Large Cell Neuroendocrine Research Articles

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer.

We performed a retrospective analysis to determine the incidence of neurotrophic tropomyosin-receptor kinase (NTRK) fusion in non-small cell lung cancer (NSCLC). Archival NSCLC tissues between 2018-2020 were screened by immunohistochemistry (IHC) with IHC-positive cases undergoing confirmatory molecular analysis. Correlative clinicopathologic parameters were collected. Of 289 samples analyzed, 10 (3.5%) cases had NTRK expression on IHC. The median age of patients with NTRK-positivity on IHC was 74.9 (range, 44-88) years and 70% had a smoking history. The cohort included seven adenocarcinomas and one each squamous cell carcinoma, large-cell neuroendocrine and not otherwise specified histologies. PDL1 expression was ≤50% in five cases. Concurrent EGFR mutations were detected in three cases, with two cases also showing a PIK3CA E542K mutation and MET amplification, respectively. Due to insufficient tumor material, RNA-sequencing was undertaken in only one IHC-positive case, with the other nine cases analyzed by Fluorescent in-situ Hybridisation. A NTRK fusion, EML4-NTRK3 gene fusion was detected in one patient, a frequency of 0.35%. NTRK fusions in NSCLC are rare. This study highlights real world diagnostic challenges regarding NTRK testing, such as requirements of adequate tumor tissue and appropriate testing methodologies.

Efficacy and safety of PD-1/PD-L1 inhibitor plus platinum-based chemotherapy vs. platinum-based chemotherapy alone in patients with previously untreated advanced large-cell neuroendocrine cancer of the lung.

9066 Background: Large-cell neuroendocrine carcinoma (LCNEC) is a rare tumor with a poor prognosis and limited treatment options. The efficacy of first-line therapies for LCNEC has not yet been established. This study evaluated the efficacy and safety of the combination of PD-1/PD-L1 inhibitor and platinum-based chemotherapy in treatment-naïve patients with advanced LCNEC. Methods: We retrospectively analyzed patients with advanced LCNEC who were treated with a PD-1/PD-L1 inhibitor plus platinum-based chemotherapy (PD-1/PD-L1 inhibitor group) or with platinum-based chemotherapy alone (chemotherapy group) based on data obtained from electronic databases of three participating cancer centers from January 2015 to August 2022. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were evaluated for each group. Safety was assessed in all patients who received at least one dose of their assigned treatment. Results: Among the 75 enrolled patients, 25 were allocated to receive PD-1/PD-L1 inhibitor plus platinum-based chemotherapy and 50 were allocated to receive platinum-based chemotherapy alone (patients were matched 1:2 on baseline characteristics). The median PFS was 15.1 months (95% confidence interval [CI], 7.1–23.2) in the PD-1/PD-L1 inhibitor group and 5.3 months (95% CI, 4.4–6.2) in the chemotherapy group (hazard ratio [HR], 0.26; 95% CI, 0.113–0.428; p < 0.0001). The 12-month OS was 88.0% (95% CI, 67.7–96.9) in the PD-1/PD-L1 inhibitor group and 56.0% (95% CI, 41.4–69.7) in the chemotherapy group ( p = 0.0056). The ORRs in the two groups were 40% and 16%, respectively ( p = 0.022), and the DCRs were 96% and 70%, respectively ( p = 0.010). Regarding safety, the most common incidences of grade ≥ 3 adverse events involved neutropenia, leukopenia, anemia, and fatigue. There were no significant differences between the two groups. Immune-related adverse events (irAEs) in the PD-1/PD-L1 inhibitor group included cutaneous hemangiomas, hypothyroidism, anaphylaxis, and pneumonitis. Grade 3 or 4 irAEs were not observed. No new safety signals were noted. Conclusions: First-line PD-1/PD-L1 inhibitor plus platinum-based chemotherapy significantly improved PFS in patients with advanced LCNEC compared with platinum-based chemotherapy alone.

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.

Abstract 4039: RET overexpression is frequent in lung neuroendocrine tumors (NET) and associates with response to RET tyrosine kinase inhibitors (RET TKIs) in NET cell lines

