Pulmonary Sarcomatoid Carcinoma Patients Research Articles

Multimodality Treatment of Pulmonary Sarcomatoid Carcinoma: A Review of Current State of Art.

Pulmonary sarcomatoid carcinoma (PSC) is an unconventional non-small-cell lung cancer (NSCLC) that is currently managed under guidelines used for conventional NSCLC and has poor survival. Surgery is the optimal choice for resectable PSC, and the prevalence of mutations in this type of tumor laid the foundation for novel systemic therapies such as targeted therapy and immunotherapy. PSC is resistant to chemotherapy and radiotherapy, and the effects of the 2 therapies are controversial. Targeted therapies have been reported to confer survival benefits, and savolitinib, an oral selective MET tyrosine-kinase inhibitor, has been approved in metastatic patients with MET exon 14 skipping mutations. Expression and positive rate of programmed death ligand 1 in PSC are high; our previous research has also revealed a high mutational burden and a T-cell-inflamed microenvironment of PSC. Correspondingly, immune checkpoint inhibitors have shown preliminary antitumor effects (overall response rates of 40.5% (15/37) and 31.6% (6/19) in two retrospective studies, respectively) in PSC patients. In summary, patients should receive operations at an early stage and multimodality treatments are needed to maximize the benefits of patients with advanced disease.

The Prognosis of Pulmonary Sarcomatoid Carcinoma: Development and Validation of a Nomogram Based on SEER.

Background: The rarity of pulmonary sarcomatoid carcinoma (PSC) and the lack of prospective clinical trials have led to limited knowledge of its clinical characteristics. This study aimed to evaluate the survival and prognostic factors of PSC and to build a nomogram for clinical practice. Methods: Eligible patients diagnosed from 2010 to 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. We compared the clinical characteristics and survival times of PSC patients with those of lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC) patients. We also used univariate and multivariable Cox regression to estimate mortality hazard ratios among patients with PSC, while a visual nomogram was established to judge the prognosis. Discrimination, calibration, clinical utility, and reproducibility were validated by Harrell's concordance index (C-index), the area under the curve (AUC), calibration curves, and decision curve analysis (DCA). Results: A total of 400 PSC patients (0.42%) were identified in the SEER database, whereas 58 474 and 33 637 patients were diagnosed with LADC and LSCC, respectively. Age, T stage, grade, surgery, and radiation were shown to be significant prognostic factors in the Cox regression analyses and were included in the nomogram as predictors. The C-index of the nomogram in the validation set was 0.759. The AUC also demonstrated the good performance of the nomogram, and DCA demonstrated its good clinical applicability. Conclusion: We established a novel nomogram to predict the prognosis of PSC, which can help clinicians make tailored decisions and adjust follow-up management strategies, and can provide accurate and individualized survival predictions.

Immune checkpoint inhibitors plus chemotherapy in patients with locally advanced or metastatic pulmonary sarcomatoid carcinoma: a multicentric real-world study.

Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy as monotherapy in patients with pulmonary sarcomatoid carcinoma (PSC). We performed the current multi-institutional, real-world study to assess the efficacy of ICIs plus chemotherapy in patients with PSC. All consecutive patients with locally advanced or metastatic PSC from three centers treated with ICIs between January 2018 and July 2021 were enrolled. Programmed death ligand 1 (PD-L1) expression was stained and evaluated using immunohistochemical with 22C3. Single-cell RNA sequencing (scRNA-seq) was performed in two patients with PSC and two patients with adenocarcinoma to understand the cell-type-specific transcriptome landscape of cancer cells and tumor microenvironment (TME) of PSC. A cohort of 42 PSC patients was identified. In the overall population, the objective response rate (ORR) was 73.8%, median progression-free survival (mPFS) was 10.3 months and median overall survival was not reached and 2-year survival rate was 51.2%. For 34 treatment-naïve patients who received first-line ICIs plus chemotherapy, the ORR was 70.6%, mPFS was 10.3 months and 2-year survival rate was 57.8%. In patients with PD-L1 tumor proportion score (TPS) < 1%, 1-49%, and ⩾50%, the ORR was 33.3%, 72.7%, and 85.7% and mPFS was 6.0, 6.7, and 10.3 months, respectively. Notably, two patients with transformed PSC from lung adenocarcinoma after epidermal growth factor receptor-tyrosine kinase inhibitor treatment also responded well to ICIs plus chemotherapy. scRNA-seq revealed immune-cell-inflamed TME, lower intratumoral heterogeneity, and activated immune response pathway in PSC. Our study demonstrated remarkable efficacy of ICIs plus chemotherapy as first-line therapy for patient with locally advanced or metastatic PSC.

P14.06 Toripalimab in Combination With Bevacizumab and Platinum-Based Chemotherapy in Patients with Untreated Advanced PSC: A Phase II Study

Although immunotherapy has emerged as a standard treatment for advanced non-small cell lung cancer (NSCLC) without driver gene mutation, there are still insufficient data on the efficacy of immunotherapy for patients with pulmonary sarcomatoid carcinoma (PSC). Due to a high tumor mutation burden and great prevalence of programmed cell death ligand 1 (PD-L1) in PSC than other subtypes of NSCLC, immunotherapy may provide promising efficacy in advanced PSC patients. Multiple immune-monotherapy or combination with chemotherapy case studies and doublet immunotherapy based on a phase II study (NCT03022500) suggested the survival benefit of immunotherapy in advanced PSC. Blood-vessel invasion as an independent factor associated with PD-L1 expression and poor prognosis in PSC, early application of anti-angiogenesis may enhance patients' response to immunotherapy. The application of anti-programmed cell death protein 1 (PD-1) antibody combined with platinum-based chemotherapy plus anti-angiogenesis in untreated advanced PSC is worth exploring. Toripalimab, a humanized IgG4 monoclonal antibody against PD-1, achieved partial response (PR) for second-line advanced PSC in a recent case report (Jiao Y Oral Oncology 2020). Based on these pieces of evidence, we explore the combination of toripalimab with platinum-based chemotherapy and bevacizumab in patients with untreated advanced PSC. This is an open-label, multicenter, single-arm, phase II study that aims to evaluate the efficacy and safety of toripalimab combination with platinum-based chemotherapy and bevacizumab in patients with untreated advanced PSC. Key eligibility criteria include age 18-75 years with Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed PSC, at least 1 measurable lesion per RECIST v1.1 that not received radiotherapy, and no prior anti-PD-1 or anti-PD-L1 therapy for stage IV PSC. Patients will be excluded if they have evidence of mutations in either EGFR, ROS-1, ALK, or c-MET. 27 untreated advanced PSC patients at 5 sites will be enrolled in Chengdu city, Sichuan province of China. All patients will receive toripalimab (240 mg, d1) combined with bevacizumab (7.5 mg/kg, d1) and nab-paclitaxel (260 mg/m2, d1 or 130 mg/m2, d1,8) plus carboplatin (AUC= 4-5, d1) of a 21-day cycle for a maximum of 6 cycles. Patients will continue to receive maintenance therapy with toripalimab and bevacizumab until disease progression or died of two years. The primary endpoint is progression-free survival (PFS) by investigator assessment per RECIST v1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), the patient-reported outcome (PRO), and safety data per NCI-CTC AE 4.0.3. Enrollment for this trial is open in April of this year and will continue for 12 months. Not applicable. Not applicable.

Clinicopathological and Prognostic Features of 67 Cases with Pulmonary Sarcomatoid Carcinoma: An 18-Year Single-Centre Experience

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a very rare subtype of non-small-cell lung cancer (NSCLC). It is frequently diagnosed in the advanced stage and is resistant to conventional chemotherapeutics. Due to the unique nature and rarity, we evaluated the epidemiological, clinicopathological, and survival data of PSC patients treated at our centre. Patients and Methods: We retrospectively collected demographic and clinical data of 67 PSC patients from a single tertiary referral hospital, between the 2000 and 2018. Univariate and multivariate analyses were performed to determine the risk factors affecting survival. Results: The median age was 61 years, and the percentage of male was 74.6%. Most of the patients had a smoking history (76.9%). The most common PSC subtype was pleomorphic carcinoma (46.3%). The median overall survival (OS) was 55.4 months, and the 5-year OS rate was 47.5%. Advanced stage, T4 tumour, and positive lymph node involvement were associated with poor OS (p < 0.05). The patients with negative epithelial markers had poorer prognosis (p = 0.027) and had more frequently stage IV disease (p = 0.016). Surgical treatment and stage IV disease were determined to be independent prognostic factors. Conclusion: PSC is an extremely rare and aggressive variant of NSCLC. Positive epithelial markers may have favourable prognostic significance in PSC. Resection of the tumour with a negative surgical margin is crucial for better survival. The prognosis of the disease is very poor in the metastatic stage.

Survival Analysis and Prediction Model for Pulmonary Sarcomatoid Carcinoma Based on SEER Database.

