Neuroendocrine Carcinoma Of Lung Research Articles

Prognostic impact of interstitial lung disease on pulmonary high-grade neuroendocrine carcinoma

Pulmonary high-grade neuroendocrine carcinomas (HGNECs) have poor prognoses and require multimodal treatment, and interstitial lung disease (ILD) restricts sufficient treatment of patients with lung cancer. We aimed to clarify ILD’s prognostic impact on pulmonary HGNEC, which has previously gone unreported. We retrospectively analyzed 53 patients with HGNEC who underwent resections at our department between 2006 and 2021 and evaluated the clinicopathological prognostic features, including ILD. The patients’ mean age was 70 years; 46 (87%) were male, and all were smokers. Large-cell neuroendocrine and small-cell lung carcinomas were diagnosed in 36 (68%) and 17 (32%) patients, respectively. The pathological stages were stage I, II, and III in 31 (58%), 11 (21%), and 11 (21%) patients, respectively. Nine patients (17%) had ILD, which was a significant overall survival prognostic factor in a multivariate Cox proportional hazards regression analysis (p = 0.048), along with lymph node metastasis (p = 0.004) and non-administration of platinum-based adjuvant chemotherapy (p = 0.003). The 5 year survival rate of the ILD patients was 0%, significantly worse than that of patients without ILD (58.7%; p = 0.003). Patients with HGNEC and ILD had a poor prognosis owing to adjuvant therapy’s limited availability for recurrence and the development of acute exacerbations associated with ILD.

686TiP Preliminary phase I results from a first-in-human study of ZG006, a trispecific anti-T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with advanced small cell lung cancer or neuroendocrine carcinoma

686TiP Preliminary phase I results from a first-in-human study of ZG006, a trispecific anti-T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with advanced small cell lung cancer or neuroendocrine carcinoma

Advances of Treatment of Pulmonary Large Cell Neuroendocrine Carcinoma

Large cell neuroendocrine carcinoma (LCNEC) of lung is a rare neuroendocrine carcinoma subtype with difficulty in early diagnosis and poor prognosis which is treated with standard strategies of small cell lung cancer and non-small cell lung cancer. In recent years, the precise types of LCNEC and its response to therapy have been identified by next-generation sequencing. Some researches have also found the correlation between different subtypes of LCNEC and the efficacy of chemotherapy regimens. However, there is no consensual agreement of its therapy. Recently, immune checkpoint inhibitors (ICIs) has provided a new option for LCNEC patients based on some retrospective research data and case reports. In this review, we aimed to summarize the epidemiological characteristics, standard therapy, the advances of molecular subtypes and clinical applications of ICIs of LCNEC, so as to provide optimal systemic clinical decision-making for LCNEC patients. .

Integrated genomic and transcriptomic characterization of neuroendocrine carcinomas for improved treatment decision-making.

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (> 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (<10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Descriptive analysis of brain metastases (BM) of solid neoplasms in an academic hospital from a low- and middle-income country (LMIC) with a Hispanic population.

e14015 Background: Multidisciplinary management of BM of solid cancers integrates different combinations of treatment modalities. The scarcity of SRS centers has prevented widespread adoption of this therapy for appropriately selected patients. Methods: One-hundred eighteen (51.7% female, 48.3% male, median age 59 years) BM patients from a National Health Institute from Mexico (INCMNSZ) were included and analyzed. Results: The most common primary tumors were lung and breast cancers (25 cases each, representing 21% of the whole cohort), kidney cancer (14%), male germ cell tumors (10%), metastatic carcinoma of unknown primary (CUP) (5%), upper- and lower- gastrointestinal cancers (5%), thyroid differentiated cancers (5%), followed by melanoma, prostate, ovarian, hepatobiliary cancers and sarcoma (3% each of them) and urothelial carcinoma (2%) being the least common. No biopsy was reported for only one case. The most common histomolecular tumors were adenocarcinoma of the lung (17 cases), renal cell carcinoma (17), triple negative (TN) breast cancer (BC) (9), HER-2+ BC (7), Nonseminomatous germ cell tumor (7), CUP (6), ER+/HER-2+ BC (5), Germ cell tumor with choriocarcinoma (5), small-cell lung cancer (SCLC) (5), melanoma (5), prostate adenocarcinoma (5), thyroid differentiated cancer not otherwise specified (NOS) (5). Rectal adenocarcinoma, high-grade serous ovarian cancer, ER+/PR+ BC, sarcomas and NSCLC (3 cases, each) and urothelial carcinoma (2). Rare tumor subtypes, with one case, each included hepatocellular carcinoma, PR+/HER2+ BC, follicular thyroid cancer, esophageal, gastric and colonic adenocarcinomas, neuroendocrine prostate, neuroendocrine gallbladder, endometrial, large cell neuroendocrine lung carcinomas and cholangiocarcinoma. A solitary BM was present in 44 patients (37.3%), 2-3 BM in 30 (25.4%) and >3 BM in 44 patients (37.3%). 18 patients (15.2%) were not symptomatic at the time of diagnosis. 79 patients were treated with Whole-Brain Radiotherapy (WBRT), ten with a combination of surgery and adjuvant WBRT, seven with surgical resection without radiotherapy, only five included SRS as part of their treatment and seventeen received only supportive care. There was no difference in overall survival (OS) between treatment modalities excluding supportive care (p=0.05). Conclusions: Our experience from a LMIC with Hispanic population highlights that more than 50% of BM metastasize from solid tumors different from lung and breast cancers. Even though SRS has been included in recent guidelines from ASCO and ESMO, WBRT is the option most commonly included in multimodality treatments.

Complex Presentation of Lung Cancer with Obstructive Jaundice

Background: Lung cancer, particularly small-cell lung carcinoma (SCLC), often presents with respiratory symptoms. However, atypical manifestations including jaundice and abdominal pain can obscure the diagnosis, leading to challenges in early detection and treatment. Case Presentation: A 49-year-old male, with a history of smoking and diagnosed with Chronic Obstructive Pulmonary Disease (COPD), presented to the emergency department with a 3-day history of jaundice and a 3-week duration of mild abdominal pain. Initial investigations, including blood tests, showed hyperbilirubinemia and elevated lipase and amylase levels. An abdominal ultrasound was performed and revealed a hypoechoic, inhomogeneous mass in the head of the pancreas and multiple liver masses, suggesting a cephalo-pancreatic formation with liver metastasis. Further diagnostic procedures, including upper endoscopy and ERCP, followed by a TAP CT scan, identified a large mediastinal-pulmonary mass with invasion into major vessels and extensive metastasis. The immunohistochemical analysis of a duodenal ulcer biopsy confirmed a diagnosis of duodenal metastasis from a small-cell neuroendocrine lung carcinoma. Conclusion: Our case highlights that while rare, the possibility of metastatic spread should be included in the differential diagnosis when obstructive jaundice occurs in the context of high-risk factors for lung cancer.

Abstract 7566: Identification of cancer subtypes with a ctDNA-based targeted methylation assay

Abstract Introduction: Identifying cancer subtypes is necessary for cancer diagnosis, prognosis determination, and treatment selection. Furthermore, as transformation between subtypes is increasingly recognized as a key resistance mechanism to targeted therapies, serial subtype reassessment is likely to gain adoption. Cancer subtypes have traditionally been determined by pathologists based on histology; more recently, molecular subtyping has been performed using IHC, RNAseq, or assays that detect genetic alterations. However, these methods have significant limitations, including tissue biopsy requirement (IHC and RNAseq), low discriminative resolution for distinct transcriptional programs (IHC and mutation detection), and poor reproducibility and feasibility (RNAseq). The GRAIL plasma-only, ctDNA-based targeted methylation platform is a robust, biopsy-free, scalable assay that can distinguish cancer methylation patterns between different cancer signal origins through the use of a proprietary classifier. Here, we explore the GRAIL platform’s potential to detect finer-scale differences in cancer biology by developing classification algorithms for subtyping of three common cancer types. Methods: As part of the Circulating Cell-free Genome Atlas (NCT02889978) and STRIVE (NCT03085888) studies, clinical data were recorded and plasma samples were collected, accessioned, stored, and processed through GRAIL’s targeted methylation assay from 3,989 cancer and 6,013 non-cancer participants. We developed algorithms to predict cancer status and subtype for breast (triple negative breast cancer [TNBC] model; 531 cancer training participants), lung (lung histology model; 334 cancer training participants), and head and neck (HPV model; 3090 cancer training participants) cancers. Dimensionality reduction of methylation data was performed to illustrate subtype separation within these cancer types. Performance of these three algorithms was assessed on a held-out cohort of cancer samples (184 breast, 241 lung, 67 head and neck) with detectable ctDNA. Results: The lung histology model correctly classified 95% (105/111) of adenocarcinomas, 88% (68/77) of squamous cell carcinomas, and 94% (59/63) of lung neuroendocrine carcinomas and tumors. The TNBC model correctly classified 84% (58/69) of TNBCs and 82% (94/115) of non-TNBCs. The HPV model correctly identified 98% (48/49) of HPV-positive head and neck cancers, and 89% (16/18) of HPV-negative head and neck cancers. Conclusions: GRAIL’s proprietary ctDNA-based targeted methylation platform demonstrates the ability to accurately predict cancer subtypes in multiple cancers using only a plasma sample without the need for tumor biopsy. Future efforts will be directed towards generalizing the GRAIL subtyping method to additional cohorts and cancer types. Citation Format: Tracy Nance, Timothy Shaver, Yifan Zhou, Margaret Antonio, Yinjie Gao, Jonathan Heiss, Robert Calef, Joseph Hiatt, Oliver Venn, Joerg Bredno, John Beausang, Lisa Newman, Charles Swanton, Chun Zhang. Identification of cancer subtypes with a ctDNA-based targeted methylation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7566.

Misleading wheeze in a case of atypical large cell neuroendocrine carcinoma of lung - A deadly variety

Neuroendocrine tumors are neoplasms arising from cells of endocrine and nervous system containing special secretory granules with biogenic amines and polypeptide hormones. One of the varieties that occurs commonly in the lung is large cell neuro endocrine carcinoma. The replicative potential of these neuroendocrine malignancies is so rapid that the patients usually present with metastatic disease. We describe a case of 29-year-old-male presented with nocturnal wheeze which led on to a misdiagnosis of bronchial asthma and finally found to be LCNEC with endobronchial obstruction. They are usually peripherally located lesions, mostly in the upper lung zones of an elderly male smoker. But he had a hilar mass with right lower lobe collapse due to endobronchial obstruction. Hence careful examination of wheeze whether unilateral or bilateral, monophonic or polyphonic, random or fixed, inspiratory or expiratory or biphasic may help in early identification of the endobronchial lesions.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas.

There is an ongoing debate about whether the management of gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) should follow the guidelines of small-cell lung cancer (SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart. We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing (NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC (LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes. We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas. Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC ( TERT amplification), colorectal NEC ( KRAS mutation), and bile tract NEC ( ARID1A mutation). The gene disparities between small-cell NEC (SCNEC) and large-cell NEC (LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/ RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

SNAP25-induced MYC upregulation promotes high-grade neuroendocrine lung carcinoma progression.

This study investigated the expression and role of Synaptosome associated protein 25 (SNAP25) in high-grade neuroendocrine carcinoma (HGNEC). We used differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) to identify key genes and modules in HGNEC. KEGG and GO analyses helped understand these genes' roles, and ROC curves assessed their diagnostic value. We also studied SNAP25's relation to immune infiltration and confirmed findings with in vitro and vivo experiments and datasets. WGCNA identified 595 key genes related to pathways like MAPK signaling, GABAergic synapse, and cancer-related transcriptional misregulation. Top genes included SNAP25, MYC, NRXN1, GAD2, and SYT1. SNAP25 was notably associated with M2 macrophage infiltration. Dataset GSE40275 confirmed SNAP25's high expression and poor prognosis in HGNEC. qRT-PCR and WB analyses showed increased SNAP25 and c-MYC levels in HGNEC, promoting MEK/ERK pathway activity. Reducing SNAP25 decreased H1299 cell proliferation, migration, invasion, and levels of c-MYC, MEK, and ERK. Finally, in vivo experiments further confirmed that SNAP25 knockout can inhibit tumor growth. SNAP25 regulates c-MYC activation by stimulating the MEK/ERK pathway, ultimately influencing the development of HGNEC.