Abstract Background: RET (rearranged during transfection) is a proto-oncogene encoding for a tyrosine kinase membrane receptor that promotes protein synthesis and cell proliferation. A small percentage of human tumors harbor RET fusions or mutations as oncogenic drivers and RET-TKIs have been developed. Two of them, selpercatinib and pralsetinib, have recently been approved. However, their effect on tumors overexpressing wild-type RET (wt-RET) has not been investigated. A large-scale mRNA analysis performed by our group revealed that ~2% of lung tumors present high expression of wt-RET in absence of fusions. Interestingly, ~60% of high wt-RET tumors presented neuroendocrine characteristics. Methods: Twenty large cell neuroendocrine (LCNEC) and 19 small cell (SCLC) lung carcinomas from two additional institutions were analyzed by nCounter® to validate the previous results. For in vitro experiments, a panel of cell lines derived from lung NETs (DMS-53, NCI-H82, NCI-H727) was used, together with a lung adenocarcinoma cell line (LC2/ad, a positive control harboring the CDCC6-RET translocation). RET fusions and mRNA expression were analyzed by nCounter®, RET protein expression by Western blotting and immunohistochemistry (IHC) and RET mutations by next generation sequencing. The inhibitory effects of selpercatinib and pralsetinib were analyzed in vitro by MTT in 2D and spheroid/3D cultures. Finally, in vivo experiments implanting tumor cells into athymic nude mice are ongoing. Results: Among the 20 LCNECs and 19 SCLCs analyzed, 3 (15%) and 3 (15%) presented very high levels of wt-RET mRNA by nCounter, respectively. Fusions were absent in all cases. The NCI-H82 and NCI-H727 NET cell lines showed very low RET mRNA and protein expression by nCounter, Western blotting and IHC. In contrast, DMS-53 cells presented levels of RET mRNA and protein higher than the observed in the RET-fusion positive LC2/ad. In 2D models, the three NET cell lines tested showed moderate resistance to pralsetinib and selpercatinib, with IC50s of 1.5 - 9.7 µM for pralsetinib and 4.6 - 6.1 µM for selpercatinib; while the RET-fusion positive LC2/ad cells showed an IC50 in the nM range, as expected. In 3D cultures, DMS-53 was found to be sensitive to RET TKIs, with IC50s of and 0.3 µM for praseltinib and 2.5 µM for selpercatinib. In contrast, spheroids of the two RET low cell lines showed complete resistance to both drugs (IC50&amp;gt;10 µM). Experiments in animal models are currently ongoing, final results will be presented at the meeting. Conclusions: Overexpression of RET is frequent in lung tumors with neuroendocrine features (LCNEC, SCLC). Selpercatinib and Pralsetinib show antitumor activity in lung NETs cells expressing high levels of wt-RET. Citation Format: Jaume Roca-Arias, Jordi Bertran-Alamillo, Ruth Román, Cristina Aguado, Laura López, Leticia Ferro-Leal, Beatriz Garcia-Pelaez, Rodrigo de Oliveira Cavagna, Silvia Teixeira, Rafael Rosell, Rui Manuel Reis, Miguel A. Molina-Vila, Ivana Sullivan. RET overexpression is frequent in lung neuroendocrine tumors (NET) and associates with response to RET tyrosine kinase inhibitors (RET TKIs) in NET cell lines. [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 4039.

Preliminary Investigation into Ultrasound and MRI Presentation of Large-Cell Neuroendocrine Carcinomas of the Uterine Cervix

Abstract Objective: The aim of this study was to analyze the ultrasound and MRI features of eight patients with cervical large-cell neuroendocrine carcinoma to improve awareness of this disease among sonographers, radiologists, and clinicians. Methods: Clinical data for eight patients with cervical large-cell neuroendocrine carcinoma confirmed by pathology at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between February 2018 and April 2021 were retrospectively analyzed according to clinical, conventional ultrasound, contrast-enhanced ultrasound, and MRI characteristics. Results: Conventional ultrasound examination of the cervical large-cell neuroendocrine carcinoma lesions in the eight patients revealed two features: (1) irregular hypoechoic areas in the muscular layer, with slightly hyperechoic inlay streaks, and poorly delineated lesions, and (2) slightly abundant blood flow distribution in the lesions. The contrast-enhanced ultrasound showed a “fast-in and fast-out” mode; after subsidence, a “fence-like” change was observed, and the enhancement range was significantly greater than the range of two-dimensional ultrasound. In MRI, T1WI showed a low signal or isosignal; T2WI showed a high signal; DWI showed a high signal and low ADC value; and most of the enhanced MRI showed inhomogeneous hyperenhancement. Conclusion: Conventional ultrasound, contrast-enhanced ultrasound and MRI are complementary methods that provide additional imaging information for the diagnosis of cervical large-cell neuroendocrine carcinoma.

Prevalence and Predictability of Occult Satellite Nodules in Clinical Stage Ia Non-small Cell Lung Cancer following Lobectomy

IntroductionWe sought to assess the prevalence and clinical predictors of satellite nodules in patients undergoing lobectomy for clinical stage Ia disease. Patients and MethodsThe National Cancer Database was queried for patients who underwent lobectomy for clinical stage cT1N0 NSCLC. Collaborative staging information was used to identify patients who were pathologically upstaged based on having separate tumor nodules in the same lobe as the primary tumor. Multivariable logistic regression was used to assess the association of clinical factors with the detection of separate nodules. ResultsA separate tumor nodule was recorded in 2.8% (n = 1284) of 45,842 clinical stage Ia patients treated with lobectomy or bilobectomy. Female gender (3.1% vs. male 2.5%; P = .002) and non-squamous histology (adenocarcinoma 3.2% and large cell neuroendocrine 3.0% vs. squamous cell 1.9% tumors; P < .001) were associated with the presence of separate nodules. The frequency increased for tumors larger than 3 cm (≤ 3cm, 2.7% vs. > 3cm, 3.8%; P < .001). Other factors associated with separate nodules were upper lobe location, pleural and/or lymphovascular invasion and occult lymph node disease. The best predictive model for separate nodules based on the available clinical variables resulted in an area under the curve of 0.645 (95% CI 0.629-0.660). ConclusionSeparate tumor nodules may be detected with a low but relatively consistent frequency across the spectrum of patients with clinical stage Ia NSCLC. The predictive ability using basic clinical factors in the database is limited.

