Combined Small Cell Lung Cancer Research Articles

Clinical features and prognostic factors of IV combined small cell lung cancer: A propensity score matching analysis.

Nowadays, the characteristics and treatment of combined small-cell lung carcinoma (CSCLC) remain controversial. This study aimed to analyze the features of clinical demographics, survival outcomes and treatment modalities among IV CSCLC, IV SCLC and IV NSCLC, to provide more evidence for the study of IV CSCLC. All CSCLC, SCLC and NSCLC patient data were obtained from the SEER database (2010-2020). Pearson's χ2 test was used to compare the differences in clinical characteristics. Propensity score matching (PSM) was utilized to balance the bias of the variables between patients. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. KM analysis was used to calculate survival. Adjusted analyses for the primary outcome of different treatment modalities of IV CSCLC, IV SCLC and IV NSCLC were performed using Cox regression models. A total of 493 patients with IV CSCLC, 35503 patients with SCLC, 122807 patients with IV NSCLC were included in this study. The demographic characteristics and tumor characteristics of the three groups were different. Before PSM, there were significant differences in OS and CSS among IV CSCLC, IV SCLC and IV NSCLC, After PSM, there was a significant difference in OS and CSS between the IV CSCLC and IV NSCLC. Risk/protective factors for OS and CSS were different in three groups. Chemotherapy, radiotherapy, and surgery can improve IV CSCLC's survival time. The combination of surgery and chemoradiotherapy treatment group for patients with IV CSCLC demonstrated best OS compared to control treatment groups, and the surgery combined chemotherapy treatment group exhibited the best CSS. Additionally, for select patients with stage IV CSCLC who have missed the window for surgical intervention at the time of initial diagnosis, chemoradiotherapy presents a viable and effective treatment option. The clinical characteristics IV CSCLC, IV SCLC and IV NSCLC were significantly different. The prognosis for IV CSCLC is notably poorer than IV NSCLC, similar to IV SCLC. Surgery combined therapy emerged as the preferred treatment modalities and chemoradiotherapy was a good choice for patients who have lost the indication of surgery for patients diagnosed with IV CSCLC.

Risk factors and nomograms for diagnosis and early death in patients with combined small cell lung cancer with distant metastasis: a population-based study.

Combined small cell lung cancer (CSCLC) with distant metastasis (DM) is an aggressive disease with a poor prognosis. Effective nomograms are needed to predict DM and early death in patients with CSCLC and DM. This retrospective study included patients with CSCLC from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Risk factors for DM and early death were analyzed by univariate and multivariate logistic regression. Nomograms were constructed based on the results in a training cohort and confirmed in a validation cohort, and their performances were assessed by concordance index (C-index), receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). A total of 788 patients with CSCLC were selected, including 364 patients with metastatic CSCLC. Sex, tumor site, T stage, and N stage were independent risk factors for DM, while age, surgery, chemotherapy, and liver metastasis were independent risk factors for early death. C-index, ROC, calibration, and DCA curve analyses all showed good predictive performances for both nomograms. These nomograms could reliably predict DM risk in CSCLC patients and early death in CSCLC patients with DM, and may thus help clinicians to assess these risks and implement individualized therapies.

Genomic and transcriptomic profiling of combined small-cell lung cancer through microdissection: unveiling the transformational pathway of mixed subtype.

Combined small-cell lung carcinoma (cSCLC) represents a rare subtype of SCLC, the mechanisms governing the evolution of cancer genomes and their impact on the tumor immune microenvironment (TIME) within distinct components of cSCLC remain elusive. Here, we conducted whole-exome and RNA sequencing on 32 samples from 16 cSCLC cases. We found striking similarities between two components of cSCLC-LCC/LCNEC (SCLC combined with large-cell carcinoma/neuroendocrine) in terms of tumor mutation burden (TMB), tumor neoantigen burden (TNB), clonality structure, chromosomal instability (CIN), and low levels of immune cell infiltration. In contrast, the two components of cSCLC-ADC/SCC (SCLC combined with adenocarcinoma/squamous-cell carcinoma) exhibited a high level of tumor heterogeneity. Our investigation revealed that cSCLC originated from a monoclonal source, with two potential transformation modes: from SCLC to SCC (mode 1) and from ADC to SCLC (mode 2). Therefore, cSCLC might represent an intermediate state, potentially evolving into another histological tumor morphology through interactions between tumor and TIME surrounding it. Intriguingly, RB1 inactivation emerged as a factor influencing TIME heterogeneity in cSCLC, possibly through neoantigen depletion. Together, these findings delved into the clonal origin and TIME heterogeneity of different components in cSCLC, shedding new light on the evolutionary processes underlying this enigmatic subtype.