ObjectiveThis study aimed to investigate the incidence of the pulmonary sarcomatoid carcinoma (PSC), to compare the clinical characteristics and overall survival (OS) of patients with PSC and those with other non-small-cell lung cancer (oNSCLC), so as to analyze the factors affecting the OS of patients with PSC and construct a nomogram prediction model.MethodsData of patients with PSC and those with oNSCLC diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results database were collected. The age-adjusted incidence of PSC was calculated. The characteristics of patients with PSC and those with oNSCLC were compared, then the patients were matched 1:2 for further survival analysis. Patients with PSC were randomly divided into training set and testing set with a ratio of 7:3. The Cox proportional hazards model was used to identify the covariates associated with the OS. Significant covariates were used to construct the nomogram, and the C-index was calculated to measure the discrimination ability. The accuracy of the nomogram was compared with the tumor–node–metastasis (TNM) clinical stage, and the corresponding area under the curve was achieved.ResultsA total of 1049 patients with PSC were enrolled, the incidence of PSC was slowly decreased from 0.120/100,000 in 2004 to 0.092/100,000 in 2015. Before PSM, 793 PSC patients and 191356 oNSCLC patients were identified, the proportion of male, younger patients (<65 years), grade IV, TNM clinical stage IV was higher in the PSC. The patients with PSC had significantly poorer OS compared with those with oNSCLC. After PSM, PSC still had an extremely inferior prognosis. Age, sex, TNM clinical stage, chemotherapy, radiotherapy, and surgery were independent factors for OS. Next, a nomogram was established based on these factors, and the C-indexs were 0.775 and 0.790 for the training and testing set, respectively. Moreover, the nomogram model indicated a more comprehensive and accurate prediction than the TNM clinical stage.ConclusionsThe incidence of PSC was slowly decreased. PSC had a significantly poor prognosis compared with oNSCLC. The nomogram constructed in this study accurately predicted the prognosis of PSC, performed better than the TNM clinical stage.

Camrelizumab monotherapy or in combination with apatinib for PD-L1-positive advanced pulmonary sarcomatoid carcinoma: A multicenter, open-label, single-arm, phase II study.

TPS9130 Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with a fairly poor prognosis. As a highly aggressive malignancy, PSC is insensitive to conventional chemotherapy or radiotherapy and no optimal treatment for PSC has been established yet. Immune checkpoint inhibitors (ICIs) were documented to possess encouraging therapeutic efficacy in PSC patients, which is demonstrated to be associated with high expression of programmed death-ligand 1 (PD-L1) in PSC. However, because of the rarity of PSC, most of the existed data were derived from case repots which could not reflect the true clinical efficacy of ICIs for PSC treatment. This clinical trial was designed to investigate the clinical outcomes of camrelizumab in treating PD-1-positive PSC. Apatinib may be used simultaneously based on the expression level of PD-L1 in PSC as the combination of camrelizumab and apatinib exhibited treatment potential in NSCLC in previous researches. Methods: In this multicenter, open-label, single-arm, phase II study conducted in 44 sites in China, 30 patients with an age of 18-80 years old, an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2, positive PD-L1 expression, no EGFR, ALK, ROS1, and MET gene mutations, and histologically or cytologically confirmed stage IIIB-IV PSC regardless of prior lines of standard therapy will be enrolled. Patients with PD-L1 expression 1-49% will receive Camre (200 mg, IV, Q3W) and Apa (250mg, QD). Patients with PD-L1 expression≥50% receive Camre (200 mg IV Q3W) alone. The treatment will continue until a maximum treatment duration of 36 months, disease progression, intolerable toxicity, death or consent withdrawal. The primary endpoint is objective response rate (ORR). The secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to objective response (TTR), duration of response (DOR) and safety. This study is ongoing. Clinical trial information: ChiCTR2000032649, China.

Nivolumab Immunotherapy Plus Hydrogen Inhalation for Treatment of KRAS-Mutant Pulmonary Sarcomatoid Carcinoma: A Case Report

Background: Pulmonary sarcomatoid carcinoma (PSC) as a rare subtype of nonsmall cell lung cancer (NSCLC) is resistant to conventional chemotherapy and radiotherapy with poor prognosis. Nivolumab is a monoclonal antibody against PD-1 and might be a valuable therapy option for PSC, but limited case reports have shown good response. Case presentation: A 61-year-old man with PSC characterized with KRAS-G12C mutation and TP53 mutation received treatment of nivolumab synchronously combined with hydrogen inhalation. Clinical symptoms gradually relieved, and evaluation on imaging revealed a response after 1 year. Conclusion: This case suggests that immunotherapy combined with hydrogen inhalation may potentially be a promising strategy to treat PSC patients.

