Atypical Carcinoid Research Articles

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft.

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.

The occurrence and associated risk factors of brain metastases in well differentiated grade 1 and 2 bronchial neuroendocrine tumours: A single centre retrospective analysis of 280 patients

Typical and atypical bronchial carcinoid account for around 2% of all neuroendocrine neoplasms of pulmonary origin. Fewer than 5% of patients with these cancers are thought to develop brain metastases, and hence routine intracranial imaging is not currently included in staging investigations. In this study, retrospective case note analysis was performed on 280 patients diagnosed with either typical carcinoid (TC) or atypical carcinoid (AC) at a large, single-site cancer centre. None of the 219 patients with TC developed brain metastases during the course of their disease, whereas seven of the 61 AC (11.5%) were found to have intracranial spread, four of which were present at the point of diagnosis. A Cox proportional hazard model showed that a Ki-67 expression ≥18%, patient age ≥65 years and disease stage at diagnosis were all independently and significantly associated with the development of brain metastases in AC. This study has found new evidence that the incidence of brain metastases in AC is significantly higher than previously thought. Of all the variables reviewed, Ki-67 expression was most strongly associated with the development of intracranial disease in AC and could be readily translated into clinical practice. Predictive factors such as age, disease stage and Ki-67 expression could be used to identify patients at particularly increased risk of brain metastases, who would benefit from early intracranial imaging. This could allow for earlier detection and treatment of metastases, with the potential to improve clinical outcomes and patient quality of life.

Volume Doubling Time of Pulmonary Carcinoid Tumors Measured by Computed Tomography

IntroductionPulmonary carcinoid tumor (PCT) is a rare neuroendocrine lung neoplasm comprising approximately 2% of lung cancer diagnoses. It is classified as either localized low-grade (typical) or intermediate-grade (atypical) subtypes. PCT is known clinically to be a slow-growing cancer, however few studies have established its true growth rate when followed over time by computed tomography (CT). Therefore, we sought to determine the volume doubling time for PCTs as visualized on CT imaging. Materials and MethodsWe conducted a retrospective analysis of all PCTs treated at our institution between 2006 and 2020. Nodule dimensions were measured using a Picture Archiving and Communication System or retrieved from radiology reports. Volume doubling time was calculated using the Schwartz formula for PCTs followed by successive CT scans during radiographic surveillance. Consistent with Fleischner Society guidelines, tumors were considered to have demonstrated definitive growth by CT only when the interval change in tumor diameter was greater than or equal to 2 mm. ResultsThe median volume doubling time of 13 typical PCTs was 977 days, or 2.7 years. Five atypical PCTs were followed longitudinally, with a median doubling time of 327 days, or 0.9 years. ConclusionsTypical pulmonary carcinoid features a remarkably slow growth rate as compared to more common lung cancers. Our analysis of atypical pulmonary carcinoid included too few cases to offer definitive conclusions. It is conceivable that clinicians following current nodule surveillance guidelines may mistake incidentally detected typical carcinoids for benign non-growing lesions when followed for less than 2 years in low-risk patients.

A Multimodal Biomarker Predicts Dissemination of Bronchial Carcinoid.