Clonality Analysis for the Relationship between the Pulmonary Combined Neuroendocrine Carcinoma and “the So-Called Reported Histologic Transformation”

Histologic transformation (HT) is common following targeted therapy in adenocarcinoma. However, whether the transformed tumor is a new component or a combined neuroendocrine carcinoma (C-NEC) remains controversial. We aimed to explore the relationship between pulmonary C-NEC and HT. Macro-dissection was performed on different components of surgically resected C-NEC samples. Molecular alterations and clonal evolution were analyzed using whole exome sequencing (WES). The gene statuses for TP53 and RB1 were determined using immunohistochemistry (IHC) and WES to analyze the relationship between C-NEC and reported HT. Sixteen combined small-cell lung cancer patients and five combined large-cell neuroendocrine carcinoma patients were enrolled. The frequency of p53 and Rb inactivation, assessed using IHC in NEC and non-NEC components, was 76.2/76.2% and 66.7/61.9%, respectively. The expression consistency between the components was 81.0 and 85.7% for p53 and Rb, respectively. The frequencies of TP53, RB1, and EGFR mutations, assessed using WES in NEC and non-NEC components, were 81.0/81.0%, 28.6/28.6%, and 42.9/42.9%, respectively. The concordance rates for TP53, RB1, and EGFR were 90.5, 71.4, and 90.5%, respectively. The consistency rate between IHC and WES was 81.0 and 61.9% for TP53 and RB1, respectively. The different components had a common clonal origin for the 21 C-NECs in the clonal analysis, consistent with previous studies on HT. Our study shows that IHC is more sensitive for Rb detection and C-NEC, and the reported HT may be due to differences in evaluations between pathologist and clinicians. Assessing the p53/Rb and EGFR status for such cases would help in recognizing potential transformation cases or uncovering potential combined components.

Exploring the molecular features and genetic prognostic factors of pulmonary high-grade neuroendocrine carcinomas

Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p=0.458) and progression-free survival (PFS; p=0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p=0.029) and PFS (p=0.015), while wild-type SPTA1 was associated with poor PFS (p=0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.

Unraveling the Benefit of Adjuvant Chemotherapy in Early Stage Combined Small-Cell Lung Cancer

Unraveling the Benefit of Adjuvant Chemotherapy in Early Stage Combined Small-Cell Lung Cancer

Efficacy of Tyrosine Kinase Inhibitors in Primary Driver-Gene-Positive Combined Small-Cell Lung Cancer: A Retrospective Study

BackgroundCombined small-cell lung cancer (c-SCLC) with gene mutations is a rare subtype often found alongside adenocarcinoma. Targeted therapy may be effective because of the presence of specific molecular targets. However, due to its rarity and unconventional genetic testing, the efficacy remains uncertain. MethodsA total of 31 c-SCLC patients with gene mutations were retrospectively included and grouped according to their treatment regimens. Treatment outcomes were evaluated. Kaplan-Meier method was used for survival analysis, with Log Rank test applied for comparison between groups. ResultsWe divided the 31 patients into 3 groups according to first-line treatment: group A (chemotherapy, n = 16), group B (targeted monotherapy, n = 7), and group C (targeted combination therapy, n = 8). The overall response rates (ORR) were 43.8%, 42.9%, and 62.5%. The disease control rates (DCR) were 87.5%, 85.7%, and 100%. The median progression-free survival (PFS) was 4.0, 5.0, and 7.93 months (P = .024), with a significant difference between group A and C (P = .010). The median overall survival (OS) was 14.10, 17.43, and 12.93 months (P = .313). Seven patients in group A received targeted therapy in later-line. Of the total 22 patients received targeted monotherapy or combination therapy, the ORR and DCR were 54.5% and 90.9%. The median PFS and OS were 5.87 and 17.30 months. Additionally, adverse events (AEs) occurred in 53.8% and 88.9% of monotherapy and combination therapy. The most common AEs in monotherapy were elevated transaminases (23.1%) and in combination anemia (66.7%). ConclusionsTKIs showed encouraging efficacy in driver-gene-positive c-SCLC. While monotherapy may be a supplementary option, combination with chemotherapy appears to be preferable and superior.

