Small Cell Lung Carcinoma Patients Research Articles

Abstract 7558: Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification

Abstract BACKGROUND: Accurate molecular characterization of lung cancer including histology classification and therapeutic target profiling is critical for treatment planning and resistance monitoring. For example, detecting lineage transformation from lung adenocarcinoma (LUAD) to small cell lung carcinoma (SCLC) following treatment, an established resistance mechanism, is challenging due to deteriorating patient health and complicated invasive procedures. Here, we describe an accurate lung cancer histological classification using an innovative, multimodal epigenomic liquid biopsy method that comprehensively profiles tumor-specific transcription activation from 1 mL of patient plasma. METHODS: 37 LUAD, 34 SCLC patient plasma samples collected from commercial biobanks, and reference cell lines were profiled for enhancer, promoter and DNA methylation activity to identify epigenomic loci characteristic of LUAD and SCLC. The resulting map of select quantified loci was used as input to a machine learning algorithm that distinguishes SCLC from LUAD, in a cross validated training and testing approach. RESULTS: The epigenomic maps derived from lung cancer patient plasma were highly informative of the regulatory programming of the tumor cells. The enhancers and promoters most strongly linked to lung cancer profiles across the patient population include key, histology-specific driver genes such as NKX2-1, FOXA1, FOXA2, ONECUT2, DLL3, and ASCL1. The resulting classifier was able to accurately predict histology with a cross validated AUC greater than 0.94. In silico simulation results suggest that accurate classification can be achieved with ctDNA content below 1%. Further correlative examination of the SCLC enhancer landscape revealed a partitioning of SCLC patients into molecular subtypes characterized by active enhancer marks at subtype-specific transcripts, including ASCL1, POU2F3, NEUROD1, and YAP1. The transcriptional regulation of ADC targets is apparent through comprehensive epigenomic profiling of plasma in both SCLC and LUAD, with the expression of Claudin 18.2, SEZ6, and others showing a strong dynamic range independent of ctDNA levels. This represents a novel liquid biopsy approach to distinguish LUAD from SCLC and provide simultaneous insight into expression of key targets at clinically relevant ctDNA levels. CONCLUSION: These data demonstrate the feasibility of epigenomic mapping from 1mL of plasma in lung cancer patients to distinguish lung cancer histology. The resulting data is biologically interpretable through the lens of transcriptional activation of key histology specific genes. This liquid-biopsy based approach may provide a non-invasive alternative to invasive and challenging tissue biopsies for biomarker investigation and therapeutic decision making. Citation Format: Jamey Guess, Aparna Gorthi, Anthony D'ippolity, Jonathan Beagan, Travis Clark, Michael Coyne, Tyrone Tamakloe, Baovy Tran, Hyun-Hwan Jeong, Kristian Cibulskis, Hathairat Sawaengsri, Juliann Chmielecki, Corrie A. Painter, J Carl Barrett, Matthew Eaton. Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7558.

Abstract A124: Beyond PD-L1: Unraveling the enigma of immunotherapy response in PD-L1 negative (<1%) NSCLC patients through quantification of PD-1/PD-L1 engagement in the tumor microenvironment

Abstract Profound advances in cancer patient treatments have come with the advent of immunotherapies directed at blocking immune-suppressive ligand-receptor interactions. However, while there has been success in the use of these immune checkpoint interventions, there has been limited success in stratifying patients for these interventions with response rates at approximately 14%.To address this issue of patient stratification, we have determined the extent of the molecular target, intercellular PD-1/PD-L1 interaction, in formalin-fixed paraffin embedded tumor samples from non–small cell lung carcinoma patients, using a high-throughput automated quantitative imaging platform (QF-Pro®). The multi-site blinded analysis across a cohort of 188 IO-treated patients (treated with nivolumab, pembrolizumab, atezolizumab or durvalumab) demonstrated the intra- and inter-tumoral heterogeneity of the PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression (rs=0.05, P=0.55). Importantly, PD-L1 expression scores used clinically to stratify the patients, correlated poorly with overall survival. By contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased OS (median 31 months vs 10 months). This relationship was particularly strong in the setting of first line treatments. Even more critically, in a subset of patients determined as being PD-L1 negative (PD-L1 TPS <1%), response to treatment was still observed in those patients with PD-1/PD-L1 interactions (median >60 months vs 14 months). This therefore may yield a mechanism to successfully treat those patients who, under current guidelines, are not be considered for these therapies, despite the therapeutic target existing within their tumor microenvironment. In conclusion using the functional read out of this immune checkpoint engagement (PD-1/PD-L1 interaction) as a predictive biomarker for the stratification of NSCLC patients instead of PD-L1 expression should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients), and additionally avoid the treatment of patients resistant to this type of treatment (low PD-1/PDL1 interaction but high PD-L1 expression) who may benefit- from alternative cancer therapeutics, such as other immunotherapies. Even at this early stage, QF-Pro® has set an unbiased quantitative cut-off to be considered for anti-PD-1/PD-L1 therapies which can be deployed directly into clinical practice. Citation Format: Juan Gumuzio, Veronique Calleja, James Miles, Lissete Sancehz-Magraner, Fernando Aguirre. Beyond PD-L1: Unraveling the enigma of immunotherapy response in PD-L1 negative (<1%) NSCLC patients through quantification of PD-1/PD-L1 engagement in the tumor microenvironment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A124.