Lung cancer presenting with central nervous system metastasis: Clinicopathological and molecular analysis of 171 cases

A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48–96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.

Pulmonary Combined Large Cell Neuroendocrine Carcinoma.

Pulmonary combined large-cell neuroendocrine carcinoma (CLCNEC) is a rare neuroendocrine tumor pertained to lung large cell neuroendocrine carcinoma (LCNEC) with aggressive behavior and poor prognosis generally. The clinical features of CLCNEC are not specific including cough, expectoration, chest distress, chest pain, etc., which are prone to have different manifestations of the mixed components. Owing to the low incidence, there are few related small-scale retrospective studies and case reports. Currently, the treatment regimen of CLCNEC mainly refers to LCNEC that complete surgical resection is preferred in the early stage and according to previous researches, platinum-based small cell lung cancer (SCLC) standard treatment regimen showed promising results in postoperative and advanced CLCNEC as compared to that of non-small cell lung cancer (NSCLC). Adenocarcinoma-CLCNEC more likely harbor driver gene mutation, and may benefit from targeted therapy. As for immunotherapy, more clinical trial data are needed to support its benefits. This article will fill the gap and will provide new insight into the clinical characteristics, pathological diagnosis and treatment endeavors of CLCNEC.

Hierarchical identification of a transcriptional panel for the histological diagnosis of lung neuroendocrine tumors.

Background: Lung cancer is a complex disease composed of neuroendocrine (NE) and non-NE tumors. Accurate diagnosis of lung cancer is essential in guiding therapeutic management. Several transcriptional signatures have been reported to distinguish between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) belonging to non-NE tumors. This study aims to identify a transcriptional panel that could distinguish the histological subtypes of NE tumors to complement the morphology-based classification of an individual. Methods: A public dataset with NE subtypes, including 21 small-cell lung cancer (SCLC), 56 large-cell NE carcinomas (LCNECs), and 24 carcinoids (CARCIs), and non-NE subtypes, including 85 ADC and 61 SCC, was used as a training set. In the training set, consensus clustering was first used to filter out the samples whose expression patterns disagreed with their histological subtypes. Then, a rank-based method was proposed to develop a panel of transcriptional signatures for determining the NE subtype for an individual, based on the within-sample relative gene expression orderings of gene pairs. Twenty-three public datasets with a total of 3,454 samples, which were derived from fresh-frozen, formalin-fixed paraffin-embedded, biopsies, and single cells, were used for validation. Clinical feasibility was tested in 10 SCLC biopsy specimens collected from cancer hospitals via bronchoscopy. Results: The NEsubtype-panel was composed of three signatures that could distinguish NE from non-NE, CARCI from non-CARCI, and SCLC from LCNEC step by step and ultimately determine the histological subtype for each NE sample. The three signatures achieved high average concordance rates with 97.31%, 98.11%, and 90.63%, respectively, in the 23 public validation datasets. It is worth noting that the 10 clinic-derived SCLC samples diagnosed via immunohistochemical staining were also accurately predicted by the NEsubtype-panel. Furthermore, the subtype-specific gene expression patterns and survival analyses provided evidence for the rationality of the reclassification by the NEsubtype-panel. Conclusion: The rank-based NEsubtype-panel could accurately distinguish lung NE from non-NE tumors and determine NE subtypes even in clinically challenging samples (such as biopsy). The panel together with our previously reported signature (KRT5-AGR2) for SCC and ADC would be an auxiliary test for the histological diagnosis of lung cancer.