Whole-Section Landscape Analysis of Molecular Subtypes in Curatively Resected Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Significance

Despite the recognition of various molecular subtypes in small cell lung cancer (SCLC), most information has been derived from tissue microarrays or biopsy samples. Using whole sections of curatively resected SCLCs, we aimed to elucidate the clinicopathologic relevance and prognostic significance of the molecular subtypes. Whole-section immunohistochemistry was conducted for 73 resected SCLC samples using antibodies representative of molecular subtypes: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Furthermore, multiplexed immunofluorescence was performed to evaluate the spatial relationship of YAP1 expression with other markers. The molecular subtype was correlated with clinical and histomorphologic features, and its prognostic role was explored in this cohort and validated in a previously published surgical cohort. Overall, the molecular subtypes were SCLC-A (54.8%), SCLC-N (31.5%), SCLC-P (6.8%), and SCLC-TN (triple negative, 6.8%). We found significant enrichment of SCLC-N (48.0%; P = .004) among combined SCLCs. Although a distinct subtype with high YAP1 expression was not found, YAP1 expression was reciprocal with ASCL1/NEUROD1 at the cellular level within tumors and was increased in areas with non–small cell–like morphology. Furthermore, the YAP1-positive SCLCs showed significantly increased recurrence at mediastinal lymph nodes (P = .047) and are an independent poor prognostic factor after surgery (adjusted hazard ratio, 2.87; 95% CI, 1.20-6.86; P = .017). The poor prognostic impact of YAP1 was also validated in the external surgical cohort. Our whole-section analysis in resected SCLCs reveals the highly heterogeneous nature of the molecular subtype and its clinicopathologic relevance. Although YAP1 is not a subtype delineator, YAP1 relates to the phenotypic plasticity of SCLC and may serve as a poor prognostic factor in resected SCLC.

Prognostic significance of eighth edition TNM stage criteria in combined small-cell lung cancer.

This study aimed to evaluate the prognostic significance of the eighth edition TNM stage criteria in patients with combined small-cell lung cancer (C-SCLC) on a population level. Using the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with C-SCLC (histology code 8245) between the years 2004 and 2015 were identified. We performed a Kaplan-Meier analysis and used the multivariable cox regression proportional hazards model to obtain prognostic overall survival estimates for each group of patients. A total of 477 patients diagnosed with C-SCLC were identified. The T, N, M, TNM, and combined TNM stage status of the eighth edition were all significant prognostic factors for patients' overall survivals, with the best discrimination identified in the combined stages. Surgery was also found to be a prognostic factor (HR =1.95, 95%CI =1.49-2.56, p<0.01) for patients with C-SCLC. The combined eighth edition of the TNM staging criteria shows reliable prognostic significance in patients with C-SCLC. Moreover, surgery might be significant for improving the patients' prognosis.

Tumors derived from lung cancer cells respond differently to treatment with sodium valproate (a HDAC inhibitor) in a chicken embryo chorioallantoic membrane model.

Lung cancer is the most frequent cause of cancer death. Some human lung malignant tumors have a combined small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) histology, with tumor cell phenotype changing during tumor progression. Valproic acid is used as an anti-seizure medication to treat migraine, and bipolar mood disorders. Recently, its efficacy as an adjuvant therapy was shown in cancer due to its histone deacetylase (HDAC) inhibitory property. HDACs are upregulated in lung tumors, and HDAC inhibitors, including valproic acid, inhibit endothelial cell proliferation in vitro and in vivo and have antiproliferative and antimigratory properties. We tested valproic acid for possible antiangiogenic and antimigratory effects on experimental lung tumors grafted onto the chicken embryo chorioallantoic membrane (CAM). Tumors were formed from two NSCLC cell lines and a single SCLC cell line. To investigate tumor and CAM interactions, in vivo biomicroscopy, visualization of blood vessels with injected fluorescent dextran, histological, immunohistochemical and histomorphometric methods were applied. Our results showed that a sodium valproate (NaVP) treatment-induced a dose-dependent decrease of experimental tumor invasion into the CAM mesenchyme and a reduction in angiogenesis. Both the invasion and the angiogenic response were dependent on the type of cell line used: invasion and angiogenesis of tumors derived from A549 and NCI-H146 cell lines responded to increasing doses of NaVP from 4 to 8 mM, whereas Sk_Lu_1 cells response were antimigratory and antiangiogenic when NaVP was used up to 6 mM. When 8mM NaVP was used, stimulated invasion and angiogenesis in tumors from Sk_Lu_1 cells were observed.

Different clinical characteristics and survival between surgically resected pure and combined small cell lung cancer.

BackgroundSmall cell lung cancer (SCLC) is the most malignant and common form of neuroendocrine lung cancer with pure (P‐SCLC) and combined subtypes (C‐SCLC). However, little is known about the differences between these two groups and in this study we aimed to provide a more comprehensive insight into SCLC.MethodsData from 580 postoperative patients with pathologically confirmed SCLC in Shanghai Chest Hospital from January 2010 to December 2020 were collected retrospectively. The clinical characteristics and prognosis were analyzed.ResultsA total of 357 P‐SCLC patients and 223 C‐SCLC patients were included. The results indicated that P‐SCLC appeared to have a higher proportion of being located in the middle lobe than C‐SCLC. The incidences of P‐SCLC in patients with visceral pleural invasion (VPI) and in stage II were higher than C‐SCLC, while C‐SCLC was more likely to be accompanied by higher incidences of epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and higher levels of CEA, SCCA and CYFRA21‐1 than P‐SCLC. The most common were SCLC combined with large cell neuroendocrine components among 223 C‐SCLCs. Survival analysis confirmed a more favorable disease‐free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.024) in patients with P‐SCLCs compared with C‐SCLCs. Histological type, tumor location, pN stage, adjuvant chemotherapy, serum NSE and CA125 levels were independent risk factors for survival rate in SCLC. In addition, adjuvant chemotherapy was beneficial in improving stage I P‐SCLC and C‐SCLC DFS and OS rates, and similar results were not seen in adjuvant radiation therapy.ConclusionsPatients with C‐SCLC have a poorer prognosis than P‐SCLC patients. We determined that large cell neuroendocrine carcinoma was the most common additional component of C‐SCLC, and patients with this component appeared to have a longer DFS and OS than other combined components.

TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.

Studies have shown that Nrf2E79Q/+ is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2E79Q/+. Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2E79Q mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2+/+ mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2E79Q allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2E79Q mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE+-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development.

Clinical features and prognostic factors of combined small cell lung cancer: development and validation of a nomogram based on the SEER database.

BackgroundCombined small-cell lung cancer (CSCLC) refers to the simultaneous presence of small cell lung cancer (SCLC) and any subtype of the non-small cell lung cancer (NSCLC). This study aimed to explore the prognosis of CSCLC, NSCLC, and pure SCLC patients, and to develop a nomogram to estimate the overall survival (OS) for CSCLC patients.MethodsPatients diagnosed with NSCLC, CSCLC, and pure SCLC between 2004 and 2015 were identified from the Surveillance Epidemiology and End Results (SEER) database. Survival analyses were performed by using the Kaplan Meier curves and Cox proportional hazards regression. All CSCLC patients were randomly split 7:3 into training and validation sets. A nomogram was developed by integrating all independent predictors for OS. The performance of the nomogram was determined by discrimination, calibration ability, clinical usefulness, and risk stratification ability.ResultsA total of 326,695 lung cancer patients, including 871 with CSCLC, 280,391 with NSCLC, and 45,433 with pure SCLC were enrolled. CSCLC was associated with worse survival compared with NSCLC both in the unmatched and matched cohorts. However, compared to pure SCLC, CSCLC was associated with significantly better survival in the unmatched cohorts only, while showed marginally non-significantly better survival after propensity score matching (PSM). For CSCLC, a nomogram was constructed for the 6-month, 1-year, and 3-year OS prediction by combining the independent risk factors, including age, gender, tumor, node, and metastasis stage, surgery, and chemotherapy. The nomogram showed good discrimination and calibration both in the training and validation sets, and better performance than the tumor–node–metastasis staging system. Risk stratification analysis indicated that the nomogram scores efficiently divided CSCLC patients into low-, intermediate-, and high-risk groups (P<0.001).ConclusionsCSCLC patients presented a significantly worse prognosis than patients with NSCLC, but comparable prognosis when compared with pure SCLC patients in the matched cohorts. In addition, we developed and validated a nomogram for predicting the 6-month, 1-year, and 3-year OS in CSCLC patients.

AN UNEXPECTED PULMONARY BIOPSY FINDING: SIMULTANEOUS SMALL CELL AND NON-SMALL CELL LUNG CANCER

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: There are rare instances in which patients are found to have small cell and non-small cell lung cancer simultaneously. combined small cell lung cancer (cSCLC) is a rare type of SCLC in which a tumor contains SCLC and another non-small cell component. (1). Mutiple primary lung cancer (MPLC) occurs when malignancies develop at anatomically separate sites in the lungs. (2) CASE PRESENTATION: A 71-year-old female with a 60-year history of cigarette smoking presented with two weeks of generalized weakness and fatigue. A computerized tomography (CT) scan of the chest (Figure 1) revealed a large subpleural thick-walled cavitary mass in the right lower lobe (RLL) measuring 10 cm in the largest dimension. Additionally, there was a peribronchovascular mass in the right upper lobe with right-sided hilar and mediastinal adenopathy. Given the patient's clinical history and radiographic findings malignancy was suspected. Bronchoscopy with TBNA of mediastinal lymph nodes and the cavitary RLL mass was performed. Immunohistochemistry of the RLL mass biopsy was consistent with moderately differentiated invasive SCC. However, immunohistochemistry of the subcarinal lymph nodes biopsies revealed a different cancer type, high-grade SCLC. Based on the biopsy results, the diagnosis could have been either cSCLC in which separate biopsy sites sampled tumor different components or MPLC. Following these findings, the patient elected for comfort care. DISCUSSION: The ACCP guidelines for the diagnosis and management of lung cancer recommend that lung cancer diagnosis be made by the least invasive method possible which is often bronchoscopy with TBNA or endobronchial ultrasound-guided needle aspiration when extensive mediastinal disease is present. (3) In this case presentation, isolated sampling of subcarinal lymph nodes would have led to an incorrect or incomplete diagnosis, as the peripheral tumor site biopsy found an additional cancer type. While it is important to minimize morbidity associated with tumor tissue collection, bronchoscopists are also tasked with obtaining adequate samples for molecular and histologic subtyping of tumors. cSCLC and MPLC present a unique challenge because limited tissue sampling can lead to under diagnosis of these cancers. As such, these cancers are likely under underdiagnosed (1,2). When possible, maximizing tissue acquisition from tumor sites and nodal stations can help prevent misdiagnosis of cSCLC and MPLC. In both MPLC and cSCLC, characterization of all malignant cell lines is needed for the effective management of patients. CONCLUSIONS: cSCLC and MPLC are both important, likely under-diagnosed cancers to consider when investigating pulmonary tumors. Bronchoscopists should balance the need to minimize morbidity with the need for obtaining adequate tissue from nodal stations and tumor sites to prevent misdiagnosis of cSCLC and MPLC. REFERENCE #1: Zhao X, McCutcheon JN, Kallakury B, et al. Combined Small Cell Carcinoma of the Lung: Is It a Single Entity? Journal of Thoracic Oncology. 2018;13(2):237-245. REFERENCE #2: Chen C, Huang X, Peng M, Liu W, Yu F, Wang X. Multiple primary lung cancer: a rising challenge. J Thorac Dis. 2019;11(Suppl 4):S523-S536. doi:10.21037/jtd.2019.01.56 REFERENCE #3: Rivera MP, Mehta AC, Wahidi MM. Establishing the Diagnosis of Lung Cancer. Chest. 2013;143(5):e142S-e165S. doi:10.1378/chest.12-2353 DISCLOSURES: No relevant relationships by Amad Chohan, source=Web Response No relevant relationships by Hannah Hameed, source=Web Response No relevant relationships by Anjan Kumar, source=Web Response No relevant relationships by mohammad Razaq, source=Web Response No relevant relationships by Mashal Tahirkheli, source=Web Response

Comparative Study of Pulmonary Combined Large-Cell Neuroendocrine Carcinoma and Combined Small-Cell Carcinoma in Surgically Resected High-Grade Neuroendocrine Tumors of the Lung.

ObjectivesPulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis.Materials and MethodsWe compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis.ResultsWe included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis.ConclusionsThe mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.