Clinicopathological features and prognostic analysis of metastatic pulmonary sarcomatoid carcinoma: a SEER analysis.

BackgroundPulmonary sarcomatoid carcinoma (PSC) is a rare type of non-small cell lung cancer (NSCLC). Metastases are often detected at the first diagnosis. Despite high rates of distant metastasis, there is insufficient data describing the characteristics of PSC metastasis.MethodsWe performed a Surveillance, Epidemiology, and End Results (SEER) database-based analysis of clinicopathological features and prognosis of distant metastasis in PSC patients. Data queried for this analysis included PSC patients in the database between 2010 and 2016.ResultsA total of 934 patients met the criteria for inclusion in the analysis and included, at the time of diagnosis, 512 (54.8%) patients with metastasis, including bone (n=152; 16.3%), brain (n=108; 11.6%), liver (n=70; 7.5%), lung (n=142; 15.2%) metastases. Binary logistic regression showed that patients with giant cell carcinoma [odds ratio (OR) 4.023, 95% confidence interval (CI): 2.113–7.661, P<0.001] and spindle cell carcinoma (OR 3.151, 95% CI: 1.699–5.843, P<0.001) were associated with metastasis. Log-rank test and Kaplan-Meier plots indicated poor prognosis in metastatic patients [the 1-, 3-, and 5-year overall survival (OS) rates were 14.1%, 5.5%, and 4.8%, respectively]. Multivariable analysis showed younger and chemotherapy as improved prognostic factors of PSC patients with single metastasis site.ConclusionsThe SEER database-based analysis revealed the clinical features of distant metastasis of PSC and showed that different histological types posed distinct metastasis potential. Besides, age and chemotherapy were the independent prognostic factors of PSC patients with single metastasis site.

Additional chemotherapy improves survival in stage II-III pulmonary sarcomatoid carcinoma patients undergoing surgery: a propensity scoring matching analysis.

BackgroundThe role of additional chemotherapy in pulmonary sarcomatoid carcinoma (PSC) is controversial. This study aimed to investigate the function of chemotherapy in PSC patients with surgical resection.MethodsPSC patient information between 2004 to 2016 was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. X-tile software was used to calculate the optimal cut-off value to divide groups. The disease stages were recalculated according to the American Joint Commission on Cancer (AJCC) 8th edition tumor-node-metastasis (TNM) staging system. Propensity score matching (PSM) analysis was conducted to balance the baseline of patients. Kaplan-Meier analysis and Cox proportional hazards analysis were used to evaluate survival outcome.ResultsA total of 865 PSC patients were included in our study. Among them, 611 patients were only operated with surgery, and the 254 others were treated with additional chemotherapy. The median age was 69.0 years (interquartile range, 61.6 to 76.3 years). Kaplan-Meier analysis showed that patients with additional chemotherapy had longer overall survival (OS) and cancer-specific survival (CSS, P<0.05). The median OS and the 1-, 3-, 5-year OS rates were 36.0 months (95% CI: 20.5–51.5 months), 72.7%, 49.6% and 38.5% in the chemotherapy group and 29.0 months (95% CI: 23.6–34.4 months), 63.2%, 44.5% and 37.6% in the non-chemotherapy group, respectively. The OS advantage of chemotherapy was not statistically significant after PSM analysis. Moreover, Cox proportional hazards model showed that chemotherapy was an independent prognosis factor for better OS and CSS. In subgroup of stages II and III, the chemotherapy group had a survival advantage (P<0.05). Patients with young age, female gender, low histology grade, large tumor size and lobectomy surgical resection benefited more from chemotherapy.ConclusionsChemotherapy is recommended for stages II and III PSC patients undergoing surgery, especially for those with young age, female gender, low histology grade, large tumor size and lobectomy surgical resection.

Clinicopathological characteristics and prognostic factors of pulmonary sarcomatoid carcinoma: a large population analysis.

BackgroundThis study was conducted to identify the clinicopathological characteristics and survival outcomes of pulmonary sarcomatoid carcinoma (PSC), and to compare prognostic factors between elderly (≥65 years) and non-elderly (<65 years) patients.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with PSC between 2004 and 2016. The Kaplan-Meier method was used for overall survival (OS) and cancer-specific survival (CSS) analysis. The Cox proportional hazards model was used to detect independent prognostic factors. A propensity score matched (PSM) analysis was conducted to compare OS and CSS in elderly versus non-elderly PSC patients.ResultsA total of 1,039 eligible cases were identified, with a median follow-up of 6 months. The 5-year OS and CSS rates were 12.3% and 18.7%, respectively, and the median survival was 6 months. Multivariate analysis revealed that female (HR =0.750, P<0.004), surgery (HR =0.484, P<0.001), chemotherapy (HR =0.504, P<0.001), and radiation (HR =0.801, P=0.041) were independent favorable prognostic factors. There was a significant difference in the OS and CSS rates between elderly and non-elderly patients after PSM (P=0.007 and P=0.017, respectively). In multivariate analysis, the predictors for OS in the elderly patients were gender, tumor stage, and chemotherapy, whereas in the non-elderly patients, the predictors were tumor stage, chemotherapy, and surgery.ConclusionsThe PSC patients in our study had poor survival outcomes. Comprehensive treatment, including surgery, chemotherapy, and radiotherapy, could improve patient prognosis. Elderly patients had different clinicopathological characteristics, compared to non-elderly patients.

An immune-based risk-stratification system for predicting prognosis in pulmonary sarcomatoid carcinoma (PSC)

ABSTRACT Pulmonary sarcomatoid carcinoma (PSC) is an uncommon subtype of lung cancer, and immune checkpoint blockade promises in clinical benefit. However, virtually nothing is known about the expression of common immune checkpoints in PSC. Here, we performed immunohistochemistry (IHC) to detect nine immune-related proteins in 97 PSC patients. Based on the univariable Cox regression, random forests were used to establish risk models for OS and DFS. Moreover, we used the GSEA, CIBERSORT, and ImmuCellAI to analyze the enriched pathways and microenvironment. Univariable analysis revealed that CD4 (P = 0.008), programmed cell death protein 1 (PD-1; P = 0.003), galectin-9 (Gal-9) on tumor cells (TCs; P = 0.021) were independent for DFS, while CD4 (P = 0.020), PD-1 (P = 0.004), Gal-9 (P = 0.033), and HLA on TILs (P = 0.031) were significant for OS. Meanwhile, the expression level of CD8 played a marginable role in DFS (P = 0.061), limited by the number of patients. The combination of Gal-9 on TC with CD4 and PD-1 on TILs demonstrated the most accurate prediction for DFS (AUC: 0.636-0.791, F1-score: 0.635–0.799), and a dramatic improvement to TNM-stage (P < 0.001 for F1-score of 1-y, 3-y, and 5-yDFS). A similar finding was also observed in the predictive ability of CD4 for OS (AUC: 0.602-0.678, F1-score: 0.635–0.679). CD4 was negatively associated with the infiltration of neutrophils (P = 0.015). PDCD1 (coding gene of PD-1) was positively correlated to the number of exhausted T cells (Texs; P = 0.020) and induced regulatory T cells (iTregs; P = 0.021), and LGALS9 (coding gene of Gal-9) was positively related to the level of dendritic cells (DCs; P = 0.021). Further, a higher combinational level of CD4, PDCD1 on TILs, and LAGLS9 on TCs were proved to be infiltrated with more M1-type macrophages (P < 0.05). We confirmed the expression status of nine immune-related proteins and established a TNM-Immune system for OS and DFS in PSC to assist clinical risk-stratification.

Genetic heterogeneity and predictive biomarker for pulmonary sarcomatoid carcinomas

PurposeThe aim of this study is to investigate the genetic heterogeneity (carcinomatous vs. sarcomatous components) and predictive biomarkers in patients with pulmonary sarcomatoid carcinoma (PSC). MethodsGenetic alterations and biomarkers of immunotherapy were performed in a discovery set (n = 6) of PSC. Next-generation sequencing (NGS) on a pan-cancer gene panel was applied to detect the genetic alterations in each component, and the respective mutation profiling and tumor mutation burden (TMB) were compared as well. Immunohistochemistry (IHC) assay with SP263 antibody was used to detect the protein expression of programmed death-ligand 1 (PD-L1) in each component. ResultsComparative genetic analysis revealed that the separate carcinomatous and sarcomatous components shared strikingly common mutations. TP53 (4/6, 66.7%) was the most common genetic alteration in 6 PSC patients. MET exon 14 skipping was detected in one case, accounting for 16.7%. An EZR-ROS1 fusion (EZR: intron10-ROS1: intron32) was identified in one case. The TMB of the two components was similar. Nevertheless, significantly higher PD-L1 expression was found in carcinomatous components compared to sarcomatous components. MDM2 amplification was detected in 2/6 (33.3%) of cases and STK11 mutation in 1/6 (16.7%) of cases. ConclusionsPSC containing carcinomatous and sarcomatous components had a mild heterogeneity; the two components may evolve from common ancestral cells. High PD-L1 expression suggests that immunotherapy could be used as a potential therapy for PSC patients, while patients with negative immune-responsive genes need to be screened out. Altogether, these findings further highlight that the detection of genetic alteration and PD-L1 expression plays an important role in treatment of patients with PSC.

