High-grade Neuroendocrine Cancer Research Articles

Results from a Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/leucovorin in refractory advanced high-grade neuroendocrine cancer (HG-NEC)

Results from a Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/leucovorin in refractory advanced high-grade neuroendocrine cancer (HG-NEC)

Abstract ND10: Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers

Abstract MYC transcription factors have been demonstrated to be drivers of many cancers, yet have remained recalcitrant to new drug development. We hypothesized that MYC-driven cancer cell lines are addicted to protein translation, and therefore are vulnerable to the loss of the translation termination factor, GSPT1. We have discovered MRT-2359, a selective GSPT1 molecular glue degrader, that demonstrates potent and preferential antiproliferative activity in MYC-driven cell lines, such as high N- and L-MYC mRNA expressing non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) lines. MRT-2359 has been optimized for differential toxicity between MYC- and non-MYC-driven cancer cell lines, kinetics and depth of degradation, oral bioavailability, and in vivo efficacy. The anti-tumor activity of MRT-2359 was assessed in more than 80 lung patient-derived xenografts (PDXs) that confirmed the preferential anti-tumor activity in N- and L-MYC high NSCLC and SCLC PDXs when dosed orally daily or intermittently. Similar levels of activity were also observed in neuroendocrine lung cancer PDXs and lymphoma models. Oral MRT-2359 is currently in a Phase 1/2 clinical trial in selected cancer patients with MYC-driven NSCLC, SCLC, high grade neuroendocrine cancers and diffuse large B-cell lymphoma (NCT05546268). Citation Format: Owen B. Wallace, Gerald Gavory, Mahmoud Ghandi, Anne-Cecile d’Alessandro, Debora Bonenfant, Maciej Cabanski, Lisa Cantagallo, Agustin Chicas, Qian Chen, Anna Diesslin, Christopher King, Vittoria Massafra, Rajiv Narayan, Arnaud Osmont, Dave Peck, Carolina Perdomo Ortiz, Martin Schillo, Ambika Singh, Ralph Tiedt, Simone Tortoioli, Silvia Buonamici, Markus Warmuth, Filip Janku, Bernhard Fasching. Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader, for MYC-driven cancers [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 ND10.

Abstract 5774: Small cell lung cancer subtype plasticity is regulated by KDM6A

Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine cancer that accounts for ~15% of lung cancers. While nearly all SCLCs are genetically driven by near universal loss of function (LOF) mutations in RB1 and TP53; several recent studies show that there are different phenotypic SCLC molecular subtypes characterized by expression of lineage transcription factors. These include the neuroendocrine ASCL1 and NEUROD1 subtypes which together comprise ~70-80% of SCLCs. Initially subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes. A recent study found that 35-40% of human SCLCs express both ASCL1 and NEUROD1, but the mechanisms driving ASCL1 and NEUROD1 intra-tumoral heterogeneity are not well understood. My laboratory previously developed an autochthonous CRISPR-based SCLC genetically-engineered mouse model (GEMM) generated by intratracheally injecting adenoviruses encoding Cre recombinase and sgRNAs targeting Rb1, Trp53, and Rbl2. Cre turns on Cas9 expression and allows for CRISPR/Cas9 editing of Rb1, Trp53, and Rbl2 in somatic cells in the lungs. The unique advantage of this model is that it allows the inclusion of sgRNAs targeting additional genes of interest in the same adenovirus. Using this CRISPR-based autochthonous SCLC GEMM approach, we studied the consequences of inactivating the epigenetic modifier KDM6A during SCLC tumorigenesis. KDM6A functions as an H3K27 histone demethylase and also exists in the COMPASS complex with KMT2C/D to promote H3K4 mono-/di-methylation at enhancers. KDM6A along with its protein binding partner KMT2D are mutated in SCLC and KDM6A has been implicated in controlling differentiation in other lineages. Strikingly, we found that KDM6A inactivation in SCLC GEMMs induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors that expressed both ASCL1 and NEUROD1. ATAC-sequencing showed open chromatin at the promoters of NEUROD1 and NEUROD1 target genes in KDM6A inactivated tumors. Interestingly, KDM6A inactivated tumors showed a spectrum of ASCL1 to NEUROD1 heterogeneity where some KDM6A inactivated tumors completely lost ASCL1 and solely expressed NEUROD1, some tumors expressed ASCL1 and NEUROD1 in a mutually exclusive manner, while others primarily expressed ASCL1 with very few NEUROD1 positive cells. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near both promoters and enhancers, and decreasing H3K4me1/2 at enhancers together leading to a cell state primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity, which is found in 35-40% of human SCLCs. Citation Format: Leslie Duplaquet, Yixiang Li, Matthew A. Booker, Yingtian Xie, Radhika A. Patel, Deli Hong, Thomas Denize, Emily Walton, Yasmin N. Laimon, Roderick Bronson, Jackson Southard, Shuqiang Li, Sabina Signoretti, Michael Y. Tolstorukov, Paloma Cejas, Henry W. Long, Michael C. Haffner, Matthew G. Oser. Small cell lung cancer subtype plasticity is regulated by KDM6A. [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 5774.

The Role of Surgery in High-Grade Neuroendocrine Cancer: Indications for Clinical Practice.

Pulmonary neuroendocrine tumors (pNET) represent a particular type of malignant lung cancers and can be divided into well-differentiated low-grade NET and poorly-differentiated high-grade NET. Typical and atypical carcinoids belong to the first group while large cell neuroendocrine carcinomas (LCNEC) and small-cell lung cancers (SCLC) belong to the second one. The aim of this mini-review is to focus on the role of surgical therapy for high grade neuroendocrine tumors. SCLC has the worst prognosis among all lung cancer neoplasms: in fact, the two-year survival rate is about 5% and median survival usually ranges between 15 and 20 months. The surgical treatment of SCLC has thus infrequently been judged as a valuable aspect of the therapeutic approach, the gold standard treatment being a combination of platinum-based chemotherapy and radiotherapy. As LCNEC are rare, there is a lack of extensive literature and randomized clinical trials, therefore the curative approach is still controversial. Current treatment guidelines suggest treating LCNEC by surgical resection in non-metastatic stages and recommend adjuvant chemotherapy according to SCLC protocol. Upfront surgery is suggested in early stages (from I to IIB), a multimodality approach is recommended in locally advanced stages (III) while surgery is not recommended in stage IV LCNEC. The rate of surgical resection is quite low, particularly for SCLC, ranging from 1 to 6% in limited diseases; lobectomy with radical lymphadenectomy is considered the gold standard surgical procedure in the case of limited disease SCLC and resectable LCNEC; pneumonectomy, although reported as an effective tool, should be avoided in the light of local and distant recurrence rates.

Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin.

TPS636 Background: The incidence of GEP HG-NEC is increasing and the prognosis is poor. Etoposide–platinum (EP) combination is considered the standard (std) therapy (Rx), but survival is less than 1 year. There is an unmet need for an optimal 2nd line Rx in these patients (pts). Nal-IRI has shown efficacy in small cell lung cancer (pathologically similar to HG-NEC) and in 2nd line pancreatic adenocarcinoma. In a retrospective study, HG-NEC pts with progression on 1st line EP when treated with 2nd line FOLFIRI (FA+5-FU+ IRI) had a good response and a tolerable safety profile (Hentic et al, 2012). Based on this data and the fact that no std 2nd line Rx option exists in HG-NEC, we are evaluating the efficacy of nal-IRI+ 5-FU/FA in a prospective single-arm multicenter study. Methods: Advanced GEP or unknown origin HG-NEC pts with progressive disease/intolerance to 1st line Rx with EP or temozolomide/capecitabine; ECOG PS 0-2 would receive nal-IRI 70 mg/m2, FA 400 mg/m2 followed by 5-FU 2400 mg/m2 on D1 & 15 of 28-days cycle. Rx to continue till disease progression or unacceptable toxicity. Tumor assessment by CT/MRI per RECIST 1.1 q6 wks. Primary end point is to measure ORR (CR+PR). Secondary endpoints include PFS, TTP, OS, safety and QOL changes. Assuming a historic ORR of 15% with std Rx, 37 pts (upto 41 pts considering non-evaluable pts) are required to show an ORR of 30% at a power of 80% at 1-sided significance of α = 0.1. In stage 1, n1= 18 pts will be enrolled. If 3 or more responses are seen, an additional n2= 19 pts to be enrolled. If 8 or more responses are observed of the n = 37 evaluable pts, the Rx would be considered promising for further study. Genomic mutational profiling to be conducted on pre-study tumor samples and correlated with circulating tumor DNA (CT DNA). CT DNA level, assessed serially, will be correlated with Rx response and disease recurrence. We plan to accrue over 3 years at 3 sites. As of August 2019, 1-patient has been enrolled. The trial is funded by Ipsen Pharmaceuticals and the North American Neuroendocrine Tumor Society through the Clinical Investigator Scholarship. Clinical trial information: NCT03736720.