Simple SummaryEvidence of prediction of disease recurrence after curative surgery in bronchial carcinoid is still limited. The aim of this study was to retrospectively investigate a set of markers as potential predictors of dissemination. This study confirmed that adding OTP, CD44, and Ki-67 to the carcinoid classification improved the identification of patients who are at risk for metastatic disease. Patients who did not develop metastasis in follow-up had typical carcinoids with proliferation index <5% and positive OTP and CD44. Atypical carcinoids with proliferation index ≥5% and loss of OTP and/or CD44 were at high risk for distant metastases. Such patients should be screened for metastatic disease at diagnosis and during follow up.Background: Curatively treated bronchial carcinoid tumors have a relatively low metastatic potential. Gradation into typical (TC) and atypical carcinoid (AC) is limited in terms of prognostic value, resulting in yearly follow-up of all patients. We examined the additional prognostic value of novel immunohistochemical (IHC) markers to current gradation of carcinoids. Methods: A retrospective single-institution cohort study was performed on 171 patients with pathologically diagnosed bronchial carcinoid (median follow-up: 66 months). The risk of developing distant metastases based on histopathological characteristics (Ki-67, p16, Rb, OTP, CD44, and tumor diameter) was evaluated using multivariate regression analysis and the Kaplan–Meier method. Results: Of 171 patients, seven (4%) had disseminated disease at presentation, and 164 (96%) received curative-intent treatment with either endobronchial treatment (EBT) (n = 61, 36%) or surgery (n = 103, 60%). Among the 164 patients, 13 developed metastases at follow-up of 81 months (IQR 45–162). Univariate analysis showed that Ki-67, mitotic index, OTP, CD44, and tumor diameter were associated with development of distant metastases. Multivariate analysis showed that mitotic count, Ki-67, and OTP were independent risk factors for development of distant metastases. Using a 5% cutoff for Ki-67, Kaplan–Meier analysis showed that the risk of distant metastasis development was significantly associated with the number of risk predictors (AC, Ki-67 ≥ 5%, and loss of OTP or CD44) (p < 0.0001). Six out of seven patients (86%) with all three positive risk factors developed distant metastasis. Conclusions: Mitotic count, proliferation index, and OTP IHC were independent predictors of dissemination at follow-up. In addition to the widely used carcinoid classification, a comprehensive analysis of histopathological variables including Ki-67, OTP, and CD44 could assist in the determination of distant metastasis risks of bronchial carcinoids.

Immuntherapie bei neuroendokrinen Tumoren

BackgroundNeuroendocrine tumors (NET) of the digestive system and lung carcinoids are rare neoplasms. In advanced unresectable disease, various systemic therapies are used. Primary tumor site, pathological classification including grading, tumor slope and tumor burden, as well as expression of somatostatin receptors and functional activity have an impact on treatment choices. Established treatment options include somatostatin analogs (octreotide, lanreotide), peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-TATE, molecular targeted therapies (everolimus, sunitinib), and systemic chemotherapy with streptozotocin- or temozolomide-based regimes in well-differentiated NET, or platinum/etoposide in poorly differentiated neuroendocrine carcinoma. There is a high unmet need for novel therapies.AimReview of the current status of immunotherapy in neuroendocrine neoplasms of the digestive system and of lung carcinoids.ResultsImmunotherapy with checkpoint inhibitors is a well-established therapy for example in non-small cell lung cancer (NSCLC), melanoma, hepatocellular carcinoma, and Merkel cell carcinoma, and in combination therapy in small cell lung cancer (SCLC). Studies are limited so far and demonstrate absent or low response rates in well-differentiated NET G1/G2. Other subgroups of patients have shown benefit particularly with dual checkpoint inhibitor therapy with 17–44% objective response rates (ORR). These include primarily neuroendocrine carcinomas of gastroenteropancreatic origin, but also atypical lung carcinoids and possibly also more proliferative NET G3, although data for NET G3 are limited.

Abstract 6080: The heterogeneity and evolution of lung neuroendocrine tumors within TRACERx

