S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway.

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.

D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRASG12C in Patients With NSCLC: Phase 1 Study Results.

INTRODUCTION: D-1553 (garsorasib) is a potent and selective oral KRASG12C inhibitor. We report results from a phase I dose-escalation and dose-expansion study of D-1553 in patients with KRAS G12C-mutated NSCLC in multiple sites in the People's Republic of China. METHODS: Patients with KRAS G12C-mutated NSCLC have administrated D-1553 600 mg orally once daily, 800 mg once daily, 1200 mg once daily, 400 mg twice a day, or 600 mg twice a day in dose escalation. In dose-expansion, all patients received 600 mg twice a day. The safety, pharmacokinetics, and efficacy of D-1553 were evaluated. RESULTS: Among a total of 79 treated patients, 75 patients (94.9%) reported treatment-related adverse events with 30 patients experiencing grade 3 or 4 events (38.0%). Most of the adverse events were manageable and the patients tolerated the study treatment well. Among 74 patients assessable for efficacy analysis, 30 patients had a partial response and 38 had stable disease with a confirmed objective response rate (ORR) and disease control rate (DCR) of 40.5% and 91.9%, respectively. The median progression-free survival was 8.2 months, and the median duration of response was 7.1 months. Among 62 patients assessable for response at the recommended phase 2 dose, partial response occurred in 24 patients (ORR, 38.7%) and stable disease in 32 patients (DCR, 90.3%). The median progression-free survival and duration of response were 7.6 months and 6.9 months, respectively. In patients with brain metastasis, ORR and DCR were 17% and 100%, respectively. CONCLUSIONS: D-1553 represents a promising therapeutic option for patients with KRAS G12C-mutated NSCLC with a well-tolerated safety profile and encouraging antitumor activity.

Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer.

OBJECTIVES: De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored. MATERIALS AND METHODS: We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted next-generation sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived organoid (PDO) model. RESULTS: We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EPHB4, THAP5, TNPO3, and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mutations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, AKT, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation. CONCLUSION: MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

The prognostic impact of immune checkpoint inhibitors for the treatment of pulmonary sarcomatoid carcinoma: A multicenter retrospective study.

Pulmonary sarcomatoid carcinoma (PSC) is an aggressive and poorly differentiated type of non-small cell lung carcinoma. Because of the rarity of PSC, the efficacy and toxicity of immunotherapy remain unclear. Hence, the aim of this study was to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) for the treatment of advanced PSC. The study cohort was limited to 33 patients with pathologically confirmed PSC treated with ICIs in four hospitals in China from March 2018 to March 2022. Expression of programmed death ligand 1 (PD-L1) was detected by immunohistochemical analysis. Categorical variables were compared with the Fisher exact test and survival analysis was conducted with the Kaplan-Meier method. Of the 33 PSC patients, 8 (24.2%) received monotherapy with ICIs and 25 (75.8%) received combination therapy with ICIs. The objective response rate (ORR) and disease control rate (DCR) were 36.4% and 78.8%, respectively. The median durations of progression-free survival (PFS) and overall survival (OS) were 6.07 and 21.33 months, respectively. PD-L1 status in 16 available samples was assessed, which included 30.3% PD-L1-positive patients. The ORRs for PD-L1-positive vs. -negative patients were 50.0% and 90.0%, the DCR was 33.3% and 83.3%, and the median PFS was 17.50 and 6.07 months, respectively (p=0.812). The median OS was not reached in PD-L1-positive and -negative patients (p=0.655). The incidence of immune-related adverse (irAEs) was 48.5% and mainly included grade 1 or 2 (39.4%), while the incidence of grade 3 or 4 was 9.1%. Pneumonia (9.1%) and skin rash (9.1%) were the most frequent irAEs. Immunotherapy with ICIs was a promising regimen to improve the prognosis of patients with advanced PSC.

Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

CpG-binding protein CFP1 promotes ovarian cancer cell proliferation by regulating BST2 transcription.

Epigenetic alterations have been functionally linked to ovarian cancer development and occurrence. The CXXC zinc finger protein 1 (CFP1) is an epigenetic regulator involved in DNA methylation and histone modification in mammalian cells. However, its role in ovarian cancer cells is unknown. Here, we show that CFP1 protein is highly expressed in human ovarian cancer tissues. Loss of CFP1 inhibited the growth of human ovarian cancer cells, promoted apoptosis, and increased senescence. CFP1 knockdown resulted in reduced levels of SETD1 (a CFP1 partner) and histone H3 trimethylation at the fourth lysine residue (H3K4me3). RNA-sequencing revealed that deletion of CFP1 resulted in mRNA reduction of bone marrow stromal cell antigen 2 (BST2). Bioinformatics analysis and chromatin immunoprecipitation showed that CFP1 binds to the promoter of BST2 and regulates its transcription directly. Overexpression of BST2 rescued the growth inhibitory effect of CFP1 loss. Furthermore, depletion of cullin-RING ubiquitin ligases 4 (CRL4) components ROC1 or CUL4A had significantly inhibited the expression of CFP1 and BST2 similar to MLN4924 treatment that blocked cullin neddylation and inactivated CRL4s. In conclusion, CFP1 promotes ovarian cancer cell proliferation and apoptosis by regulating the transcription of BST2, and the expression of CFP1 was affected by CRL4 ubiquitin ligase complex.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Hepatoid adenocarcinoma of the lung: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