Abstract CT039: A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort

Abstract Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in metastatic rare solid tumors. We report here the results of the neuroendocrine cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg q6 weeks) plus nivolumab (240mg intravenously every 2 weeks) across multiple cohorts of rare tumors, with the neuroendocrine cohort reported here. Pancreatic neuroendocrine tumors are currently being accrued to a separate cohort of S1609. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) >6 months, and toxicity. Results: Thirty-three eligible patients received therapy; 58% (N= 19) had high-grade disease; most common sites were gastrointestinal (non-pancreatic) (45%; N = 15) and lung (18%; N = 6). Patients had received a median of 2 lines of prior therapy. The overall response rate was 24% (CR, 3%; PR, 21%). Patients with high-grade neuroendocrine cancer had a 42% (8 of 19 patients) response rate vs. 0% in low/intermediate grade tumors (0/14 patients; p = 0.01). The 6-month PFS was 30%; median OS was 11 months. The most common toxicities were fatigue (30% of patients) and nausea (27%). Alanine aminotransferase (ALT) elevation (9%) was the most common grade 3-4 irAE, with no grade 5 toxicities. Conclusions: Ipilimumab plus nivolumab was well tolerated with a 42% ORR in patients with high-grade neuroendocrine cancer, regardless of primary site. Further investigation of this combination is warranted. Best Response Summary in 33 Patients with Neuroendocrine CancerResponse TypeAll Patients (n=33)High grade (n=19)Low/Intermediate grade (n=14)Complete Response (CR)1 (3%)1 (5%)0Partial Response (PR)7 (21%)7 (37%)0Stable Disease (SD)>6months2 (6%)02 (14%)SD11 (33%)3 (17%)8 (57%)Progressive Disease (PD)12 (36%)8 (42%)4 (29%)CR+PR8 (24%)8 (42%)0CR+PR+SD>6mo10 (30%)8 (42%)2 (14%) Citation Format: Sandip Pravin Patel, Megan Othus, Young Kwang Chae, Francis Giles, Donna Hansel, Preet Singh, Annette Fontaine, Manisha Shah, Anup Kasi, Tareq Al Baghdadi, Marc Matrana, Zoran Gatalica, W. Michael Korn, Jourdain Hayward, Christine MMcLeod, Helen X. Chen, Elad Sharon, Edward Mayerson, Christopher W. Ryan, Melissa Plets, Charles D. Blanke, Razelle Kurzrock. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT039.

Human papillomavirus-related small cell carcinoma of the oropharynx: a case report and literature review

BackgroundSmall cell carcinoma (SCC) is a rare variant of head and neck cancer characterized by a high-grade neuroendocrine cancer with similar features to small cell lung carcinoma (SCLC). Human papillomavirus (HPV) is an increasingly recognized cause of head and neck cancer but usually associated squamous cell carcinoma of the oropharynx. In this report, we present the clinical presentation, diagnosis, and management of a patient with HPV-related SCC of the oropharynx that responded favorably to chemotherapy with cisplatin plus etoposide and concomitant radiation therapy, a regimen typically used in SCLC.Case presentationWe present a rare case of a 56-year-old man who presented with a three-month history of an enlarging left-sided neck mass. Imaging was consistent with a soft tissue density at the left tongue base, left level IIB nodal conglomerate, and multiple bilateral cervical lymph nodes, without evidence of distant metastasis. The patient underwent a core biopsy of the left neck level II node which read as a poorly differentiated neuroendocrine carcinoma consistent with small cell carcinoma. Polymerase chain reaction revealed that the tumor was positive for HPV16. The tumor was staged T1N2cM0 (stage IVA). He went on to receive four cycles of cisplatin and etoposide. On cycle two, he started radiotherapy to the oropharynx and involved neck nodes. He received a dose of 70 Gray (2 Gy/fraction) over a seven week-period. During the concomitant phase of chemo-radiation, the patient experienced grade IV mucositis, grade II nausea, and dehydration for which he received additional outpatient fluid and electrolyte replacement. Three months after completion of therapy, a PET/CT showed complete resolution of the tumor and metastatic lymph nodes along with no evidence of distant metastasis.ConclusionPatients with HPV-related cancer of the oropharynx require identification of the small cell variant to optimize therapy and improve outcomes.