Large Cell Neuroendocrine Carcinoma of the Prostate Gland: A Review and Update

It has been documented that the 2016 World Health Organization’s histological classification of prostate cancer has included well-differentiated carcinoid tumours and small- or large-cell poorly differentiated tumours within the category of neuroendocrine tumours. Up to May 2021, only 20 cases of large-cell neuroendocrine tumours of the prostate gland (LCNTPs) had been reported within the literature, among which are nine cases of primary tumours. LCNTPs are a rare histological entity whose evolutive profile and therapeutic potential do differ from those of conventional adenocarcinoma of the prostate gland. Primary neuroendocrine tumours of the prostate gland could be pure or associated with an adenocarcinoma component. Mixed forms of large cell neuroendocrine cancers of the prostate gland (LCNECPs) tend to associated with better prognosis when diagnosed early at a localized stage. Nevertheless, most cases of (LCNTPs) at the time of initial diagnosis could tend to be advanced, locally advanced or metastatic. Even though LCNECPs that are diagnosed initially tend to primary prostate cancers that may be pure primary prostate cancers, few large LCNECPs have been found to be metastatic large cell neuroendocrine carcinomas that had metastasised from other sites of the body for example the lung. Primary LCNECP does tend to manifest similarly to primary adenocarcinoma of prostate gland with lower urinary tract symptoms, haematuria, or signs of obstruction of the upper urinary tract or inability to empty the urinary bladder. Cases of primary LCNECP that manifest tend also to be associated with symptoms related to the sites of the metastases. Serum prostate specific antigen levels tend to be slightly elevated with cases of primary LCNECP, but the levels generally tend not to be as high as most cases of advanced, locally advanced or metastatic primary adenocarcinomas of the prostate gland. Diagnosis of LCNECPs tend to be made pursuant to the undertaking of histopathology and immunohistochemistry staining studies of specimens of the prostate that had been obtained from prostate biopsies, trans-urethral reception of prostate specimens or prostatectomy specimens. The microscopy histopathology examination features of LCNECP the prostate gland have been summarized as follows: (a) Microscopy histopathology examination of LCNECP gland does tend to demonstrate large islands or sheets of tumour cells. (b) Large tumour cells with prominent neuroendocrine features such as salt and pepper chromatin and small nucleoli tend to be visualised upon microscopy examination of specimens of the prostate tumour. (c) High grade features such as lack of glandular formation, frequent mitoses and apoptotic bodies and tumour necrosis tend to be frequent findings upon microscopy examination of specimens of LCNECP. Immunohistochemistry staining features of LCNECP include: (a) At least one of the ensuing neuroendocrine tumour markers should be demonstrated upon immunohistochemistry staining including exhibition of positive immunohistochemistry staining for: chromogranin A, synaptophysin, neuron specific enolase, and CD56 may be positive: It has been stated that immunohistochemistry staining studies may exhibit positive staining in cases of LCNECP with utilization of the following: o TTFI tends to be positive in less than 50% of cases of LCNECP. o Positive AMACR immunohistochemistry staining, but this may be focal or weaker than for adenocarcinoma of the prostate gland. o Positive markers including: PSA, PSMA, NKX3.1 prostein (P501S) tend to be negative in majority of cases of LCNECP, but they could be focally positive in a small subset of the tumours. It has been iterated that in cases of LCNECP, immunohistochemistry staining studies tend to demonstrate negative staining for the ensuing markers: • Urothelial markers such as GATA3, p63, and high molecular weight cytokeratins such as CK5 / 6. • CD99. • Carcinoid tumour of the prostate gland. • PNET/Ewing sarcoma of the prostate gland. • Adenocarcinoma of the prostate gland with focal neuroendocrine differentiation. • Urothelial carcinoma with neuroendocrine differentiation. A high index of suspicion is required in order to diagnose early cases of primary large cell neuroendocrine carcinomas by undertaking early biopsies of prostate glands in all patients who have significant lower urinary tract symptoms if their serum prostate specific antigen (PSA) levels are slightly high or high even if they are commenced on Tamsulosin in an attempt to help improve the symptoms of voiding. There is no consensus opinion on the best management of LCNECP, therefore, there is an urgent need for the establishment of a global multi-centre trial related to various management options for the disease in order to ascertain the best options of management for LCNECP. gland.

Genomic landscape of non-small-cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency.

New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP). Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p=0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p=0.001) and low (30% vs. 28%, p=0.01) and high PD-L1 (32% vs. 30%, p=0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups. MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.

Abstract 921: The Nrf2E79Q activating mutation accelerates growth of pure-small cell lung cancer but not combined small cell lung cancer Tp53floxed/floxed/Cdkn2afloxed/floxed mice