Hepatoid adenocarcinoma of the lung (HAL) is a rare malignant tumor that is defined as a primary alpha-fetoprotein (AFP)-producing lung carcinoma. We aimed to identify prognostic factors associated with the survival of patients with HAL using data from the Surveillance, Epidemiology, and End Results (SEER) database. We collected data from patients diagnosed with HAL, adenocarcinoma (ADC), and squamous cell carcinoma (SCC) of the lung between 1975 and 2016 from the SEER database. The clinical features of patients with ADC and SCC of the lung were also analyzed. The clinical features of HALs were compared to ADCs and SCCs. A chi-square test was used to calculate the correlations between categorical variables, and a t test or Mann-Whitney U test was used for continuous variables. The Kaplan-Meier method and Cox regression analysis were used to identify the prognostic factors for the overall survival (OS) of HALs. Two-tailed p values < 0.05 were considered statistically significant. Sixty-five patients with HAL, 2,84,379 patients with ADC, and 1,86,494 with SCC were identified from the SEER database. Fewer males, advanced stages, and more chemotherapy-treated HALs were found. Compared to patients with SCC, patients with HAL were less likely to be male, more likely to be in an advanced stage, and more likely to receive chemotherapy (p < 0.05). The American Joint Committee on Cancer staging was the only prognostic factor for OS in patients with HAL, and stage IV was significantly different from other stages (hazard ratio = 0.045, 95% confidence interval: 0.005-0.398, p = 0.005). Males with HAL were more likely to receive radiotherapy compared to females with HAL (61.8 vs 31.5%, p = 0.034). Younger patients with HAL were more likely to receive chemotherapy (59.4 + 10.2 years vs 69 + 11.3 years, p = 0.001). The primary tumor size of HAL was associated with the location of the primary lesion (p = 0.012). No conventional antitumor therapies, including surgery, chemotherapy, and radiotherapy, were shown to have a significant survival benefit in patients with HAL (p > 0.05). This study showed that stage IV was the only prognostic factor for OS in HALs compared to other clinicopathologic factors. Conventional antitumor therapies failed to show survival benefit; thus, a more effective method by which to treat HAL is needed. Interestingly, the clinical features and the location of the primary lesion were shown to be associated with primary tumor size and treatment in patients with HAL, which have not been reported before.

A real-world study in advanced non-small cell lung cancer with de novo brain metastasis.

Brain metastases are the major cause of life-expectancy shortened for patients with lung cancer. The prognostic value of EGFR mutation subtypes and survival benefit of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) patients with de novo brain metastasis is still not clear. Here, we present a real-world study nation-wide focusing on the prognostic value of genomic and therapeutic factors in overall survival (OS) of those patients. We enrolled a total of 233 patients diagnosed with advanced NSCLC and de novo BM from multi-medical centers across China. The enrolled patients were divided into 4 groups, including EGFR 19del, EGFR L858R, EGFR wild-type, and EGFR unknown groups. The median OS of patients with EGFR mutations and all patients were 29.0 and 25.0 months, respectively. There was significant difference in OS of patients among EGFR 19del (n=76), EGFR L858R (n=94), EGFR wild-type (n=46) and EGFR unknown (n=17) groups (30.5 vs 27.5 vs 16.0 vs 25.0, P=0.025). Patients treated by icotinib showed better OS than gefitinib and erlotinib (31.0 vs 25.5 vs 26.5, P=0.02). There was a difference in OS of patients received the whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or WBRT+SRS (20.0 vs 31.0 vs 30.0 months, P<0.001), respectively. In multivariate analysis, patients treated with icotinib had superior iPFS benefit than gefitinib and erlotinib (HR=0.86[95%CI (0.74-1.0)], P=0.04). Besides, the histology of non-adenocarcinomas, the number of BM (>3), and extracranial metastases status could have an independent negative impact on the OS of all patients (P<0.001). EGFR mutant NSCLC patients with de novo BM had a better OS than patients with EGFR wild type. Patients treated with icotinib had longer iPFS than gefitinib and erlotinib but not in OS. Non-adenocarcinomas, number of BM (>3) and extracranial metastases were independent negative prognostic factors in iPFS and OS of all patients. Prospective clinical trials are warranted to explore more effective multimodality in this population.

Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: a multicenter study.

BACKGROUND: Chemotherapy is the major choice for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor exon 20 insertion (EGFR ex20ins). The efficacy of pemetrexed-based with other chemotherapy regimens and EGFR ex20ins subtypes in this population has not been well studied. METHODS: We screened patients with EGFR ex20ins by next-generation sequencing (NGS) from a large cohort. The clinicopathologic and medical information were collected in advanced NSCLC patients with EGFR ex20ins. We also compared the clinical outcomes among patients with different subtypes of EGFR ex20ins. RESULTS: We retrospectively collected 119 stage IIIB/IV NSCLC patients with EGFR ex20ins from 9142 NSCLC patients across China from June 2013 to December 2018. The subtypes of EGFR ex20ins included A767_V769dupASV (33/119, 27.73%), S768_D770dupSVD (19/119, 15.97%), N771_H773dupNPH (11/119, 9.24%), A763_Y764insFQEA (2/119, 1.68%) and others (54/119, 45.38%). A total of 64.7% (77/119) of patients received pemetrexed-based first-line chemotherapy and 13.45% (16/119) of patients received pemetrexed-based second-line chemotherapy. Pemetrexed-based chemo-treated patients had longer median progression-free survival (PFS) than patients without pemetrexed-based chemo-treated (5.5 vs. 3.0 months, P=0.0026). