High-grade Neuroendocrine Carcinoma Research Articles

An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas. The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness, improved diagnostic modalities, and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms. GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation, histopathologic features, and molecular biology. Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone. The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas, which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors. As our understanding of the biology of GEP-NENs has grown, new and improved diagnostic modalities can be developed and optimized. Here, we discuss clinical features and updates in diagnosis, including histopathological analysis, biomarkers, molecular techniques, and radiology of GEP-NENs. We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.

Histologic transformation of epidermal growth factor receptor–mutated lung cancer

PurposeThis study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). Patients and methodsWe conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. ResultsIn total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%–3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non–small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. ConclusionHT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors

BackgroundPancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown.MethodsWe performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas.ResultsPhylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin.ConclusionsOur study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification.

7MO WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in small cell lung cancer

Small cell lung cancer (SCLC) is a poorly immunogenic, high-grade neuroendocrine carcinoma arising in the lung. Immune checkpoint blockade (ICB) added to chemotherapy is now the standard upfront therapy for SCLC but leads to a modest increase in overall survival and progression-free survival. These modest benefits underscore the critical need to identify pathways and targets that can durably enhance the antitumor responses of ICB in SCLC. SCLC is characterized by a ubiquitous loss of TP53 which disrupts the G1-S cell cycle checkpoint and as a result, most SCLC is dependent on G2-M cell cycle checkpoint regulators including WEE1.

METASTATIC NEUROENDOCRINE TUMOR OF THE OVARY - AN UNUSUAL SITE

A 22 year old female with stage III small cell neuroendocrine carcinoma of the lung presented two years later with a large abdomino-pelvic mass. Core biopsy showed a metastatic high-grade neuroendocrine carcinoma. She responded poorly to chemotherapy. An exploratory laparotomy revealed bilateral large ovarian masses. Total hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathology showed a metastatic high grade neuroendocrine carcinoma of both ovaries, consistent with metastasis from small cell neuroendocrine carcinoma of the lung. Post adjuvant chemotherapy she remained controlled over four years. We present a rare case of small cell neuroendocrine tumor of the lung with metastasis to the ovary.

Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas.

BackgroundAlthough the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear.MethodsData from the National Cancer Database between 2004 and 2016 were used for this study.ResultsOf 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients.ConclusionsTreatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.

Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective.

Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.

ASO Visual Abstract: Prognosis for Poorly Differentiated High-Grade Rectal Neuroendocrine Carcinomas

ASO Visual Abstract: Prognosis for Poorly Differentiated High-Grade Rectal Neuroendocrine Carcinomas

Sinonasal Neuroendocrine Carcinoma: 15 Years of Experience at a Single Institution.

Objectives Sinonasal neuroendocrine carcinomas (SNECs) are among the rarest paranasal sinus cancers. Consensus guidelines for therapy are difficult to develop due to limited data regarding the natural history and successful treatment of these tumors. This study presents 15 years of experience treating SNEC at a single institution and a review of the literature. Design Retrospective review. Setting Academic medical center in the United States. Participants Patients diagnosed with primary SNEC. Main Outcome Measures Overall survival. Results Thirteen patients were identified and included. Overall estimated survival was 74.6% at 5 years. Ten of 13 (76.9%) patients were diagnosed with high-grade neuroendocrine carcinoma and three (23.1%) with intermediate or low grade. All three patients with low- or intermediate-grade cancer survived more than 10 years from their initial diagnosis (median survival: 11.6 years) and are currently alive. The four patients who died had high-grade carcinoma, and estimated overall 5-year survival for all patients with high-grade carcinomas was 65.6%. Five patients, all with high-grade carcinoma, of seven who completed primary chemoradiation therapy (CRT) required salvage resection, and 60% are alive without disease. Conclusion This cohort has a higher overall rate of survival than many recent case series and reviews. There is consensus that multimodal therapy is preferred over monotherapy, but approaches to treatment vary widely. Our approach of surgical resection as primary therapy for low-grade tumors and primary CRT for high-grade SNEC has been successful, and could indicate hope for improved survival among these patients.

SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors

BackgroundSynaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers.MethodsWe evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs).ResultsWe found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs.ConclusionsTherefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.

Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract.

Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.

125P LSD1 inhibition restores MHC class I expression and augments the anti-tumor response of immune checkpoint blockade in small cell lung cancer

Small cell lung cancer (SCLC) is a poorly immunogenic, high-grade neuroendocrine carcinoma. SCLC is largely unresponsive to immune checkpoint blockade (ICB) due to immunosuppressive mechanisms like repression of the major histocompatibility complex class I (MHC-I) and lack of T cell infiltration. Chromatin regulator, histone H3K4 demethylase LSD1 (gene KDM1A), is highly expressed in SCLC cells and has been shown to have immunosuppressive effects in other cancers. However, how LSD1 modulates the immune microenvironment and tumor responses to cancer immunotherapy in SCLC is still poorly understood.

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Prognosis for Poorly Differentiated, High-Grade Rectal Neuroendocrine Carcinomas.

Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. Patients captured in the National Cancer Database (NCDB; 2004-2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1year, 41%; 3 years, 13%; 5years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.

Primary neuroendocrine tumors of the ovary: Management and outcomes.

BackgroundThere is currently no recognized first‐line treatment strategy for ovarian neuroendocrine tumors (NETs). Furthermore, because of the low incidence of ovarian NETs, no studies have reported prognostic statistics derived from large samples. This retrospective study aimed to investigate the clinical behavior of ovarian NETs.MethodsThe Surveillance, Epidemiology, and End Results database was used to identify women diagnosed with ovarian NETs from 2004 to 2015. Overall survival (OS), cancer‐specific survival (CSS), and independent prognostic factors for ovarian NETs were evaluated. The effects of different treatments on prognosis were also compared, as were OS and CSS rates for histological subtypes.ResultsThe 5‐year OS rates were 83.3%, 30.0%, 20.3%, and 9.8% for patients in stages I (n = 159), II (n = 23), III (n = 101), and IV (n = 148), respectively. The 5‐year CSS rates were 85.6%, 41.7%, 21.2%, and 9.8% for patients in stages I–IV, respectively. Age, American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, treatment, and histological type were related to poor OS and CSS. In the early stage, the 5‐year OS and CSS rates were 97.03% and 96.90%, respectively. For patients in the advanced stage receiving comprehensive treatment (surgery + chemotherapy + radiotherapy), the 5‐year OS and CSS rates were 72.9% and 70.00%, respectively. When comparing low‐ and high‐grade neuroendocrine carcinoma, 5‐year OS rates were 93.96% and 7.01%, 5‐year CSS rates were 97.44% and 7.31%, 10‐year OS rates were 93.56% and 2.34%, and 10‐year CSS rates were 97.44% and 4.88%, respectively.ConclusionAge, AJCC stage, treatment, and histological type are independent prognostic factors of ovarian NETs. OS and CSS are relatively good for early‐stage cases treated with surgery alone, whereas more comprehensive treatment is required to improve OS and CSS in the advanced stage.

Role of CD200 in the Detection of Nonhematologic Neoplasms by Routine Flow Cytometry Analysis

Abstract Objectives While flow cytometry is routinely used in the diagnostic work-up of hematolymphoid malignancies, its role in identifying non-hematolymphoid neoplasms is controversial. While a diagnosis of “non-hematolymphoid process” may be suggested by flow cytometry, typically, CD45-negative entities are not further characterized by their immunophenotypic profile. Some markers, such as CD56, have been well documented in non-hematolymphoid malignancies, such as high-grade neuroendocrine carcinomas (Stacchini, et al, 2018; Bryson et al, 2002). Other cell surface markers that are routinely studied with flow cytometry panels, such as CD200, are less well-described in the literature with regards to their presence/absence in non-hematolymphoid processes. We examined all flow cytometry cases from our institution over a 5-year period to identify trends in the immunophenotypes of non-hematolymphoid malignancies that were known to be CD45-negative and CD56-positive by flow cytometry. Methods We examined 3634 flow cytometry cases (2015-2020) and identified non-hematolymphoid cases based upon lack of CD45 expression. After excluding multiple myeloma cases from the CD45-negative entities, we were left with 19 CD45-negative cases. Chart review of these cases confirmed them as non-hematolymphoid by concurrent surgical pathology/cytopathology studies. Of these 19 cases, 2 were excluded because CD56 was not evaluated. Results Of the 17 CD45-negative/CD56-positive cases, 16 showed CD200 positivity (94%). Of these CD200-positive cases, 10 were ultimately diagnosed as small cell carcinoma (59%), 1 was diagnosed as Merkel cell carcinoma (6%), 1 was diagnosed as melanoma (6%), 1 was diagnosed as poorly-differentiated carcinoma (6%), 1 was diagnosed as Ewing-like sarcoma (6%), and 2 were unclassified further (12%). The single CD200-negative case was diagnosed as poorly-differentiated acinar cell carcinoma (6%). All cases of small cell carcinoma that were evaluated by flow cytometry showed expression of CD200 and CD56. Conclusions Our findings suggest that in CD45-negative/CD56-positive non-hematolymphoid malignancies, particularly small cell carcinoma, CD200 is frequently positive. CD200 was also found to be positive in rare cases of other non-hematolymphoid malignancies within the differential diagnosis of small round blue cell tumors. These findings indicate that CD200 may be a useful marker in suggesting the possibility of small cell carcinoma in non-hematolymphoid specimens that are evaluated by flow cytometry.

A Rare Case of Rectal Mixed Adeno-Neuroendocrine Carcinoma (MANEC) with Liver Metastasis

Abstract Introduction/Objective Mixed Adeno-Neuroendocrine Carcinoma (MANEC) is a rare subtype of colorectal cancer which was recognized and described by the world health organization (WHO) in 2010. It was defined as malignant neoplasms in which each component represents at least 30% of the lesion. In this abstract, we present a case of mixed adeno-neuroendocine carcinoma of the rectum with metastasis of the neuroendocrine component to the liver. We discuss the histomorphological and immunohistochemical features of this tumor. Methods/Case Report A 64-year-old male presented with abdominal pain in the right upper quadrant area. An abdominal CT scan showed multiple nodules in the liver as well as a mass lesion in the rectum. Liver needle core biopsy revealed infiltrating nests of atypical cells with marked pleomorphism, a variable amount of cytoplasm, and prominent nucleoli. Mitotic activity and necrosis were seen. By immunohistochemical staining, the tumor cells were negative for CK7 and CK20, positive for CD56, and partially positive for CDX2. Although glands formation was not seen; however, given the positivity of CDX2 as well as the colonic mass, mismatch protein analysis (MMR) was performed and it was intact. These findings were consistent with poorly differentiated high-grade neuroendocrine carcinoma. The rectal mass was excised through colonoscopy and revealed invasive carcinoma with morphology similar to that of the liver biopsy in addition to a vague glandular differentiation. Tubulovillous adenoma was also seen. On immunohistochemical staining, the invasive component was positive for CD56, synaptophysin, and chromogranin A, partially positive for CDX2, and negative for CK20, consistent with the neuroendocrine component. The adenoma was positive for CK20, and CDX2, and negative for CD56. Rare positivity was seen by synaptophysin and chromogranin A. The carcinoma and the adenoma were both positive for P53. The neuroendocrine carcinoma comprised 40-50% of the tumor. Results (if a Case Study enter NA) NA Conclusion Only a few cases of Mixed Adeno-Neuroendocrine Carcinoma (MANEC) were reported. We add a new case with liver metastasis. The systematic application of immunohistochemical studies aided in the recognition of each component of the neoplasm.

Complete response of a colonic high-grade neuroendocrine carcinoma to platinum-based therapy: Insights from comprehensive genomic profiling

Abstract Introduction/Objective Comprehensive genomic profiling (CGP) is an essential tool in precision medicine, providing diagnostic, prognostic, and predictive (therapeutic) information to enable personalized and optimized care for cancer patients. We present the case of a patient with a metastatic high-grade tumor of the colon who showed an impressive response to systemic therapy and discuss the role of CGP in cancer management. Methods/Case Report A 54-year-old woman with was diagnosed with stage IV large-cell neuroendocrine carcinoma (LCNEC) of the colon with large volume liver and nodal metastases with imminent hepatic failure. CGP was performed on the resected tumor (TSO500 panel, 523 cancer-related genes, Illumina), showing pathogenic mutations in multiple oncogenes and tumor suppressor genes, including BRCA1, BAP1, and BRAF. Additionally, global parameters revealed a very high tumor mutation burden (TMB, 351 / Mb), and high-degree microsatellite instability (MSI-H). Treatment of the patient’s metastases with platinum-based systemic therapy resulted in a complete radiographic response, with no evidence of disease recurrence after 6.5 years. This type of complete response to therapy is rarely reported in colonic LCNEC. Assessment by Medical Genetics did not identify a germline mutation suggestive of hereditary breast/ovarian cancer or Lynch syndrome. Results (if a Case Study enter NA) NA Conclusion The patient’s extraordinary response to therapy is likely due to loss of BRCA1 and/or BAP1 function, as deleterious mutations in both genes predict sensitivity to platinum-based therapy through exploitation of deficient homologous recombination repair (HRR). The high TMB and MSI-H status suggest the immune system may have contributed to tumor clearance through neoantigen activation of T-cells. The information provided by CGP also suggested potential tumor sensitivity to poly(ADP-Ribose) polymerase inhibitors (PARPi), immunotherapy (IT), and BRAF/MEK inhibitor therapy, should the tumor recur. This case highlights the value of CGP in guiding management of rare and aggressive tumors.

P63.14 Three Weekly Irinotecan for Refractory/Relapsed Small Cell Lung Cancer

Studies that evaluated Irinotecan for solid malignancies includes both weekly and three weekly regimens. However, NCCN guidelines support weekly irinotecan regimen for refractory/relapsed SCLC (small cell lung cancer). Current guidelines do not acknowledge three weekly regimen for SCLC due to insufficient data. We aimed to study clinical efficacy, side effect profile, and cost analysis of three weekly irinotecan regimens for refractory/relapsed SCLC. Retrospective analysis of relapsed/refractory SCLC or high-grade neuroendocrine carcinoma (HGNEC) patients treated with every 3 weekly irinotecan (300 mg/m2) regimen between 2010 and 2020 at an National Cancer Institute designated cancer care center was performed. Median progression free survival(PFS) and adverse events per CTCAE 5.0 were determined. A total of thirty-nine patients were included in our analysis, 33 with SCLC and 6 with HGNEC. Primary site for patients with HGNEC includes bladder (n=1), prostate(n=1), gastroesophageal junction(n=1) and unknown primary (n=3). The median age at diagnosis was 63 years (IQR = 14 years). The median prior line of therapies was 2 (IQR=0.5), and median number of irinotecan cycles was 2 (IQR=2). None of our study patients had a complete response to therapy. Stable disease was noted among 38.5% patients and the rest experienced disease progression. Median progression-free survival was 2.1 months (95% CI-1.6 to 8.1). Overall grade (G) 2 adverse events were noted among 20.5%, G3 in 35.9%, and G4 among 7.7% of study patients. Following G1, G2, G3 and G4 adverse events were noted. Nausea: 15.4%, 5.1%, 12.8% and 0% ; vomiting: 7.7% , 5.1%, 10.3% and 0%; diarrhea: 10.3%, 5.1%, 23.1% and 0%; neutropenia: 0%,0%,2.6% and 5.1%; transaminitis: 7.7%, 0%, 7.7% and 0% respectively. Ileus was noted among 5.3%; enterocolitis among 2.6%. None of study patients experienced mucositis, pneumonitis, skin rash and liver failure. Estimated overall costs per cycle to deliver three 100mg/m2 doses with every weekly regimen was $661 compared to only $268 for a single 300mg/m2 dose with every three-weekly regimen. In patients with progressive refractory / relapsed SCLC, every three weekly irinotecan regimen was found to have comparable efficacy and adverse event profile. Moreover, cost-effectiveness and reduced number of infusions with of every 3 weekly regimen might potentially benefit patients who live far from health care facility as is the case in rural Appalachia and also help reduce financial toxicity.

P66.08 Differential Expression of INSM1 Between Pure SCLC and LCNEC After Surgical Resection and Its Clinicopathological Significance

According to WHO diagnostic criteria, both Small cell lung cancer (SCLC) and Large cell neuroendocrine (LCNEC) are categorized into high grade neuroendocrine carcinoma, based on morphological features and immunostaining of neuroendocrine markers including CD56, chromogranin A (CgA) and synaptophysin (Syn). However, the above markers have limited satisfactory significance of specificity and sensitivity. Insulinoma-associated protein 1 (INSM1) is highly expressed in SCLC cells as a zinc finger protein, and numerous studies have shown that INSM1 positive staining has a strong correlation with NE differentiation in SCLC and an alternative diagnostic biomarker for SCLC, but few studies are involved in LCNEC and its significance remains unclear in LCNEC. The aim of this study was to investigate the potential of INSM1 as a neuroendocrine marker by comparing the expression of INSM1 in SCLC and LCNEC and its clinicopathological significance. 347 surgically resected lung cancer including 290 pure SCLC and 57 pure LCNEC samples were retrieved in this retrospective study. INSM1 expression was detected by immunohistochemistry staining in SCLC and LCNEC tissue microarrays. The different expression of INSM1 between SCLC and LCNEC as well as the correlation with clinicopathological features including gender, age, smoking history, tumor location, AJCC 7th stage, reginal lymph node metastasis, pleural invasion and tumor thrombosis were analyzed by chi-square test. Of the included patients, male/female ratio was 2.33 (203/87) in SCLC and 10.4 (52/5) in LCNEC, the smoker rate was 64.5% (187/290) in SCLC and 43.9% (25/57) in NSCLC. According to the AJCC Cancer Staging Manual (7th edition), the SCLC patients were 29.0% (84/290) in stage I, 27.2% (79/290) in stage II, 40.7% (118/290) in stage III, and 3.1% (9/290) in stage IV, while the NSCLC patients were 49.1% (28/57) in stage I, 26.3% (15/57) in stage II, and 24.6% (14/57) in stage III, respectively. INSM1 was localized in the nucleus of lung cancer cells, a significant higher positive rate was detected in SCLC than that in LCNEC (271/290,93.4% in SCLC; 32/57,56.1% in LCNEC; p<0.05). INSM1 protein expression significantly correlated with smoking history (p=0.023), pleural invasion (p=0.010), and a positive trend of regional lymph node metastasis (p=0.052) in SCLC, but did not correlate with any of the clinicopathological features in LCNEC (p＞0.05). INSM1 protein was found no prognostic significance neither in SCLC nor in LCNEC (p＞0.05). INSM1 protein is highly expressed in SCLC and positively correlated with pleural invasion and smoking history. In contrast, INSM1 expression in LCNEC is significant lower and does not correlated with such clinicopathological features. Further research needs to be done on exploring the potential different underlying mechanisms and diagnostic significance of INSM1 in SCLC and LCNEC.