Abstract Inactivating mutations in TP53/P16 are found in most types of non-small cell lung cancer while RB1/P16 losspredominates in small cell lung cancer (SCLC). NRF2 activating mutations are also found frequently in lungcancer, especially in lung squamous cell carcinoma. However, how concurrent mutations in these genes maycontribute to lung cancer development is not fully understood. To address this problem, we compared lung tumordevelopment in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 deficiency, +/- expressionof one of the most common mutations in NRF2 found in human tumors, Nrf2E79Q/+. Surprisingly, both groups,Nrf2E79Q/+ and Nrf2+/+, developed combined-SCLC (C-SCLC): a mixture of SCLC and large cell neuroendocrine(NE) carcinoma along with pure-SCLC (P-SCLC). The appearance of C-SCLC implicates Trp53/p16 double lossin the development of this type of lung cancer. Both groups developed C-SCLC at the same penetrance andincidence; all tumors labeled positive for NE-markers by immunohistochemistry (IHC) including ASCL1, SYP andINSM1. However, C-SCLCs developed by Nrf2E79Q/+ mice did not show NRF2 labeling by IHC, despiterecombination of the Nrf2E79Q/+ allele. In contrast, the Nrf2E79Q/+ mice showed significantly higher incidence of P-SCLC compared to Nrf2+/+ mice. All P-SCLC from Nrf2E79Q/+ mice were NRF2-positive by IHC, while the fewtumors developed by Nrf2+/+ mice were negative. All P-SCLC lesions labeled positive for NE-markers includingASCL1, CGRP &amp; SYP. Both C-SCLCs &amp; P-SCLCs were positive for NKX1.2 (lung cancer-marker) and negativefor P63 (squamous cell-marker). Interestingly, phospho-RB1 was positive for both C-SCLCs &amp; P-SCLCs,suggesting the loss of p16 in our GEMM inactivates Rb1 through loss of inhibition of the cyclin dependent kinases4/6 (CDK4/6). This is the first study showing that the concurrent inactivation of Trp53/p16 in mice drivesdevelopment of C-SCLC. Our study also implicated activation of NRF2 signaling in the progression of SCLC.Our next studies will dissect the mechanisms by which NRF2 activation contributes to the development of SCLCdevelopment. Citation Format: Samera Hamad, Stephanie A. Montgomery, Jeremy M. Simon, Brittany M. Bowman, Kyle B. Spainhower, Ryan M. Murphy, Agnieszka Witkiewicz, Suzanne E. Fenton, Scott H. Randell, Neil Hayes, Erik Knudsen, Trudy G. Oliver, Ben Major, Bernard E. Weissman. The Nrf2E79Q activating mutation accelerates growth of pure-small cell lung cancer but not combined small cell lung cancer Tp53floxed/floxed/Cdkn2afloxed/floxed mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 921.

Identification of pretreatment genomic biomarkers and mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers.

9100 Background: Despite its widespread use, few series explore genomic biomarkers that impact progression-free survival (PFS) for first line osimertinib use and how mechanisms of acquired resistance impact post-osimertinib progression survival. Methods: All pts treated with first line osimertinib at Memorial Sloan Kettering Cancer Center were identified; available pre-osimertinib and post-progression tumor samples underwent next-generation sequencing (NGS) using MSK-IMPACT. Real-world (rw)PFS was estimated with Kaplan-Meier methods from start of osimertinib to progression, defined using interpretation of imaging reports. Post-baseline factors were evaluated using time-dependent covariate Cox model. Results: We identified 331 pts, of which 67 had paired tumor samples and 28 had post-progression tumor samples that underwent MSK-IMPACT. Most pts with biopsies were women (68%), never smokers (83%) and did not have baseline brain metastases (56%). With median follow-up of 24 months (mo), median rwPFS was 14 mo (95% confidence interval (CI) 13 -17 mo, n = 331). EGFR driver alterations (n = 40 atypical, n = 108 L858R, n = 182 exon 19 deletion) were associated with distinct rwPFS (median 8 (95% CI 6-12), 14 (12-18) and 16 mo (13-21), respectively, p &lt; 0.001 logrank test). Pts with concurrent pre-treatment TP53 (14 mo,12-17) or TP53/RB1 (12 mo, 9-15) alterations had shorter median rwPFS compared to pts without these alterations (20 mo,16-24, p &lt; 0.001, logrank test). Fifty patients (53%) had an identified mechanism of resistance. Off target mechanisms (n = 9 MET amplification (amp), n = 3 HER2 amp, n = 3 PIK3CA mutations, n = 3 acquired fusions, n = 2 RB1 loss and n = 1 CCND1 amp, MYC amp, CDK4 amp, KRAS G12A, respectively) and histological transformation (n = 7 small cell, n = 5 squamous and n = 2 large cell neuroendocrine) were detected. On target acquired mechanisms were EGFR amplification (n = 7), and G724S (n = 2) and C797S (n = 3) mutations. Pts with an identified mechanism of resistance did not have improved post-progression survival (12 mo HR 1.6, p = 0.09), but receiving next line of therapy based on post-progression tumor biopsy results (including platinum-etoposide for transformation) did improve post-progression survival (12 mo HR 0.4, p = 0.01). Conclusions: Pts with atypical EGFR drivers or concurrent TP53+/- RB1 alterations have significantly shorter rwPFS on first line osimertinib, highlighting need for additional interventions for these patients. Given the high frequency of transformation and improvement in post-progression survival by tailoring next line of therapy to the identified mechanism, pts with EGFR-mutant lung cancer on first line osimertinib may benefit from tissue biopsies at progression. For pts without an identified resistance mechanism by NGS, additional methods of interrogating tumors at progression are needed.

