

Recent progress of experimental model in pancreatic neuroendocrine tumors: drawbacks and challenges.

The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.

Prediction of Pathological Grades of Pancreatic Neuroendocrine Tumors Based on Dynamic Contrast-Enhanced Ultrasound Quantitative Analysis.

To investigate whether the dynamic contrast-enhanced ultrasound (DCE-US) analysis and quantitative parameters could be helpful for predicting histopathologic grades of pancreatic neuroendocrine tumors (pNETs). This retrospective study conducted a comprehensive review of the CEUS database between March 2017 and November 2021 in Zhongshan Hospital, Fudan University. Ultrasound examinations were performed by an ACUSON Sequioa unit equipped with a 3.5 MHz 6C-1 convex array transducer, and an ACUSON OXANA2 unit equipped with a 3.5 MHz 5C-1 convex array transducer. SonoVue® (Bracco Inc., Milan, Italy) was used for all CEUS examinations. Time intensity curves (TICs) and quantitative parameters of DCE-US were created by Vuebox® software (Bracco, Italy). Inclusion criteria were: patients with histopathologically proved pNETs, patients who underwent pancreatic B-mode ultrasounds (BMUS) and CEUS scans one week before surgery or biopsy and had DCE-US imaging documented for more than 2 min, patients with solid or predominantly solid lesions and patients with definite diagnosis of histopathological grades of pNETs. Based on their prognosis, patients were categorized into two groups: pNETs G1/G2 group and pNETs G3/pNECs group. A total of 42 patients who underwent surgery (n = 38) or biopsy (n = 4) and had histopathologically confirmed pNETs were included. According to the WHO 2019 criteria, all pNETs were classified into grade 1 (G1, n = 10), grade 2 (G2, n = 21), or grade 3 (G3)/pancreatic neuroendocrine carcinomas (pNECs) (n = 11), based on the Ki-67 proliferation index and the mitotic activity. The majority of the TICs (27/31) of pNETs G1/G2 were above or equal to those of pancreatic parenchyma in the arterial phase, but most (7/11) pNETs G3/pNECs had TICs below those of pancreatic parenchyma from arterial phase to late phase (p &lt; 0.05). Among all the CEUS quantitative parameters of DCE-US, values of relative rise time (rPE), relative mean transit time (rmTT) and relative area under the curve (rAUC) were significantly higher in pNETs G1/G2 group than those in pNETs G3/pNECs group (p &lt; 0.05). Taking an rPE below 1.09 as the optimal cut-off value, the sensitivity, specificity and accuracy for prediction of pNETs G3/pNECs from G1/G2 were 90.91% [58.70% to 99.80%], 67.64% [48.61% to 83.32%] and 85.78% [74.14% to 97.42%], respectively. Taking rAUC below 0.855 as the optimal cut-off value, the sensitivity, specificity and accuracy for prediction of pNETs G3/pNECs from G1/G2 were 90.91% [66.26% to 99.53%], 83.87% [67.37% to 92.91%] and 94.72% [88.30% to 100.00%], respectively. Dynamic contrast-enhanced ultrasound analysis might be helpful for predicting the pathological grades of pNETs. Among all quantitative parameters, rPE, rmTT and rAUC are potentially useful parameters for predicting G3/pNECs with aggressive behavior.

Rapid and Deep Response to Lorlatinib in Pancreatic High-Grade Neuroendocrine Carcinoma With a Treatment Emergent Novel KANK1-ALK Fusion

Rapid and Deep Response to Lorlatinib in Pancreatic High-Grade Neuroendocrine Carcinoma With a Treatment Emergent Novel KANK1-ALK Fusion

CNSC-03. NEURONAL INTERMEDIATE FILAMENT (NIF) ANTIBODY POSITIVE PARANEOPLASTIC SYNDROME IN A PATIENT WITH METASTATIC NEUROENDOCRINE PANCREATIC CARCINOMA AND TREATMENT WITH IPILIMUMAB/NIVOLUMAB