Abstract Introduction: Primary pulmonary neuroendocrine tumors (NETs) contribute to 20-25% of all lung cancer diagnoses and lie on a spectrum of malignant behavior, ranging from low grade classical carcinoid tumors to high grade, aggressive small cell carcinomas. The evolutionary relationships between NETs of different grades remain poorly understood, here we seek to use the TRACERx study to explore the genomic evolution of these lung cancers. Methods: Tissue and blood samples were taken from a cohort of 20 patients with pulmonary NETs in a sub-study within TRACERx. Multi-region sampling (84 total regions) and whole exome sequencing was performed on fresh frozen tissue from each tumor. Histological classification of each tumor region was confirmed and scoring of tumor infiltrating lymphocytes (TILs) was performed. The data were then analyzed using the established TRACERx bioinformatics pipeline. Results: Phylogenetic evolutionary histories were generated, illustrating the genomic divergence in each tumor and identifying points at which specific known drivers were acquired during tumor evolution. Lower grade classical and atypical carcinoids were characterized by a low mutational and copy number burden with a high fraction of subclonal mutations, with 5/12 cases having no apparent somatic mutational driver mutation. In contrast higher grade large cell neuroendocrine carcinomas and small cell carcinomas had higher mutational and copy number burden, as well as higher rates of genome instability and whole genome doubling. We identified no evolutionary link between subtypes such as commonly shared clonal drivers, suggesting that atypical or classical carcinoids later evolve into higher grade carcinomas. Dn/ds was used to investigate for evidence of selection in the carcinoid tumors; while there was no evidence for selection in known cancer driver genes associated with NETs or lung cancer, there was a high global dn/ds value suggesting the existence of unknown drivers for this cancer type. Furthermore, there was evidence of parallel evolution in one atypical carcinoid case with two distinct subclonal MEN1 frameshift mutations co-occurring with loss of the other allele. One small cell carcinoma patient was identified as having two genetically unrelated tumors. A germline predisposition for this tumor was suspected since we identified a variant in BRCA2 (rs11571833) that was maintained under loss of heterozygosity in one tumor with a corresponding somatic BRCA2 mutation in the other, suggesting two independent double hit events. Conclusions: Genomic differences are identifiable between different members of the pulmonary NET family, with high grade tumors showing increased whole genome instability indices and phylogenetic divergence than low grade tumors. This work has shed light on the genomic landscape of pulmonary NETs and enabled the identification of distinct evolutionary trajectories in the different subtypes. Citation Format: Robert Bentham, David A. Moore, Lorelle Brownlee, Raju Veeriah, Lizi Manzano, Fiona Blackhall, Colin R. Lindsay, TRACERx Consortium, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. The heterogeneity and evolution of lung neuroendocrine tumors within TRACERx [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 6080.

Abstract 3744: Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation

Abstract Introduction: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. Methods: We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing, Epic-850K-methylation array) of 58 typical-, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross validated using targeted pyrosequencing on 35 carcinoids. Results: Results showed bimodality of OTP expression in carcinoids (OTPhigh versus OTPlow group, likelihood-ratio test p=1.5x10-2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (fdr&amp;lt;0.05 &amp; β-value effect size&amp;gt;0.2). Overall, OTPlow carcinoids harbor a high DNA methylation level as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (logrank test p=0.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, i.e., sustaining proliferative signaling, evading growth suppressor, and genome instability and mutation. Conclusion: High OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis. In poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels. Citation Format: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel. Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation [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 3744.

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

ObjectiveMEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland.Design/MethodsWe evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985–2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients.ResultsThere were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm2, qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%.ConclusionIn this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients.

Targeting ALK in Neuroendocrine Tumors of the Lung.

BackgroundAnaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements.MethodsTo illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.ResultsWithin the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.ConclusionsALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.

Prognosis of Patients with Bronchopulmonary Neuroendocrine Neoplasms in a Tertiary Neuroendocrine Tumor Centre of Excellence

Introduction: The European Neuroendocrine Tumor Society (ENETS) reports variables of prognostic significance in bronchopulmonary neuroendocrine neoplasms (BP-NENs). The aim of this study was to investigate prognostic factors, recurrence-free survival (RFS), and overall survival (OS) for patients with typical carcinoid (TC), atypical carcinoid (AC), and large-cell neuroendocrine carcinoma (LCNEC). Current follow-up practices vary as the evidence is sparse, and we aimed to explore the relevance of routine bronchoscopy in follow-up. Methods: This was a cohort study of 208 patients with BP-NENs followed at Aarhus University Hospital in 2008–2019. RFS and OS were determined using the Kaplan-Meier method for the variables such as primary tumor, primary treatment, smoking status, gender, and histological subtypes. Results: The study included 153 patients with TC, 29 with AC, and 26 with LCNEC. Median follow-up was 48 months. The majority of patients (n = 191) received surgical resection, of which 22 (11%) recurred over time. Seventeen patients had nonsurgical treatment, of which 10 (59%) progressed. The 5-year OS rate was 86% for operated and 9% for nonoperated patients (p < 0.05). Patients with TC had a 5-year OS of 90% compared with 63% and 39% for AC and LCNEC, respectively. As for prognostic factors, nonsmokers did not secure a significant difference in OS compared with current/previous smokers (p = 0.51). In the follow-up period, only 2 (9%) of the 22 recurrences were found on a routine bronchoscopy. Both of these recurrences were also found by diagnostic imaging. Conclusions: Surgical treatment, especially, and diagnosis of TC were associated with a good prognosis. Furthermore, our data did not support routine bronchoscopy as part of a follow-up program for bronchial carcinoids.