Molecular subtypes, predictive markers and prognosis in small-cell lung carcinoma

AimsA new molecular subtype classification was proposed for small-cell lung carcinoma (SCLC). We aimed to further validate the classification in various SCLC patient samples using immunohistochemistry (IHC) to highlight its...

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case–control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on ‘TERT rs2736100 polymorphism and LC susceptibility’ in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.

Junctional adhesion molecule 3 is a potential therapeutic target for small cell lung carcinoma

There are few effective therapies for small cell lung carcinoma (SCLC); thus, we need to develop novel and efficacious treatments. We hypothesized that an antibody–drug conjugate (ADC) could be a promising option for SCLC. Several publicly available databases were used to demonstrate the extent to which junctional adhesion molecule 3 (JAM3) mRNA was expressed in SCLC and lung adenocarcinoma cell lines and tissues. Three SCLC cell lines, Lu-135, SBC-5, and Lu-134 A, were selected and examined for JAM3 protein expression by flow cytometry. Finally, we examined the response of the three SCLC cell lines to a conjugate between an anti-JAM3 monoclonal antibody HSL156 (developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. In silico analyses revealed that JAM3 mRNA was expressed higher in SCLC cell lines and tissues than in those of lung adenocarcinoma. As expected, all the three SCLC cell lines examined were positive for JAM3 at the mRNA and protein levels. Consequently, control SCLC cells, but not JAM3-silenced ones, were highly sensitive to HSL156-DT3C conjugates, resulting in dose- and time-dependent decreased viability. Finally, silencing JAM3 alone suppressed the growth of all SCLC cell lines examined. Taken together, these findings suggest that an ADC targeting JAM3 could represent a new approach to treating SCLC patients.

Mapping the immune landscape in small cell lung cancer by analysing expression of immuno-modulators in tissue biopsies and paired blood samples

Small cell lung carcinomas (SCLC) are aggressive tumors with high propensity to metastasize. Recent NCCN guidelines have incorporated immunotherapy in extensive stage SCLC. Limited benefit in few patients compounded by side effects of unwonted immune-checkpoint-inhibitor (ICPI) usage necessitates identification of potential biomarkers predicting response to ICPIs. Attempting this, we analysed expression of various immunoregulatory molecules in tissue biopsies and paired blood samples of SCLC patients. In 40 cases, immunohistochemistry for expression of immune inhibitory receptors CTLA-4, PD-L1 and IDO1 was performed. Matched blood samples were quantified for IFN-γ, IL-2, TNF-α and sCTLA-4 levels using immunoassay and additionally for IDO1 activity (Kynurenine/Tryptophan ratio) using LC–MS. Immunopositivity for PD-L1, IDO1 and CTLA-4 was identified in 9.3%, 6.2% and 71.8% cases, respectively. Concentration of serum IFN-γ (p-value < 0.001), TNF-α (p-value = 0.025) and s-CTLA4 (p-value = 0.08) were higher in SCLC patients while IL-2 was lower (p-value = 0.003) as compared to healthy controls. IDO1 activity was significantly elevated in SCLC cohort (p-value = 0.007). We proffer that SCLC patients show immune suppressive milieu in their peripheral circulation. Analysis of CTLA4 immunohistochemical expression along with s-CTLA4 levels appears prospective as biomarkers for predicting responsiveness to ICPIs. Additionally, evaluation of IDO1 appears cogent both as prognostic marker and potential therapeutic target as well.

Clinicopathological and Treatment Patterns of Combined Small-Cell Lung Carcinoma with Future Insight to Treatment: A Population-Based Study.

Primary lung cancer is the most common cause of cancer-related mortality in the United States (US). Approximately 90% of lung cancers are associated with smoking and the use of other tobacco products. Based on histology, lung cancers are divided into small-cell lung carcinomas (SCLCs) and non-small-cell lung carcinomas (NSCLCs). Most SCLCs are of the pure subtype, while the rare combined SCLCs contain elements of both small-cell and non-small-cell morphologies. This study sought to evaluate the demographics, clinical factors, molecular abnormalities, treatment approaches, and survival outcomes with combined SCLC and NSCLCs. Data on 2126 combined SCLC patients was extracted from the Surveillance Epidemiology and End Result (SEER) database from 2000 to 2018. Data extracted for analyses included age, sex, race, tumor size, tumor location, metastasis status, stage at diagnosis, treatment received, and treatment outcomes. Multivariate analysis was performed using Statistical Product and Service Solutions (SPSS) software. The patients had a median age of 68 years; 43.9% of the patients were female and 56.1% were male; 84.5% were White and 11.7% were African Americans. The majority of patients had a poorly differentiated disease at 29.6%; 17% were undifferentiated, 3.2% were moderately differentiated, and 0.8% were well differentiated. Chemotherapy was the most common treatment modality (45.3%); 17% underwent surgery only, 10.3% underwent surgery followed by adjuvant chemotherapy, and 10% underwent radiation after surgery. Five-year cancer-specific survival was 15.2% with surgery alone, and combined surgery and chemotherapy provided the highest percentages (38.3% and 34.7%, respectively). Females had significantly higher 1- and 5-year cancer-specific survival rates compared to males (59.3% and 29.9% vs. 48.0% and 23.7, respectively; p < 0.001). Well-differentiated tumors had significantly higher survival compared to other gradings (p < 0.001). Survival decreased as tumor staging moved distally from localized to regional to distant (p < 0.001). Metastasis to bone, liver, brain, and lung significantly decreased survival in comparison to patients who did not have any metastasis (p < 0.001). Females had significantly shorter survival compared to their counterparts when metastasis was to the bone, brain, or liver (p < 0.001). Multivariate analysis identified male sex (Hazard Ratio (HR) = 1.2), undifferentiated grade (HR = 1.9), regional extent of disease (HR = 1.7), distant extent of disease (HR = 3.7), and metastasis to liver (HR = 3.5) as variables associated with worse survival. Combined SCLC is overall very rare. However, the frequency of presentation with combined SCLC is on the rise, in part due to improvements in diagnostic techniques. Despite advances in therapies, treating combined SCLC is challenging, and novel therapies are not utilized, owing to low rates of targetable mutations. Combined SCLC has higher survival rates if well differentiated.

Single-nucleotide polymorphisms of nucleotide excision repair genes and their association with overall survival in North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

The aim of the study is to understand the association of Nucleotide excision repair (NER) inter-genetic polymorphic combinations with overall survival (OS) in lung cancer as well as its histological subtypes in the North Indian population. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. For survival analysis, the univariate Kaplan-Meier and multivariate Cox regression model were applied. Recursive partitioning method, survival analysis tree was applied to study unfavorable genotypic combinations in NER single-nucleotide polymorphisms. Combinatorial studies suggested no association between polymorphic combinations of NER genes and OS in lung cancer patients. When stratified as per lung cancer histological subtypes, adenocarcinomas patients with XPG 670 and XPC 499 polymorphism a significant increase in OS in combined heterozygous and mutant genotype with a lower hazardous ratio (Hazard Ratio1 (HR) = 0.20; P = 0.004). Small-cell lung carcinoma (SCLC) patients with XPF 11985A>G and XPD Arg156Arg polymorphism showed a 4-fold hazard ratio among heterozygous genotype (HR1 = 4.84; P = 0.007) where no significant results are obtained in patients suffering from squamous cell carcinoma histological subtypes. STREE showed XPG Asp1104His (W), XPD Lys751Gln (H + M), XPF Arg415Gln (H + M) genotype was associated with a lower hazard ratio (P = 0.0007) showing survival of 11.6 months when compared with the reference (median survival time = 3.52). It can be concluded that SCLC patients with polymorphic combinations of the NER pathway were associated with a higher risk of mortality. STREE depicted the association of NER polymorphic combinations with a lower hazard ratio predicting them to be a good prognostic factor for lung cancer.

The postoperative prognosis of skip-N2 metastasis is favorable in small-cell lung carcinoma patients with pathological N2 classification: a propensity-score-adjusted retrospective multicenter study.

The study on skip-N2 metastasis in small-cell lung cancer (SCLC) is lacking. Therefore, this study aimed to explore the prognostic significance of skip-N2 metastasis based on a multicenter cohort. We collected 176 SCLC patients with pathological categories T1-4N1-2M0 from four hospitals in China. Survival curves were drawn through the Kaplan-Meier method and compared by the log-rank test. The Cox regression method was used to calculate the hazard ratio (HR) and 95% confidence interval of the characteristics for cancer-specific survival (CSS). Two propensity-score methods were used to reduce the bias, including the inverse probability of treatment weighting (IPTW) and propensity-score matching (PSM). This multicenter database included 64 pN1 patients, 63 non-skip-N2 cases, and 49 skip-N2 cases. Skip-N2 and the non-skip-N2 patients had gap CSS rates (skip-N2 no versus yes: 41.0% versus 62.0% for 1-year CSS, 32.0% versus 46.0% for 2-year CSS, and 20.0% versus 32.0% for 3-year CSS). After PSM, there were 32 pairs of patients to compare survival differences between N2 and skip-N2 diseases, and 34 pairs of patients to compare prognostic gaps between N1 and skip-N2 diseases, respectively. The results of IPTW and PSM both suggested that skip-N2 cases had better survival outcomes than the non-skip-N2 cases (IPTW-adjusted HR = 0.578; PSM-adjusted HR = 0.510; all log-rank p < 0.05). Besides, the above two analytic methods showed no difference in prognoses between pN1 and skip-N2 diseases (all log-rank p > 0.05). Skip-N2 patients were confirmed to have a better prognosis than non-skip-N2 patients. Besides, there was no survival difference between pN1 and skip-N2 cases. Therefore, we propose that the next tumor-node-metastasis staging system needs to consider the situation of skip metastasis with lymph nodes in SCLC.

Proteomics analysis of meclofenamic acid-treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival.

Small cell lung carcinoma (SCLC) is a highly aggressive cancer with low survival rate. Although initial response to chemotherapy in SCLC patients is well-rated, the treatments applied after the disease relapses are not successful. Drug resistance is accepted to be one of the main reasons for this failure. Therefore, there is an urgent need for new treatment strategies for SCLC. Meclofenamic acid, a nonsteroidal anti-inflammatory drug, has been shown to have anticancer effects on various types of cancers via different mechanisms. The aim of this study was to investigate the alterations that meclofenamic acid caused on a SCLC cell line, DMS114 using the tools of proteomics namely two-dimensional gel electrophoresis coupled to MALDI-TOF/TOF and nHPLC coupled to LC-MS/MS. Among the proteins identified by both methods, those showing significantly altered expression levels were evaluated using bioinformatics databases, PANTHER and STRING. The key altered metabolism upon meclofenamic acid treatment appeared to the cellular energy metabolism. Glycolysis was suppressed, whereas mitochondrial activity and oxidative phosphorylation were boosted. The cells underwent metabolic reprogramming to adapt into their new environment for survival. Metabolic reprogramming is known to cause drug resistance in several cancer types including SCLC. The identified differentially regulated proteins in here associated with energy metabolism hold value as the potential targets to overcome drug resistance in SCLC treatment.

Thoracic radiotherapy may improve the outcome of extensive stage small cell lung carcinoma patients treated with first-line immunotherapy plus chemotherapy.

Immunotherapy plus etoposide and platinum (EP)-based chemotherapy is the standard of care for patients with extensive stage-small cell lung carcinoma (ES-SCLC). In the era of immunotherapy, the role of thoracic radiotherapy for ES-SCLC remains unclear. We retrospectively included ES-SCLC patients treated with first-line EP-based chemotherapy plus atezolizumab or durvalumab at Taichung Veterans General Hospital to evaluate the prognostic role and safety of thoracic radiotherapy. A total of 22 patients were included. The median age was 64 years and most of them were male and smokers. Sixteen patients (72.7%) received durvalumab, while the other 6 patients (27.3%) underwent atezolizumab treatment. Among these patients, 11 (50.0%) had a history of thoracic radiotherapy. There was no significant difference in baseline characteristics between patients with and without thoracic radiotherapy. In the overall population, the objective response rate to immunotherapy plus chemotherapy was 73.7%. The progression-free survival and overall survival were 6.0 months (95% CI: 4.0-7.9) and 13.8 months (95% CI: 8.0-19.6), respectively. The overall survival was significantly longer in patients with thoracic radiotherapy (not-reached [NR] [95% CI NR-NR] vs. 9.6 months [95% CI 2.5-16.6]), respectively ( P value by log-rank test <0.001). Both multivariate analysis and subgroup analysis specifically comparing patients with consolidative thoracic radiotherapy and patients with clinical benefits to systemic therapy who did not undergo thoracic radiotherapy indicated that thoracic radiotherapy improved survival. The real-world efficacy of EP-based chemotherapy plus atezolizumab or durvalumab was comparable with that of clinical trials. Thoracic radiotherapy may improve the outcome of ES-SCLC.

P2.10-04 Immunologic Subtype of Small Cell Lung Carcinoma Dictates Susceptibility to NK Cell-Mediated Cytotoxicity

Small cell lung carcinoma (SCLC) comprises approximately 15% of all lung cancer cases and SCLC patients initially respond to cytotoxic chemotherapy, but resistance inevitably emerges. Despite recent incorporation of immune checkpoint blockade (ICB) into first line treatment, predictive biomarkers of response remain lacking and patients with SCLC continue to have a poor prognosis with limited treatment options. Notably, recent transcriptomic profiling of SCLC cell lines and patient samples has indicated significant inter-tumoral and intra-tumoral heterogeneity.

What is the effect of tumor diameter, lymph node metastases, and SUVmax value on prognosis in limited-stage small cell lung cancer?

SUMMARYOBJECTIVE:This study was designed to investigate the link between survival and prognostic factors such as tumor size, lymph node metastasis, and metabolic activity detected on positron emission tomography/computed tomography in patients with limited-stage small cell lung carcinoma.METHODS:Patients who were admitted to our hospital with pathological diagnosis of limited-stage small cell lung cancer between January 2015 and December 2019 and were older than 18 years were retrospectively screened.RESULTS:A total of 77 patients, including 10 females and 67 males, were included in the study. While there were 39 patients over 60 years of age, 38 patients were under 60.The ratios of male patients, N stage, multiple lymph nodes, distant metastasis, brain metastasis, and prophylactic cranial irradiation in the deceased patients’ group were significantly (p=0.008, p=0.000, p=0.000, p=0.000, p=0.013, p=0.000, respectively) higher than those in the living patients’ group.In the univariate model, we observed that gender, smoking, T stage, N stage, multiple lymph nodes, distant metastasis, brain metastasis, liver metastasis, sequential chemotherapy, sequential radiotherapy, concurrent chemoradiotherapy, and prophylactic cranial irradiation had significant effect (p=0.049, p=0.021, p=0.022, p=0.000, p=0.000, p=0.000 p=0.003, p=0.037, p=0.029, p=0.049, p=0.000, respectively) on survival time. In the multivariate model, smoking, N stage, liver metastasis, and prophylactic cranial irradiation demonstrated significant independent effect (p=0.010, p=0.003, p=0.004, p=0.000, respectively) on survival time.CONCLUSION:Our findings provide useful information for better patient management, especially in terms of negative factors on the continuation of survival during and after the treatment of limited-stage small cell lung carcinoma patients.

EP05.01-030 CRISP: First Real-World Evidence of NSCLC Stage I, II and III in Germany - AIO-TRK-0315

CRISP (Clinical Research platform Into molecular testing, treatment and outcome of (non-)Small cell lung carcinoma Patients) is a non-interventional, prospective, multi-center clinical research platform whose aim is to understand current treatment reality of patients with lung cancer in Germany. Here we present data of patients diagnosed with early-stage NSCLC (IIIB/C only if treated with curative intent), including first outcome data in routine-care.

1542P First real-world outcome data of SCLC in Germany: Data from the Clinical Research platform Into molecular testing, treatment and outcome of (non-)Small cell lung carcinoma Patients (CRISP; AIO-TRK-0315)

Treatment options for patients with small cell lung cancer (SCLC) have substantially improved with the approval of the first two checkpoint inhibitors (CPI), atezolizumab (2019) and durvalumab (2020), for stage IV SCLC. How are patients with SCLC treated outside of clinical trials and how do these new treatments change the outcome in routine care in Germany?

A novel therapy to combat non-small cell lung carcinoma (A549) using platinum (IV) and barium titanate conjugate

Lung cancer is the most commonly diagnosed and leading cause of carcinoma related death in the world. Platinum based chemotherapy through cisplatin is one of the most common drug of choice to the control of disease progression and survival of the non small cell lung carcinoma patients. But cases of drug resistance and harmful side effects of cisplatin treatment motivated us to develop a platinum-based nanoformulation with improved bio-distribution and minimum toxicity. A cisplatin prodrug [Pt(IV) prodrug] was conjugated to functionalized hydrothermally synthesized barium titanate nanoparticles (BTNPs) through coupling reaction to form a novel barium titanate and platinum(IV) prodrug conjugate i.e., BT-Pt(IV) conjugate. In the present study, BTNPs, Pt(IV) prodrug, and BT-Pt(IV)conjugate were characterized by elemental analysis. In vitro assay of cellular uptake and cytotoxicity against non-small cell lung carcinoma (A549) cell line and noncancerous HEK293 cells were evaluated. BT-Pt(IV) conjugate demonstrated greater and sustained antiproliferative activity in a dose and time-dependent manner compared to cisplatin in A549 cells. The IC50 value of BT-Pt (IV) conjugate was estimated to be 5.42 μg/mL which was significantly less (almost 50%) than cisplatin (12.04 μg/mL). The in vitro mechanistic studies revealed that the BT-Pt(IV) conjugate increased the intracellular basal reactive oxygen species levels, which have led to the death of non-small cell lung carcinoma. However, HEK293 cells could escape the anti-proliferative capacity of the new drug conjugate. BaTiO3 has been chosen for its effectiveness as a biocompatible uptake enhancer of drugs. The current study has explored the therapeutic efficacy of a novel nanoformulation based on a clinically approved platinum-based anti-cancer agent with less toxicity and more bioavailability.

Expression of MAGE-A3 in and histopathological analysis of forceps biopsy specimens of non– small-cell lung carcinoma patients

Abstract Non–small-cell lung cancer (NSCLC) is a type of epithelial lung cancer and associated with cigarette smoking (passive or active). Melanoma-associated antigen 3 (MAGE-A3) is widely expressed in various types of tumours, including NSCLC. This study aimed to examine the MAGE-A3 expression in forceps biopsy specimens as a tumour biomarker to be used for early diagnosis and screening of lung cancer. This study was an observational, analytical study with a cross-sectional study design. The sample size was determined based on Ronald Fisher’s classic z transformation formula, and samples were selected using consecutive sampling. The study population included 14 lung tumour patients. Samples were obtained by forceps biopsy with bronchoscopy guidance. Histopathological analysis was carried out using Giemsa staining. The expression of MAGE-A3 was determined using RT-PCR. All data were analysed using SPSS statistics software (IBM SPSS Statistics, IBM® SPSS® Statistics is a powerful statistical software platform RRID: SCR_019096). In this study, there were 6 subjects (42.9%) with NSCLC adenocarcinoma and 8 subjects (57.1%) with squamous cell carcinoma. The positive MAGE-A3 expression was found in 5 (35.7%) of the total research subjects, and the expression on RT-PCR analysis was at 569 bp. We found that MAGE 3 gene was mostly expressed in adenocarcinoma of NSCLC, even though there was no statistical correlation with histopathological results (P &gt; 0.05). MAGE-A3 expression in forceps biopsy specimens of NSCLC was mostly found in the adenocarcinoma type at 569 bp. Therefore, it could be used as a tumour biomarker for early diagnosis and screening of lung cancer.