YAP1 protein expression has variant prognostic significance in small cell lung cancer (SCLC) stratified by histological subtypes

BackgroundRecently, expression of YAP1, a nuclear effector of an inactivated HIPPO pathway, has been identified as one of four molecular subtypes of SCLC. However, the clinicopathological relevance and prognostic significance of YAP1 expression in SCLC stratified by histological subtypes has not been systematically reported to date. MethodsTumor sections and corresponding formalin-fixed paraffin-embedded (FFPE) samples of 297 SCLC patients were retrieved from the pathological specimen repository and were subsequently reviewed by pathologists. Forty-six C-SCLCs (combined SCLCs) (15.5%) and 251P-SCLCs (pure SCLCs) (84.5%) were identified respectively. YAP1 expression was examined by immunohistochemistry (IHC) and assessed semi-quantitatively on tumor tissue array (TMA). Propensity score was used to match C-SCLCs and P-SCLCs in a ratio of 1 to 2 to balance age, gender, tumor stage and treatment methods. Finally, 46C-SCLCs and 92P-SCLCs were included for prognostic analysis. ResultsThe positive rate of YAP1 expression was significantly higher in C-SCLCs than P-SCLCs before matching (52.2% vs 29.1%, P = 0.004). After matching by propensity score, the prescribed clinical parameters were well balanced between P-SCLCs and C-SCLCs. Expression of YAP1 was associated worse overall survival (OS) (5- year OS%, 39.0% vs. 74.9%, P = 0.013) and was an independent risk factor for OS (HR = 2.93, 95% CI: 1.01–8.51; P = 0.048) exclusively in C-SCLC. Univariate survival analysis in subgroups of different clinical variables also confirmed the prognostic impact of YAP1 was most significant in C-SCLC. But for P-SCLCs, expression of YAP1 showed no prognostic impact. ConclusionsExpression of YAP1 in small cell components of C-SCLC was significantly higher than that in P-SCLC. Besides, it served as an unfavorable predictor for OS in C-SCLC but not in P-SCLC, which suggested different entities of small cell components with variant YAP1 expression and potential different targetable oncogenic pathway between C-SCLC and P-SCLC.

P38.09 Clinicopathological Characteristics of Combined Small-Cell Lung Cancer

P38.09 Clinicopathological Characteristics of Combined Small-Cell Lung Cancer

Comprehensive genomic profiling of combined small cell lung cancer.

BackgroundCombined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC.MethodsThe clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC.ResultsThere were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that TP53 and RB1 were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components.ConclusionsThere were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations.

Treatments for combined small cell lung cancer patients.

BackgroundCombined small cell lung cancer (CSCLC) is a subtype of small cell lung cancer (SCLC) which contains both components of SCLC and non-small cell lung cancer (NSCLC). The prognostic outcomes and treatment strategy of it are still unclear. A large-scale retrospective study was performed to investigate proper treatments for CSCLC.MethodsAll cases of CSCLC were identified from the SEER database during the period of 2004–2016. Clinical characteristics, first-line treatments, surgical procedures and survival data including overall survival (OS) and cancer-specific survival (CSS) were analyzed.ResultsA total of 37,639 SCLC patients were identified. CSCLC accounted for 2.1% (784/37,639). The mean age of CSCLC cohort is 67.3±9.9 years old. Male and white ethnicity patients were accounted for larger proportions (55.7% and 80.4%). The oncological characteristics of CSCLC were consistent with SCLC that most of patients were diagnosed as higher grade and advanced stages. The prognosis of CSCLC was better than SCLC but worse than NSCLC in IA-IIIA stages. No difference was observed in IIIB-IV. Surgery was beneficial in IA-IB stage CSCLC. Adjuvant chemotherapy seemed to have few effects on early stage patients. Trimodality treatment could significantly improve OS in IIA-IIIA CSCLC patients. Chemotherapy-based treatment is predominant choice in advanced stage patients.ConclusionsCSCLC is a rare and special subtype of SCLC. It has better survival outcome than non-CSCLC in early stage. Surgical treatment is crucial in early stage of CSCLC. Prognostic improvement might be achieved from trimodality treatment in stage IIA-IIIA. Chemotherapy-based treatments should be considered in advanced stage. The effect of surgical treatments in advanced stage patients should be further investigated.