Updated efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9024 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated an objective response rate (ORR) of 73% across 15 investigator-assessed patients (pts) with lung cancer (Drilon et al, JCO Precis Oncol 2022). We report data on an expanded cohort of pts with TRK fusion lung cancer treated with larotrectinib. Methods: Pts with TRK fusion lung cancer enrolled in two larotrectinib clinical trials (NCT02576431 and NCT02122913) were included for this analysis. Larotrectinib was administered at 100 mg twice daily. Response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2021, a total of 26 pts with TRK fusion lung cancer (24 non-small cell lung cancer, 1 atypical carcinoid, 1 neuroendocrine) were enrolled, including 10 pts with CNS metastases at baseline. Median age was 51.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n =21; 81%) or NTRK3 (n =5; 19%). Pts received a median of 2 prior lines of systemic therapies with 19 (73%) receiving ≥2. Among 23 pts evaluable per IRC, the ORR was 83% (95% confidence interval [CI] 61–95): two complete responses, 17 partial responses (PR), and four stable disease (SD). The median time to response was 1.8 months. Among 10 evaluable pts with baseline CNS metastases, the ORR was 80% (95% CI 44–97): eight PR and two SD. Median duration of response (DoR) and progression-free survival (PFS) were not reached; median follow-up was 12.9 and 14.6 months, respectively. The 24-month rates for DoR and PFS were 72% and 67%, respectively. Median follow-up for overall survival (OS) was 12.9 months. The 24-month and 36-month rates for OS were both 72%. For the 10 evaluable pts with CNS metastases, the 12-month DoR, PFS, and OS rates were 26%, 22%, and 78%, respectively. Duration of treatment for all pts evaluable per IRC ranged from 2.1 to 52.7+ months. At data cut-off, six pts had progressed, with all six continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in five pts (increased alanine aminotransferase, increased aspartate aminotransferase, hypersensitivity, myalgia, and increased weight). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results support testing for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431, NCT02122913.

Are anaplastic lymphoma kinase (ALK) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation driver biomarkers of pulmonary neuroendocrine tumors (NETs) and carcinomas (NECs)?

Background: Novel targets in neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are needed to improve outcome. The presence of O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation in NETs and NECs may act as a predictive marker for response on treatment with temozolomide. As anaplastic lymphoma kinase (ALK) plays an important role in the nervous system we hypothesized that ALK rearrangement can act as a biomarker in patients with NETs and NECs.Materials and Methods: We performed a retrospective analysis to establish the frequency of MGMT promoter methylation and ALK expression in tissue samples of patients with NETs and NECs.Results: 21% (14/67) of patients tested positive for MGMT promoter methylation. MGMT promoter methylation was present in 33% (3/9) patients with typical carcinoid, in 22% (2/9) patients with atypical carcinoid, in 22% (8/37) patients with small cell lung cancer and in 8% (1/12) patient with large cell neuroendocrine carcinoma. ALK- expression was present in 14% (10 of 70 patients). In all of these patients, no ALK-rearrangement nor ALK-mutation was revealed.Conclusions: Routine testing of NET and NEC samples for an ALK rearrangement is not recommended as ALK-expression is not associated with an ALK-rearrangement. Routine testing of NET and NEC samples for MGMT will detect a promoter hypermethylation in a sizable minority of patients who are eligible for a targeted treatment with temozolomide.

Interim results of an ongoing phase 1/2a study of HPN328, a tri-specific, half-life extended, DLL3-targeting, T-cell engager, in patients with small cell lung cancer and other neuroendocrine cancers.