Challenges in the diagnosis of mandible metastasis

Aim: To report the clinical course of a patient with long-lasting pain and swelling of mandible who was subsequently diagnosed with large cell neuroendocrine carcinoma (LCNEC) of the lung and to point out the importance of expanding the diagnostic approach. Case report: A 61-year-old female patient was referred to the Department of maxillofacial surgery due to severe pain in the area of temporomandibular joint (TMJ) spreading to the upper and lower jaw. Physical examination revealed tenderness, swelling and pain of the preauricular area. MR imaging showed anterior disc displacement with degenerative signs on the left side which indicated arthrocentesis. It resulted with clinical improvement that lasted for 1.6 years. Newly made orthopantomogram revealed unclear changes of the left mandibular corpus. Due to the unclear diagnosis patient underwent biopsy on two occasions, which excluded IgG4 disease, other rheumatology and hematology diseases as well as the tumor. Five years after the initial admission, the patient stated the occasional dyspnea and cough leading to administration of the chest RTG, showing visible round mass in the upper left lobe of the lung. PET/ CT showed accumulation of radiopharmaceutical substance in the corresponded area, affected regional and distant lymph nodes and accumulation within mandible. Somatostatin receptor scintigraphy confirmed the diagnosis, which may indicate the possibility of distant malignancies. Wedge resection of the lung mass was performed and pathohistological examination confirmed the large-cell neuroendocrine carcinoma (LCNEC) stage 3. Chemotherapy was administrated. Patient referred to an emergency medical tract due to the threatening cardiac tamponade and died 11 days after. Conclusions: Mandibular metastases are often presented by atypical signs and symptoms and often present the first sign of the malignant disease. Broad spectrum of examinations must be performed in order to prove or exclude distant malignancies so the best therapy option can be provided.

Differences in Characteristics and Outcomes Between Large-Cell Neuroendocrine Carcinoma of the Ovary and High-Grade Serous Ovarian Cancer: A Retrospective Observational Cohort Study.

BackgroundOwing to its extremely low incidence and the paucity of relevant reports, there is currently no recognized first-line treatment strategy for ovarian large-cell neuroendocrine carcinoma, and there are no statistics related to prognosis derived from large samples. This study aimed to investigate the characteristics, outcomes, and independent predictors of survival for ovarian large-cell neuroendocrine carcinoma and compare them with those of high-grade serous ovarian cancer.MethodsThe Surveillance, Epidemiology, and End Results database was used to identify women diagnosed with ovarian large-cell neuroendocrine carcinoma or high-grade serous ovarian cancer from 1988 to 2015. Clinical, demographic, and treatment characteristics were compared between the groups. Propensity-score matching, Cox risk regression analysis, and Kaplan–Meier survival curves were used to analyze the data.ResultsIn total, 23,917 women, including 23,698 (99.1%) diagnosed with high-grade serous ovarian cancer and 219 (0.9%) diagnosed with ovarian large-cell neuroendocrine carcinoma, were identified. Age >77 years, diagnosis before 2003–2010, and advanced-stage disease were more common in patients with ovarian large-cell neuroendocrine carcinoma than in those with high-grade serous ovarian cancer. Women with ovarian large-cell neuroendocrine carcinoma were less likely to receive adjuvant chemotherapy (54.8% vs. 81.9%) but more likely to receive radiotherapy (3.2% vs. 1.5%; both P<0.001) than women with high-grade serous ovarian cancer. Stage, chemotherapy, and tumor size were independent predictors of overall survival, and the risk of death was greater in the advanced stage than in the early stage (P=0.047). Chemotherapy and tumor size were also independent predictors of cancer-specific survival. Overall and cancer-specific survival rates were significantly low for ovarian large-cell neuroendocrine carcinoma than for more malignant high-grade serous ovarian cancer.ConclusionsCompared to patients with high-grade serous ovarian cancer, those with ovarian large-cell neuroendocrine carcinoma presented more often with advanced-stage disease and had decreased overall and cancer-specific survival rates.

Clinical and molecular pathological features of bronchopulmonary large cell neuroendocrine carcinoma