Abstract Immune checkpoint inhibitors, such as ipilimumab (CTL-4) and nivolumab (PD-1) have shown effectiveness in many types of neoplasia. This combination has been used as salvage immunotherapy for high grade metastatic pancreatic carcinoma. Nevertheless, severe neurologic immune-mediated adverse effects can result from the use of this treatment. We present a case of a 64-year-old woman with metastatic neuroendocrine pancreatic carcinoma with abrupt left facial and oculomotor cranial nerve palsy as well spastic tetraplegia after one dose of ipilimumab/nivolumab. She had a history of sudden onset diplopia, fever and ground-level fall a few hours after her initial dose of immunotherapy. Initial laboratory assessment showed pronounced lymphocyte predominant leukocytosis and mild chronic hyponatremia. In the following hours, she developed right mydriasis, right sided fast phase nystagmus and right central facial paralysis along with weakness and spasticity in four extremities. Neuroimaging of brain, orbits and CTL spine showed enhancement of intra-orbital and intracranial optic nerves as well chiasm, linear enhancement from C4-C7 and cauda equina, as well as abnormal signal along thoracic spinal cord and conus medullaris. Routine EEG demonstrated non-etiology specific encephalopathy. Lumbar puncture had normal opening pressure, mild pleocytosis, hyper-proteinorrhachia and normal glucose. Viral panel and cytology in the CSF were negative, and myeline basic protein was elevated. She was treated with high dose steroids which improved overall strength and CN palsies. Twenty days after initial presentation, she suddenly developed hypotension, tachypnea, and altered cognition. The patient and family opted for comfort measures only. She passed away that same day. Late report of CSF antibody panels showed positive cell-based assay for heavy and light chain NIF with a titer of 1:512. This case emphasizes the importance of recognition of anti-body mediated paraneoplastic syndromes in patients treated with immunotherapy, their appropriate treatment and prognosis.

Capecitabine and temozolomide for metastatic intermediate to high-grade pancreatic neuroendocrine neoplasm: a single center experience

The combination of capecitabine and temozolomide (CAPTEM) is one of the treatment options for metastatic pancreatic neuroendocrine neoplasms (pNENs). This study aims to evaluate the efficacy of CAPTEM in patients with metastatic intermediate to high-grade pancreatic neuroendocrine tumor (pNET) or carcinoma (pNEC). This study was conducted retrospectively in a single center. Patients were treated for intermediate to high-grade tumor with 750 mg/m² of capecitabine twice daily from day 1 to 14 and 200 mg/m² of temozolomide once daily from day 10 to 14, repeating twice in a cycle of 28 days. The primary outcomes were durations of overall survival (OS) and progression-free survival (PFS). The secondary outcomes consisted of objective response rate and disease control rate. A total of 12 patients (grade 2 NET in six, grade 3 NET in three, NEC in three patients) who received CAPTEM were included in this study. Patients received a median of five cycles (range, 2 to 46) of CAPTEM. The median dose combined 1,150 mg of capecitabine and 300 mg of temozolomide. The median OS and PFS were 41.2 months (range, 3.2 to 167) and 39.7 months (range, 2.1 to 100), respectively. Patients with NET had longer OS and PFS compared to those of patients with NEC (p = 0.002 and p = 0.028). High Ki-67 proliferative index (&gt; 50%) was significantly associated with poor survival outcomes. CAPTEM showed favorable survival outcomes in patients with metastatic intermediate to high-grade pNENs. Our study supports that CAPTEM may be an effective treatment option for metastatic pNENs.

Comparison of the mutational profiles of neuroendocrine breast tumours, invasive ductal carcinomas and pancreatic neuroendocrine carcinomas

The pathophysiology and the optimal treatment of breast neuroendocrine tumours (NETs) are unknown. We compared the mutational profiles of breast NETs (n = 53) with those of 724 publicly available invasive ductal carcinoma (IDC) and 98 pancreatic NET (PNET) cases. The only significantly different pathogenetic or unknown variant rate between breast NETs and IDCs was detected in the TP53 (11.3% in breast NETs and 41% in IDCs, adjusted p value 0.027) and ADCK2 (9.4% in breast NETs vs. 0.28% in IDCs, adjusted p value 0.045) genes. Between breast NETs and PNETs, different pathogenetic or unknown variant frequencies were detected in 30 genes. For example, MEN1 was mutated in only 6% of breast NETs and 37% in PNETs (adjusted p value 0.00050), and GATA3 pathogenetic or unknown variants were only found in 17.0% of breast NETs and 0% in PNETs (adjusted p value 0.0010). The most commonly affected oncogenic pathways in the breast NET cases were PI3K/Akt/mTOR, NOTCH and RTK-RAS pathways. Breast NETs had typically clock-like mutational signatures and signatures associated with defective DNA mismatch repair in their mutational landscape. Our results suggest that the breast NET mutational profile more closely resembles that of IDCs than that of PNETs. These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.