P1.17 Comparison of Genetic Profiles of Pulmonary Sarcomatoid Carcinoma (PSC) Between Asian and Western Populations

Pulmonary sarcomatoid carcinoma (PSC) is a rare type of NSCLC characterized by aggressive behavior and poor clinical outcome. Earlier reports have revealed the genomic characterization of PSC in Western populations. However, the genomic alterations of Chinese PSC remain unclear. A total of 21 Chinese PSC patients were enrolled in the study. 14 Tissue biopsy and 10 ctDNA testing were analyzed for mutation profiling. All samples were analyzed using next-generation sequencing based target region capture method, which enables simultaneously assess genomic profile across at 1021 cancer genes. Tumor mutational burden (TMB) was calculated from 1.17 megabases (Mb) of sequenced DNA. Western PSC genomic data were quoted from Schrock’s study. A total of 24 samples from 21 PSCs were enrolled in this study. The most frequently altered genes were TP53 (58.3%), EGFR (29.2%), KRAS (29.2%), SMARCA4 (20.8%), MET (16.7%), MLL3 (16.7%), NF1 (16.7%), EPHA5 (12.5%), GATA3(12.5%), and ATM (12.5%) in our patient group. In comparison with Schrock’s study, alterations in TP53, KRAS, MET and NF1 were appeared in both races with high frequencies, some gene alterations such as SMARCA4, MLL3, ATM, EPHA5 and GATA3 were more commonly occurred in Asian patients, and other genes including CDKN2A, CDKN2B, TERT, PTEN, LRP1B and PIK3CA were more commonly existed in Western patients. And 70.8% PSC featured a genomic alteration in KRAS (29.2%) or one of seven genes recommended for testing in NSCLC NCCN guidelines, including EGFR (29.2%), MET (16.7%), ALK (8.3%). The frequency of EGFR mutation was higher in Asian patients than in Western patients. ALK alterations was only identified in our group, whereas BRAF, HER2 or RET alterations were only identified in Western populations. We also found that EGFR alterations were significantly more common in TP53 mutated cases than in TP53 wild-type cases (42.9% versus 10.0%). In addition, high TMB (>9 mutations per Mb) was found in 29.2% of cases, which was higher than that in 20% of the Western populations. Genetic profiles differences were observed between Asian and Western PCS patients that maybe lead to different disease characteristics. Limited by a small number of samples, our study is still ongoing for validation these findings.

PD-L1 and CD47 co-expression in pulmonary sarcomatoid carcinoma: a predictor of poor prognosis and potential targets of future combined immunotherapy.

Combined immunotherapy with anti-programmed cell death-ligand 1 (PD-L1) and an inhibitor of cluster of differentiation 47 (CD47) have exhibited preliminary anti-tumor effect. Our study attempted to describe the PD-L1/CD47 expression status in pulmonary sarcomatoid carcinoma (PSC), and explore its survival impact and relevance with cytotoxic T lymphocytes and macrophages infiltration. 148 patients with PSC who underwent surgeries were retrospectively reviewed. Tissue microarrays were conducted for immunohistochemistry (IHC) of PD-L1, CD47, CD8 and CD68. 54 (36.5%) and 78 (52.7%) caseswere positive for PD-L1 and CD47, respectively, and 36 (24.3%) of them demonstrated PD-L1/CD47 co-expression. There was a significant correlation between PD-L1 and CD47 expression (P = 0.011). The median overall survival (OS) was 22.5months (range 0.9-102.4months). The univariate analysis demonstrated a significantly worse OS in cases with CD47 expression (hazard ratio [HR], 1.66; 95% CI, 1.14-2.42, P = 0.008) and PD-L1/CD47 co-expression (HR, 1.75; 95% CI, 1.15-2.67, P = 0.009). The multivariate analysis demonstrated PD-L1/CD47 co-expression (HR, 1.83; 95% CI, 1.17-2.87, P = 0.008), T stage, M stage, completeness of resection and adjuvant therapy were independent prognostic factors for OS. There was a significant relevance between PD-L1 expression and PD-L1/CD47 co-expression with higher densities of CD8-positive T lymphocytes (P = 0.004, 0.012, respectively) and CD68-positive macrophages (P = 0.026, 0.034, respectively). We demonstrated the PD-L1/CD47 co-expression status in PSC. PD-L1 expression correlated with CD47 expression, and PD-L1/CD47 co-expression correlated with poorer prognosis and may serve as a predictive biomarker for combined dual-targeting immunotherapy in PSC patients.