Objective: To investigate the clinical manifestations, imaging, pathological and molecular features of bronchopulmonary large-cell neuroendocrine carcinoma (LCNEC). Methods: The clinical data of 216 LCNEC patients in the First Affiliated Hospital of Zhengzhou University from 2011 to 2021 were analyzed retrospectively. The clinical manifestations, tumor location and size, characteristics of CT images, immunohistochemical and molecular pathological features were analyzed and compared with 115 cases of mixed small cell carcinoma (M-SCLC) diagnosed in the same period. Results: Among the 216 LCNEC patients, there were 190 males and 26 females, with a median age of 65 years. The first symptoms of the patients were mainly cough (106 cases, 49.1%) and bloody sputum (48 cases, 22.2%). The median tumor length were 4.7cm, including 55 cases of nodular type (25.5%) and 161 cases of mass-forming type (74.5%). CT imaging results showed that LCNEC lesions had soft tissue density, and the proportion of slight enhancement lesions was significantly lower than that in M-SCLC group (52.3% vs 74.8%, P<0.001). In contrast, the proportion of necrosis (87.0% vs 58.3%, P<0.001) and calcification (26.9% vs 2.6%, P<0.001) in LCNEC patients was significantly higher than that in M-SCLC group. Immunohistochemical results showed that the positive rate of CK in LCNEC was significantly higher than that in M-SCLC (99.0 % vs 90.5%, P<0.05), while the positive rate of TTF-1 was significantly lower than that in M-SCLC (51.6% vs 67.0%, P<0.05). In LCNEC group, the proportion of patients with Ki-67 positive index between 50% and 80% was significantly higher than that of M-SCLC (41.2% vs 25.2%), while the proportion between 80% and 100% was lower than that of M-SCLC (51.9% vs 72.2%). There was no significant difference in the positive rates of CD56 (91.7% vs 94.6%, P=0.336), Syn (83.8% vs 84.7%, P=0.838) and CgA (54.8% vs 50.0%, P=0.632) in both tumor types. Molecular pathology results showed that frequent mutatios were TP53 (54.5%), RB1 (36.4%), KEAP1 (18.2%), MYC(18.2%), and PTEN (14.3%), and the rate of tumor mutation burden which is more than 25 mutation/Mb was 27.3%. Conclusions: LCNEC lacks specific clinical manifestations. CT imaging is powerful in distinguishing LCNEC from M-SCLC. LCNEC contains a specific mutation spectrum. Pathology combined with immunohistochemical staining is still the gold standard for LCNEC diagnosis, and the differentiation from M-SCLC mainly depends on cell size and nuclear chromatin pattern with light microscopy.

34P RET-MAP: An international multi-center study on clinicopathologic features and treatment response in patients with NSCLC and RET fusions

Nearly 1-2% of patients (pts) with non-small cell lung cancer (NSCLC) harbour RET fusions and this rare population is not well characterized. This retrospective multi-center study included pts from 17 European centres with any stage RET+ NSCLC. Molecular profile included DNA/RNA sequencing and/or FISH analyses. Clinical, pathological, biological features and treatment outcomes (assessed by investigators) including surgery, chemotherapy (CT), immunotherapy (ICI), CT-ICI, multityrosine kinase inhibitors (MTKi) and RET inhibitors (RETi) were evaluated. In 131 pts, median (m) age was 60 years, 57% were female, 92% had adenocarcinoma (5 NOS, 1 squamous, 2 large cell neuroendocrine, 2 atypical carcinoids). 44% had smoking history, 67% were metastatic at diagnosis including 19% with brain metastases (BM). At last follow up, 30% of pts had BM. RET fusions partners were KIF5B (71%), CCDC6 (20%), others (19%). mPD-L1 expression (n=101) was 5% (0-90), mTMB (n=18) was 3.50 (0-32) mut/mB. The most frequent co-mutation was TP53 (21%). The table reports treatment outcomes. Overall survival was higher in pts treated with RETi versus no RETi (2 lines: 62 vs 17.7 months, p=0.19; >2 lines: 53.5 vs 21.2 months, p=0.0087). Progression-free survival (PFS) under RETi was 16.23 vs 7.69 months in pts with and without TP53 mutations, respectively (p=0.43). In pts treated with single agent ICI, mPD-L1 was numerically higher in responders (CR/PR/SD ≥ 6 months, n=13) than in non-responders (SD<6 months/PD, n=19) (55% vs 0%, p=0.059) and mPFS was 12.91, 7.94 and 2.18 months in pts with PR, SD and PD as best objective response, respectively. ICI was permanently stopped in 3 pts for toxicity. Pts with RET+ NSCLC may have a smoking history and heterogeneous histologies. RETi treatment improves survival in pretreated pts. ICI may be effective especially in pts with high PD-L1.Table: 34POutcomes by treatmentStageEarlyAdvancedFirst use ofSurgery N=31Double agent CT N=72Single agent CT N=23CT-ICI N=19ICI N=33MTKi N=15RETi N=87Median n. of line (range)NA3 (2-4)5 (3-6)2 (1-2)4 (3-5)4 (3-6)2 (2-3)ORR (N, %)NA38/64 (59)5/18 (28)9/19 (47)10/31 (32)5/12 (42)57/77 (74)mDFS/PFS (months, 95% CI)20 (13.4-29.3)8.71 (6.97-11-.8)2.99 (2.17-6.57)7.36 (3.88-NA)4.37 (2.76-11)3.88 (1.51-NA)17.1 (12.2-NA)mDOR (months, 95% CI)NA7.03 (5.13-12.5)3.81 (1.84-NA)10.6 (8.8 -NA)9.46 (8.74-NA)5.82 (1.84-NA)23.9 (12.3-NA) Open table in a new tab

Turkish Thoracic Society Early Career Members Task Force Group's Virtual Congress Notes: European Respiratory Society International Congress 2020.