8566 Background: HPN328 is a delta like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE) derived from the TriTAC platform, designed to minimize off-target toxicities. HPN328 contains 3 binding domains, engineered to redirect T cells to kill DLL3-expressing cancer cells: anti-DLL3 for target engagement, anti-CD3 for T-cell engagement, and anti-albumin for half-life extension. Methods: This ongoing Ph1/2a study is evaluating HPN328 in patients (pts) with metastatic small cell lung cancer (SCLC) and other neuroendocrine (NE) cancers associated with DLL3 expression. Eligible pts must have disease that is relapsed/refractory to standard systemic therapy. Primary endpoints are safety, tolerability, and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity (RECIST 1.1). HPN328 is administered IV, once weekly. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of Feb 3rd, 2022, 16 pts were enrolled in 8 dose-escalation cohorts at doses from 0.015mg to 12.0mg (SCLC n = 10 (62.5%); NE prostate cancer (NEPC) n = 2 (12.5%); other NE neoplasms (NEN) n = 4 (25%)). Median pt age was 61 (43-73) yrs. Pts received a median of 3 (1-5) prior treatments; 75% received a PD-1 blocker. At baseline, 6 pts (37.5%) had treated brain metastases and 8 (50%) had liver metastases. Median treatment duration was 10.6 (3.3-31.3 plus) weeks. Treatment is ongoing in 7 pts (44%; median 16.5 weeks). CRS was reported in 5 pts (31%); events were grade 1 or 2, occurred within 24 hrs of the 1st or 2nd dose and did not recur with rechallenge. No ≥ Grade-3 CRS occurred. No dose-limiting toxicities were observed, and no AEs led to discontinuation. HPN328 exhibited linear PK, with dose-proportional increases in exposure and a median half-life of 71 hrs. Small, transient increases in select cytokines and chemokines were observed up to 24 hrs post dose. T-cell activation and margination were observed, consistent with target engagement. DLL3 expression was confirmed on IHC analysis of most baseline biopsies. 15 pts were efficacy evaluable. 6 of 15 (40%) had decrease in sum of target lesion diameters (4 SCLC, 1 NEPC, 1 NEN). 3 of 9 (33%) SCLC pts across all doses had &gt; 30% decrease (weeks on treatment: 17.2, 16.9 [ongoing], and 25.1 [ongoing, confirmed PR]). At doses ≥1.215mg, 2 of 4 (50%) SCLC pts had &gt; 30% decrease and 1 had &gt; 20% decrease. 4 pts (25%) had stable disease: 2 SCLC, 1 NEPC, 1 NEN (Thymic atypical carcinoid). Conclusions: HPN328 is a novel half-life extended DLL3-targeting TCE that is well tolerated and clinically active. AEs have been transient, manageable, and consistent with class. No ≥ Grade-3 CRS occurred. Tumor shrinkage has been observed, including 1 confirmed PR. Dose escalation is ongoing; updated data will be presented. Clinical trial information: NCT04471727.

Checkpoint Inhibitor Immunotherapy to Treat Temozolomide-Associated Hypermutation in Advanced Atypical Carcinoid Tumor of the Lung.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00009 JCO Precision Oncology no. 6 (2022) e2200009. Published online June 23, 2022. PMID: 35737914 Checkpoint Inhibitor Immunotherapy to Treat Temozolomide-Associated Hypermutation in Advanced Atypical Carcinoid Tumor of the Lung Fangdi Sun, MD1xFangdi SunSearch for articles by this author; James P. Grenert, MD, PhD2xJames P. GrenertSearch for articles by this author; Lisa Tan, BS1xLisa TanSearch for articles by this author; Jessica Van Ziffle , PhD2xJessica Van ZiffleSearch for articles by this author; Nancy M. Joseph, MD, PhD2xNancy M. JosephSearch for articles by this author; Claire K. Mulvey , MD1xClaire K. MulveySearch for articles by this author; and Emily Bergsland , MD1xEmily BergslandSearch for articles by this author Show More 1Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA2Department of Pathology, University of California, San Francisco, San Francisco, CA https://doi.org/10.1200/PO.22.00009 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologySUPPORTSupported by the National Cancer Institute of the National Institutes of Health under award No. P30CA082103.AUTHOR CONTRIBUTIONSConception and design: Fangdi Sun, Emily BergslandCollection and assembly of data: Fangdi Sun, Lisa Tan, Jessica Van ZiffleData analysis and interpretation: Fangdi Sun, James P. Grenert, Nancy M. Joseph, Claire K. Mulvey, Emily BergslandManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Jessica Van ZiffleEmployment: Adaptive Biotechnologies (I)Stock and Other Ownership Interests: Adaptive Biotechnologies (I)Patents, Royalties, Other Intellectual Property: Adaptive Biotechnologies (I)Claire K. MulveyHonoraria: OncLive/MJH Life SciencesResearch Funding: GenentechEmily BergslandStock and Other Ownership Interests: More Health (I), Exai Bio (I)Consulting or Advisory Role: More Health (I)Research Funding: MerckPatents, Royalties, Other Intellectual Property: UpToDateNo other potential conflicts of interest were reported.