Abstract 3400: Comprehensive genomic profiling in Chinese patients with pulmonary sarcomatoid carcinoma

Abstract Background:Pulmonary sarcomatoid carcinoma (PSC) is a unique type of lung tumor with low incidence and poor prognosis. There is no standard treatment for advanced PSC patients. Most of them refer to NSCLC chemotherapy. The molecular characteristic of PSC was not as clear as other histological subtypes of NSCLC. Comprehensive genomic analysis of PSC would provide guidance for targeted and immune therapies. Methods:Next generation sequencing (NGS) targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 13 Chinese PSC patients (16 samples). Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Microsatellite instability (MSI) status was assessed by NGS algorithms. Tumor tissues were analyzed for PDL1 expression by immunohistochemistry (IHC) staining. . Results:The median age of PSC patients was 63 years (range 32-79), among them 10 were male and 3 were female. Average of 12.4 GAs /sample and 2.2 actionable GAs/sample were detected. The most frequently mutated genes were TP53 (10/13), PDGFRA (4/13), KRAS (3/13), MET (3/13), BAP1 (3/13), SPTA1 (3/13), FAT3 (3/13), LRP1B (3/13). In seven of the 13 patients (53.8%), two or more gene variants were co-existed, with up to five mutations in a single case. RB1 and KRAS alterations were found only in TP53-mut cases. The frequencies of the seven genes recommended by NCCN guidelines for NSCLC were MET (3/13), BRAF (2/13), EGFR (2/13), ALK(1/13), respectively. No RET, HER2 and ROS1 variations were found. Notably, the genomic alteration frequencies of MET and BRAF were higher compared with that in other NSCLC (MET: 4.9%, BRAF: 4.4%). MET exon 14 alterations including splice point mutation (c.3028+1G&amp;gt;C) and point mutation (D1010Y) were identified in two patients. BRAF and EGFR mutations occurred in PSC patients were all hotspot including V600E for BRAF and exon 19 deletion and L858R for EGFR. The variations of ALK include gene rearrangement and point mutation (A1200V). In addition, other potential therapeutic targets were also detected: PDGFRA (4/13), PIK3CA(2/13), PTEN (1/13), FGFR1 (1/13) and CDKN2A (1/13). MSI status was evaluated in 12 patients, and all the 12 patients were MSS. PD-L1 IHC assay was only performed in 4 available patients, and 3 patients were PD-L1 positive and 1 patient was PD-L1 negative. More pts will be collected and involved in the study. Conclusion: Chinese PSC patients have multiple genomic alterations that can be targeted for treatments. The proportion of MET exon 14 mutations in PSC was higher, which was consistent with previous literatures. Therefore, the use of full-scale genome sequencing to explore potential therapeutic targets can help PSC patients benefit from potential targeted therapy and immunotherapy. Citation Format: Rong Shen, Fabo Qiu, Hao Zou, Lixin Li, Bin Yue, Zhihao Lu, Hanxia Han, Lijuan Chen, Lin Zhang. Comprehensive genomic profiling in Chinese patients with pulmonary sarcomatoid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3400.

Mutation landscape and tumor mutation burden analysis of Chinese patients with pulmonary sarcomatoid carcinomas.

Pulmonary sarcomatoid carcinoma (PSC) is a group of rare tumors with the presence of both cancerous and sarcoma components in tumor. In this study, we explore their cancer genomic background and the relationship with clinical prognosis. A cohort of 32 PSC patients were retrospectively collected from the First People's Hospital of Changzhou between 2005 and 2016. Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 32 PSC tumors. EGFR (28%), KRAS (22%), and MET (16%) are the most commonly mutated oncogenes, while the top mutated tumor suppressor genes are TP53 (69%) and RB1 (25%). The majority of EGFR mutations are rare mutations, some of which have not been reported before. Moreover, 4 out of 6 MET alterations are exon 14 skipping, far more frequent than in NSCLC. Interestingly, ARID1A was found to be co-mutated with TP53 at all times. The tumor mutation burden (TMB) is ranging from 3.3 to 52.2 per megabase (MB) with a median of 11.7 per MB and 13 patients have more than 20 mutations per MB. Patients mutated in BRCA2, KMT2B, SMARCA4 or TSC2 have significantly higher TMB compared to patients with wide-type genes. Our study characterizes the genetic background of Chinese PSC patients and demonstrates the importance of involving EGFR rare mutations and MET exon 14 skipping targeted therapies into clinical trials for treating PSC patients. High TMB are seen in about 40.6% Chinese patients with PSC, which could benefit from immune checkpoint inhibitors.

Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1–24 of KIF5B and exons 15–21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients.

Clinical features and prognosis of pulmonary sarcomatoid carcinoma

Objective: To investigate the clinical features and prognosis of patients with pulmonary sarcomatoid carcinoma (PSC). Methods: The study retrospectively reviewed the clinical, radiological, pathological characteristics and prognosis of 76 patients with PSC who were treated in the First Affiliated Hospital of Medical School of Zhejiang University from January 2011 to December 2016. Gender, age, smoking history, tumor location, tumor size, lymph node metastasis, distant metastasis, TNM staging and treatment methods were analyzed to determine the factors affecting the prognosis of PSC patients. Results: The 76 patients with PSC consisted of 61 men and 15 women, the average age was (62.9±9.8) years old. Cough (31 cases, 40.8%), hemoptysis (29 cases, 38.2%) and chest pain (15 cases, 19.7%) were the main clinical manifestations; the average diameter of tumor was (4.7±2.3) cm; the peripheral type (48 cases, 63.2%), right lung (51 cases, 67.1%) and upper lobe of the lung (46 cases, 60.5%) were the common locations. The tumors usually were with a smooth margin, showing an irregular annular enhancement around the area, but the central part of the tumors were not enhanced obviously. The main pathologic type was pleomorphic carcinoma, and immunohistochemistry showed that vimentin and cytokeratin were usually expressed.Tumor size, lymph node metastasis, distant metastasis, TNM staging and early surgical treatment (P<0.05) were prognostic factors for survival, and distant metastasis and TNM staging (P<0.001) were independent prognostic factors affecting the prognosis of patients. Conclusions: There are no specificity in the clinical and radiological features of PSC patients in our study, and the diagnosis of PSC depends mainly on pathological analysis. Distant metastasis and TNM staging are independent prognostic factors.

Pulmonary sarcomatoid carcinoma: an analysis of a rare cancer from the Surveillance, Epidemiology, and End Results database.

Pulmonary sarcomatoid carcinoma (PSC) is a rare malignant neoplasm that accounts for a small percentage of non-small-cell lung carcinoma (NSCLC). At least 10% of PSCs has a spindle and/or giant cell component, which is often associated with a poor prognosis. We reviewed the Surveillance, Epidemiology, and End Results (SEER) database for the clinicopathological characteristics and surgical outcomes of PSCs. The SEER database (1973-2013) was queried for PSC. A comparison between PSC and other NSCLC patients was performed. Cox regression for overall survival (OS) and logistic regression for node-positive predictors were performed. A propensity-matched (1:2) analysis (including age, gender, grade and stage) among surgically treated cases was done to compare OS in PSC versus other NSCLCs. A total of 955 899 NSCLC patients were identified; of these, 4987 patients had been diagnosed with PSC (0.52%). Men represented 60.9% of cases, with a median age of 68 years. The median size of the tumour was 5 cm and 3.5 cm in PSCs and NSCLCs, respectively (P < 0.001). PSC patients had significantly less Stage I, more high-grade tumours, advanced T stage, N+ disease and M1 disease (P < 0.001). In the PSC cohort, the most significant predictor of N+ disease on multivariate analysis was advanced T stage (P < 0.001). Predictors of OS in Stages I/II PSC on multivariate analysis were advanced age [P < 0.001, hazard ratio (HR) = 1.03], male gender (P = 0.024, HR = 1.25), carcinosarcoma (P = 0.002, HR = 1.76), grade (P = 0.033, HR = 1.81), T stage (P = 0.003, HR = 1.75), N status (P = 0.001, HR = 1.90) and surgical resection (P < 0.001, HR = 0.58). Among matched surgically resected cohorts, a poorer prognosis for OS was evident in PSCs in early stages (I/II) than in other NSCLCs (P = 0.009). PSC patients present with more advanced stage and with worse survival outcomes than other NSCLC patients. While surgical resection conveys a survival advantage in PSC, this group represents a population at a high risk for relapse and should be evaluated for novel adjuvant therapies.