Long-term survival in small-cell lung cancer patients: Extension of the SMALLBRAIN study.

e20605 Background: Long-term survivors of metastatic Small Cell Lung Carcinoma (SCLC) with overall survival (OS) greater than 12 months are not frequent and have not been deeply studied. Therefore, we conducted the descriptive study SMALLBRAIN to characterize these patients with central nervous system metastases (mCNS), since at least a 20% of SCLC patients has mCNS at the diagnosis. The survival results were reported at the NCCN 2022 Annual Conference, showing no statistically significant survival difference between presenting mCNS at diagnosis or later and no correlation between the mCNS volume and OS. After these results, we have extended our study to metastatic SCLC patients without mCNS to analyze possible differences. Methods: We carried out a systematic search for metastatic SCLC patients with OS &gt; 12 diagnosed and first treatment between January 2016 and April 2020 in our academic medical center in Spain, we excluded those with missing data. The included patients were classified in 3 cohorts: COHORT NA: Stage III at diagnosis with metastatic progression and no mCNS. COHORT NB: Stage IV patients without mCNS. COHORT Y: mCNS during the course of the disease, regardless of onset time. The number of treatment lines received and the survival were analyzed using Kaplan-Meier and multi-variable Cox proportional hazard analysis. Results: A total of 45 patients met study criteria (NA = 5, NB = 11 and Y = 29). The female - male ratio was of 1:3.14 for cohort Y and 1:2.2 for all the patients without mCNS (NA+NB), not statistically significant. The median OS was 24.9 months for cohort NA (range 16 – 64.83), 21.4 months for NB (range 12.30 – 31.83) and 18.6 months for Y (range 12.67 – 60.83), not statistically significant. Only three patients are currently alive, two from cohort NA and one from Y. The median of treatment lines was 3 for all the cohorts with a maximum of 8 for one patient in cohort Y. Best responses were two complete response with later progression in one patient from cohort NA and one from NB. Best response of cohort Y was a partial response. Conclusions: No statistically significant differences were found regarding survival or treatment lines between the population of long-term survivors of metastatic SCLC with and without mCNS. Their infrequency with few living individuals makes their characterization a challenge. These patients are also highly complex, more than 50% received at least 3 lines of treatment. Future research should explore the possibility of extracting long-term SCLC survivors from existing cancer registries of different countries. [Table: see text]

Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901).

BackgroundPulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers.MethodsWe investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis.ResultsBoth LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC.ConclusionWe performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.

Survival rate comparison of non small cell lung carcinoma patients who are given by epidermal growth factor receptor-tyrosin kinase inhibitor and those given by first-line chemotherapy treatment

Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Wahidin Sudirohusodo hospital. Methods. This study is a retrospective study between 2017 to 2019 from the medical records of NSCLC patients who receive first-line chemotherapy and thise who recieve EGFR-TKI. Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day and or afatinib 1x40 mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the  study is     discontinued. Result. From 239 subject of NSCLC patients consisted of 135 patients who receive first-line chemotherapy, and 104 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are more than 40 years old (chemotherapy 124 (91.9%) and EGFR-TKI 101 (97.1%) with the male gender that dominates (chemotherapy 98 (72.6%), EGFR-TKI 64 (61.5%). Smoking patients who received first-line chemotherapy are 65.2% and 61.5% of EGFR-TKIs with chemotherapy highest IB (severe IB 28.9%) and for EGFR-TKI (moderate IB are 26.9%). 73.2% of adenocarcinoma histology type with a predominance of stage IV 86.6% (83.7% for chemotherapy and EGFR-TKI 90.4%). Survival rate of patients are 98,7% for 6 months survival, 1 year survival rate is 94.1% and 2 years survival rate of 24.3%. Median survival patients who receiving EGFR-TKI longer than they received first- line chemotherapy (21 months versus 20 months). The 18 months PFS showed that patients treated with EGFR-TKI were 15 months, while patients receiving chemotherapy was 11 months. (P 0.000). Conclusion. Survival rates in NSCLC patients with EGFR-TKI therapy had significantly the highest survival rates compared with all other chemotherapy. Progression was faster in patients with first-line chemotherapy than EGFR-TKI. The factors that most influence the survival rate is type of therapy with p value&lt;0.05.