Radiomics in pulmonary neuroendocrine tumours (NETs)

ObjectivesThe aim of this single-centre, observational, retrospective study is to find a correlation using Radiomics between the analysis of CT texture features of primary lesion of neuroendocrine (NET) lung cancer subtypes (typical and atypical carcinoids, large and small cell neuroendocrine carcinoma), Ki-67 index and the presence of lymph nodal mediastinal metastases.MethodsTwenty-seven patients (11 males and 16 females, aged between 48 and 81 years old—average age of 70,4 years) with histological diagnosis of pulmonary NET with known Ki-67 status and metastases who have performed pre-treatment CT in our department were included. All examinations were performed with the same CT scan (Sensation 16-slice, Siemens). The study protocol was a baseline scan followed by 70 s delay acquisition after administration of intravenous contrast medium. After segmentation of primary lesions, quantitative texture parameters of first and higher orders were extracted. Statistics nonparametric tests and linear correlation tests were conducted to evaluate the relationship between different textural characteristics and tumour subtypes.ResultsStatistically significant (p < 0.05) differences were seen in post-contrast enhanced CT in multiple first and higher-order extracted parameters regarding the correlation with classes of Ki-67 index values. Statistical analysis for direct acquisitions was not significant. Concerning the correlation with the presence of metastases, one histogram feature (Skewness) and one feature included in the Gray-Level Co-occurrence Matrix (ClusterShade) were significant on contrast-enhanced CT only.ConclusionsCT texture analysis may be used as a valid tool for predicting the subtype of lung NET and its aggressiveness.

Value of [68Ga]Ga-somatostatin receptor PET/CT in the grading of pulmonary neuroendocrine (carcinoid) tumours and the detection of disseminated disease: single-centre pathology-based analysis and review of the literature

BackgroundAlthough most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [18F]FDG PET/CT in a subgroup of patients.MethodsSSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [18F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUVmax) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUVmax values were related to the tumour type (TC versus AC) for both SSTR and [18F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUVmax values were compared to the pathological status (N+ versus N−) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed.ResultsA total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [18F]FDG PET/CT was available in 46 patients. Analysis of the SUVmax values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUVmax 18.4 vs 3.8; p = 0.003) and significantly higher [18F]FDG uptake in AC compared to TC (median SUVmax 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [18F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[18F]FDG SUVmax values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [18F]FDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed.ConclusionOur findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [18F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines.

Lymphadenectomy for lung carcinoids: Which factors may predict nodal upstaging? A multi centric, retrospective study.