Surgery Versus Radiation Treatment for High-Grade Neuroendocrine Cancer of Uterine Cervix

Surgery Versus Radiation Treatment for High-Grade Neuroendocrine Cancer of Uterine Cervix

Abstract 3875: Merkel cell carcinomas in Australia have distinct mutation profiles reflecting viral etiology and UV-related DNA damage

Abstract Background/Aims: Merkel cell carcinoma (MCC) is rare but aggressive cutaneous high-grade neuroendocrine cancer. Viral infection and sun-exposure are known risk factors for development of MCC, the latter being important in Australia, which has the highest reported incidence of MCC worldwide. There is growing evidence to suggest that MCC associated with the Merkel cell polyoma virus (MCPyV) is clinically, biologically and genetically distinct to those tumors without viral infection. We aimed to assess mutations arising in MCC in the Australian population by targeted massively-parallel sequencing (MPS) to gain new biological insight and identify novel therapeutic opportunities in this disease. Methods: MCPyV was detected in tumours by PCR amplification of large-T antigen coding DNA. The tumor cohort was comprised of seven MCPyV-positive and 16 MCPyV-negative tumors reflecting the reported prevalence of these subtypes in the Australian population. We also sequenced two viral negative MCC cell lines. Hybridization-based DNA capture was used for enrichment of 625 cancer genes for high-depth MPS of tumor and the matching germline DNA, where available. Single nucleotide variants and small insertions and deletions were detected using GATK and muTect variant calling tools and annotated using ENSEMBL variant effect predictor. Somatic variants were enriched in the data by filtering out any variants found in matching germline samples or population-based polymorphism databases Results: High mutation burden was found exclusively in the MCPyV-negative cases with the hallmark signature of UV induced DNA damage. Somatic mutations were identified in known cancer genes specific to the MCPyV-negative tumors. Deleterious RB1 and TP53 mutations were found in 17 and 16 of the MCPyV-negative cases, respectively. Canonical mutations were identified in PIK3CA, HRAS as well as truncating NF1 mutations, indicating that activation of the PI3K and RAS-MAPK pathways are important for pathogenesis of MCPyV-negative tumors. Treatment of two cell lines harboring either PIK3CA or HRAS mutations, respectively, showed in vitro sensitivity to the dual PI3K/mTOR inhibitor PF-04691502. Conclusions: The identification of a UV-induced DNA damage signature and mutations in PI3K and MAPK pathways specific to viral negative tumors confirms the distinct routes to pathogenesis in this disease subtype. This study provides new insight into the biology of viral negative MCC and potential opportunities for the deployment of targeted therapies in this patient group. Citation Format: Stephen Q. Wong, Kelly Waldeck, Ismael A. Vergara, Jason Li, Richard Lupat, Timothy Semple, Carleen Cullinane, Gisela Mir Arnau, Meredith Johnston, Annette Hogg, Anthony T. Papenfuss, Stephen Fox, Grant McArthur, Anthony Gill, Rodney J. Hicks, Richard W. Tothill. Merkel cell carcinomas in Australia have distinct mutation profiles reflecting viral etiology and UV-related DNA damage. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3875. doi:10.1158/1538-7445.AM2015-3875

Neuroendocrine tumours: the role of imaging for diagnosis and therapy

In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5-hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed.

Collision Tumor of the Large Bowel in the Context of Advanced Pregnancy and Ulcerative Colitis

A woman aged 33 years, during week 30 of pregnancy, presented with metastatic, high-grade neuroendocrine cancer. Investigation revealed a collision-type primary tumor of the large bowel, containing adenocarcinoma and neuroendocrine elements. Platinum-based chemotherapy resulted in a divergent pathologic response as assessed after colectomy. The diagnosis and classification of mixed endocrine-exocrine tumors of the colon are discussed, along with treatment considerations.