Musashi-1 Is a Novel Immunohistochemical Marker of Neuroendocrine Carcinoma of the Lung

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with a morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but is still not an ideal or better marker. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 98% (41/42) SCLC and in 90% (40/44) LCNEC. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining > 10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

A RARE PRESENTATION OF SMALL CELL LUNG CARCINOMA METASTASIZING TO PHEOCHROMOCYTOMA

Abstract Introduction/Objective Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize hematogenously into another unrelated tumor. We report an interesting case of a tumor-to-tumor metastasis of small cell lung carcinoma to pheochromocytoma of the adrenal gland. Methods/Case Report A 75-year-old female former cigarette smoker with a past medical history of hypertension presented with a two-day history of dyspnea and epigastric pain. Physical examination demonstrated elevated blood pressure only. A computerized axial tomography scan of the chest and abdomen showed an incidental 3.1 cm right adrenal mass and right hilar lymphadenopathy. Detailed biochemical workup showed elevated serum epinephrine, norepinephrine, and 24-hour urine metanephrine. Adrenalectomy showed a 5.8 cm tumor mass with solid lobulated yellow to pink-tan and focally hemorrhagic cut surfaces. Microscopic examination showed a neoplasm composed of two distinct components. The predominant component consisted of nests ("zellballen") of large polygonal cells with variable nuclear pleomorphism, abundant amphophilic to basophilic cytoplasm, and a delicate intervening fibrovascular stroma, without significant mitotic activity. The minor component was characterized by sheets and nests of "small blue cells" with round to ovoid nuclei, stippled nuclear chromatin pattern, scanty cytoplasm, patchy necrosis, and high mitotic activity (>20 mitoses per 10 HPF). Foci of small cell carcinoma deposits were also present in the lymphatic channels of pheochromocytoma. Immunohistochemical stains demonstrated cytoplasmic staining of predominant component tumor cells for synaptophysin, chromogranin, and the absence of staining for TTF-1, CK CAM 5.2, and Ki-67. However, minor component tumor cells demonstrated cytoplasmic staining for synaptophysin, membranous staining for CK CAM 5.2, and nuclear staining for TTF-1 and Ki-67(60%). A final diagnosis of composite pheochromocytoma (predominant) and small cell neuroendocrine carcinoma (minor) was rendered. The possibility of a” collision” tumor comprising primary small cell carcinoma of pulmonary origin metastatic to an adrenal pheochromocytoma in light of the patient's cigarette smoking history and the presence of right hilar lymphadenopathy was favored. The subsequent biopsy of the right subcarinal adenopathy showed small cell carcinoma. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, this is the only case of metastasis to a pheochromocytoma from a small cell neuroendocrine lung carcinoma.

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers.

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 μM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 μCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 μCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

P2.16-05 Durvalumab+EP in Advanced Large-Cell Neuroendocrine Carcinoma of Lung (aLCNEC): a Pilot Phase II study

P2.16-05 Durvalumab+EP in Advanced Large-Cell Neuroendocrine Carcinoma of Lung (aLCNEC): a Pilot Phase II study

Novel Mouse Cell Lines and In Vivo Models for Human High-Grade Neuroendocrine Lung Carcinoma, Small Cell Lung Carcinoma (SCLC), and Large Cell Neuroendocrine Carcinoma (LCNEC).

There is a clear need to expand the toolkit of adequate mouse models and cell lines available for preclinical studies of high-grade neuroendocrine lung carcinoma (small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)). SCLC and LCNEC are two highly aggressive tumor types with dismal prognoses and few therapeutic options. Currently, there is an extreme paucity of material, particularly in the case of LCNEC. Given the lack of murine cell lines and transplant models of LCNEC, the need is imperative. In this study, we generated and examined new models of LCNEC and SCLC transplantable cell lines derived from our previously developed primary mouse LCNEC and SCLC tumors. RNA-seq analysis demonstrated that our cell lines and syngeneic tumors maintained the transcriptome program from the original transgenic primary tumor and displayed strong similarities to human SCLC or LCNEC. Importantly, the SCLC transplanted cell lines showed the ability to metastasize and mimic this characteristic of the human condition. In summary, we generated mouse cell line tools that allow further basic and translational research as well as preclinical testing of new treatment strategies for SCLC and LCNEC. These tools retain important features of their human counterparts and address the lack of LCNEC disease models.

First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC).

8502 Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .

Generation of an induced pluripotent stem cell line SDPHi002-A from a patient with lung cancer

Here, an induced pluripotent stem cell (iPSC) line from a patient with lung neuroendocrine carcinoma was generated. The iPSCs were developed using nonintegrating episomal vectors carrying OCT4, SOX2, KLF4, BCL-XL and c-MYC. The established iPSCs (SDPHi002-A) had normal karyotype, excellent differentiation potential in vitro, showing pluripotent stem cell morphology and high expression of pluripotent markers.

Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Abstract Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p&amp;lt;0.01) delay in tumor growth. There were no significant changes in body weights, complete blood counts, and serum alanine aminotransferase indicating the combination treatments were well tolerated. Radiation dosimetry estimates using quantitative SPECT/CT imaging with Pb203-Pent demonstrated average absorbed doses of 0.133 Gy/µCi (liver), 0.098 Gy/µCi (kidneys), 0.013 Gy/µCi (H292 xenografts), 0.028 Gy/µCi (DMS53 xenografts), 0.057 Gy/µCi (DMS273 xenografts), and 0.096 Gy/µCi (H69AR xenografts). Xenograft absorbed dose levels were positively correlated with CXCR4 expression. Conclusion: The use of 212Pb-Pent therapy to target CXCR4 on NECs showed pre-clinical efficacy in a dose dependent manner that was enhanced by Aur without significant normal tissue toxicity supporting the hypothesis that CXCR4 can be successfully targeted with the radionuclide theragnostic pair, Pb212/Pb203-pentixather. Citation Format: Melissa A. Fath, Dijie Liu, Claudia Robles-Planells, Jordan T. Ewald, Keegan A. Christensen, Spenser S. Johnson, Stephen A. Graves, Douglas R. Spitz, Yusuf Menda, M. Sue O’Dorisio. Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5034.

Therapeutic efficacy of platinum/etoposide regimens in the treatment of advanced poorly differentiated neuroendocrine carcinomas of the lung: A retrospective analysis.

Lung neuroendocrine neoplasms (NENs) are rare malignancies developed from bronchial mucosa. Because of its rarity and complex histopathology, there is limited data on the role of chemotherapy in this subset of tumors. Few studies regarding the treatment of poorly differentiated lung NENs, known as neuroendocrine carcinomas (NECs), are available and many limits are detectable as heterogeneity of tumor samples including different origins and different clinical behaviors, moreover, no evidence of therapeutic advances have been achieved along the last thirty years. We performed a retrospective analysis of 70 patients affected by poorly differentiated lung NECs: half of patients underwent a first line therapy with a combination of cisplatin plus etoposide; the remaining patients receiving carboplatin instead of cisplatin, plus etoposide. Results: In our analysis, the outcomes of patients treated with either cisplatin or carboplatin schedule are similar in terms of ORR (44% versus 33%), DCR (75% versus 70%), PFS (6.0 versus 5.0 months) and OS (13.0 versus 10 months). Median number of chemotherapy cycles was 4 (range 1-8). The 18% of patients required a dose reduction. Main toxicities reported were hematological (70.5%), gastrointestinal (26.5%) and fatigue (18%). Survival rate in our study suggests that high grade lung NENs are characterized by an aggressive behavior and a poor prognosis, despite the treatment with platinum/etoposide according to available data. Clinical results of present study contribute to strengthen available data on the usefulness of platinum/etoposide regimen in the treatment of poorly differentiated lung NENs.

CLINICAL CASE OF NON-TYPICAL METASTASIS OF NEUROENDOCRINE LUNG CARCINOMA TO THE VASCULAR MEMBRANE OF THE EYE

Metastases in eye structures are rare (1-5% cases at systemic spread of different malignancies, mainly breast and lung cancers). The prognosis is poor. The overall survival usually does not exceed 12or even 6months. If metastases are found in the choroid membrane, the probability that the patient has multiple metastatic lesions of other organs increases significantly. Lung neuroendocrine neoplasms are rare (1-2% of all malignancies in adults), but mainly aggressive tumors. They are cha-racterized by "blurred", nonspecific clinical symptoms, the correct diagnosis is delayed seriously, and distant metastases are seen in more than 40% of patients (usually in chest structures, liver, bones, brain, and adrenal glands; metastasis to vascular membrane of the eye ranks the 6th place). Own clinical observation of a male patient with rare metastasis of lung neuroendocrine carcinoma to the choroid of the left eye is presented. The disease is manifested by an ocular metastasis, which was initially considered an embryonic tumor. Other metastatic lesions (hilar lymph nodes, liver, soft tissues) were detected on computed tomography a little bit later. The diagnostic algorithm using routine histological examination and immunohistochemistry, including detection of neuroendocrine markers (chromogranin A, synaptophysin), cytokeratin 7 and Ki-67expression in primary and metastatic tumors is described.