In this article, Early Career Task Force Group members of the Turkish Thoracic Society summarize the European Respiratory Society 2020 virtual congress. Current developments in the field of respiratory diseases were compiled with the addition of sessions specific to coronavirus disease 2019 this year. Almost all of the congress sessions were examined, and the important and striking results of the congress were highlighted. Congress sessions were attended by expert researchers, and the prominent messages of each session were highlighted in short summaries. They were then grouped under relevant titles and ranked in order of meaning and relation. It was finalized by a team of researchers.

Clinical Outcomes of Postoperative Adjuvant Chemotherapy for Surgically Resected High-Grade Pulmonary Neuroendocrine Carcinoma

Introduction: Data on the clinical outcomes of patients receiving adjuvant chemotherapy for surgically resected high-grade pulmonary neuroendocrine carcinoma (HGNEC) (large-cell neuroendocrine carcinoma and small-cell lung cancer) are limited. This study aimed to evaluate the prognostic significance of adjuvant chemotherapy in patients with HGNEC. Methods: We retrospectively analyzed patients with surgically resected HGNEC at five institutions in Japan between January 2006 and May 2016. Results: A total of 143 patients were enrolled. Among them, 65 received adjuvant chemotherapy. Four patients who participated in clinical trials were excluded; the remaining 61 patients were included in the study. Fifty-six patients received adjuvant small-cell lung cancer-based chemotherapy. Twenty-five of 29 patients who relapsed after postoperative adjuvant chemotherapy received chemotherapy. The most commonly administered chemotherapy agent was amrubicin. The 3-year relapse-free and overall survival rates were 55.2% and 66.8%, respectively. The median relapse-free and overall survival times for the 25 patients who received chemotherapy after relapse were 12.9 and 27.5 months, respectively. Among them, 22 relapsed within 2 years. Patients who received platinum-doublet chemotherapy after relapse tended to have better time to progression disease and overall survival than those who received single-agent chemotherapy. Conclusions: Most patients with HGNEC received small-cell lung cancer-based regimens as postoperative adjuvant chemotherapy. Those who relapsed after adjuvant chemotherapy were mainly treated with amrubicin. Our findings suggest that platinum-doublet chemotherapy tends to improve the time to progression disease and overall survival in patients who relapse after postoperative adjuvant chemotherapy.

Impact of Routine Surveillance Imaging on Detecting Recurrence in Sinonasal Malignancies

<h3>Purpose/Objective(s)</h3> Surveillance imaging guidelines for sinonasal malignancies are varied and lack scientific data supporting the basis of these recommendations. This study wishes to examine the utility of surveillance imaging in detecting local, regional, and distant failures as well as second primary tumors in patients with sinonasal malignancies treated with surgical resection followed by adjuvant radiation. <h3>Materials/Methods</h3> Using an IRB-approved institutional database of head and neck cancer patients, we performed a retrospective review of 41 patients with sinonasal malignancies treated at a single institution between the years 2005 to 2021. Patient information regarding tumor location, staging, pathology, smoking status, alcohol use, chemotherapy, radiation treatment plan, and data surrounding surveillance imaging including type, frequency, and concern for recurrence were collected. Patients were divided into two groups comparing the frequency and type of imaging ordered: patients with <4 scans/year Group 1 and ≥ 4 scans/year Group 2. We compared the time to recurrence between the two groups using log-rank test and Cox proportional hazard ratio. A p-value of < 0.05 was considered the threshold for significance. <h3>Results</h3> Median follow up was 37.5 months (14.4-68.9 months). Overall 80% (n=32) patients had primary nasal cavity malignancies and 20% (n=8) had paranasal sinus disease. Thirteen (32.5%) patients had a squamous cell carcinoma (32.5%), twelve (30.0%) patients had an esthesioneuroblastoma, 5 (12.5%) patients had an adenocarcinoma and 3 (7.5%) patients had sinonasal undifferentiated carcinomas. The remaining few patients had sarcomatoid squamous cell carcinoma, adenoid cystic carcinoma, large cell neuroendocrine, and small cell neuroendocrine tumors – with a majority of patients having advanced disease (AJCC 7^th edition). In 27.5% (n=11) patients there was a recurrence: 4 had local failures, 4 had regional failures, and 3 had distant failures. The type of imaging (CT vs. PET/CT vs. MRI) ordered had a non-significant association with recurrence (p=0.802). There was no association with the frequency (HR: 1.13, 95% CI: 0.73-1.74) and total number of scans (HR: 1.24 [0.93-1.66]) with time to recurrence. Rate of recurrence-free survival at 2-years was 86% and 80% in patients with <4 scans/year and ≥ 4 scans/year, respectively. <h3>Conclusion</h3> In our study, the recurrence rates were limited for patients with sinonasal malignancies treated with definitive intent. Increasing the total number or frequency of scans in the first year after treatment was not associated with time to recurrence. These findings suggest a judicious approach in using post-treatment surveillance imaging.