To investigate risk factors for nodal upstaging in patients with lung carcinoids and to understand which type of lymphadenectomy is most appropriate. Data regarding patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from January 1, 2005to December 31, 2019, were collected and retrospectively analyzed. Clinical and pathological tumor characteristics were correlated to analyze lymph node upstaging. The analysis was conducted on 283 patients. Pathology showed 230 typical and 53 atypical carcinoids. Nodal and mediastinal upstaging occurred in 33 (11.6%) and 16 (5.6%) patients, respectively. At the univariable analysis, nodal upstaging was significantly correlated with central location (p = 0.003), atypical histology (p < 0.001), pT dimension (p = 0.004), and advanced age (p = 0.043). The multivariable analysis confirmed atypical histology (odds ratio[OR]: 11.030; 95% confidence interval [CI]: 4.837-25.153,p < 0.001) and central location (OR: 3.295; 95%CI: 1.440-7.540,p = 0.005) as independent prognostic factors for nodal upstaging. Atypical histology (p < 0.001), pT dimension (p = 0.036), number of harvested lymph node stations (p = 0.047), and type of lymphadenectomy (p < 0.001) correlated significantly with mediastinal upstaging. The multivariable analysis confirmed atypical histology (OR: 5.408;95% CI: 1.391-21.020,p = 0.015) and pT (OR: 1.052; 95%CI: 1.021-1.084,p = 0.001) as independent prognostic factors. Atypical histology, dimension, and central location are associated with a high-risk for occult hilo-mediastinal metastases, and mediastinal radical dissection may predict nodal upstaging. Thus, we suggest radical mediastinal lymph node dissection in high-risk tumors, reserving sampling, or lobe-specific dissection in peripheral, small typical carcinoids.

Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials

BackgroundHigher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. MethodsNET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0–2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. ResultsTwenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37–80), 30% ECOG PS 1–2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10–100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2–24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3–4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). ConclusionSingle-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

Small‑cell lung carcinoma. Cytological diagnosis

The purpose of this article is to evaluate the possibilities of cytology for lung neuroendocrine tumors (small‑cell lung carcinoma and carcinoids) diagnostics. Cytology specimens obtained by bronchoscopy (n = 112), biopsy of metastatic lymph nodes (n = 27) or from pleural effusion (n = 8) were collected within over 1 year from 147 patients and studied. Small-cell lung carcinoma was diagnosed in 143 patients, representing 23,9 % of all lung carcinomas. The proportion of carcinoid tumors was 2,7 % of all neuroendocrine tumors. Typical carcinoid was observed in three cases, and atypical carcinoid — in one case. Cytologic features most significant for cytological diagnosis of small‑cell lung carcinoma and carcinoids were identified (n = 11). Discriminant analysis demonstrated that the proportion of accurate cytological diagnosis of small‑cell lung carcinoma and carcinoids was 96,69 %. Cytology is a reliable method for neuroendocrine tumor diagnosis. Immunocytochemistry with neuroendocrine markers along with light microscopy should be used to differentiate small‑cell lung carcinoma metastases from other tumors and non‑malignant pathology in pleural effusion specimens.

Sex-based differences in the outcomes of patients with lung carcinoids.

Objective: To assess the impact of sex on the outcomes of patients with well-differentiated lung neuroendocrine neoplasms in a real-world setting. Methods: The Surveillance, Epidemiology and End Results Research Plus database (2000-2018) was accessed, and patients with a diagnosis of typical or atypical carcinoid of the lung were reviewed. Trends in age-standardized rates (per 100,000) of the incidence of lung carcinoid tumors were reviewed among male and female patients as well as the overall population, and annual percent change (APC) was determined for the three groups. Multivariate Cox regression analysis was then used to assess the factors associated with overall and cancer-specific survival. Results: Among all patients, APC (2000-2018) for lung carcinoid diagnosis was 2.9 (95% CI: 2.4-3.5). Among male patients, APC (2000-2018) for lung carcinoid diagnosis was 1.8 (95% CI: 1.2-2.5). By contrast, among female patients, APC (2000-2018) for lung carcinoid diagnosis was 3.4 (95% CI: 2.8-4.1). Based on Kaplan-Meier survival estimates, female sex was associated with better overall survival compared with male sex (p <0.001). Based on multivariate Cox regression analysis, the following factors were associated with worse cancer-specific survival: older age (hazard ratio [HR]: 1.036; 95% CI: 1.031-1.041), atypical carcinoid histology (HR: 3.10; 95% CI: 2.71-3.56), stage (distant vs localized stage HR: 4.05; 95% CI: 3.48-4.71), sex (male vs female sex HR: 1.76; 95% CI: 1.56-1.99) and no surgical treatment (HR: 3.77; 95% CI: 3.22-4.42). Conclusion: Female patients with lung carcinoid tumors have better overall survival compared with male patients, particularly among patients with typical carcinoid tumors.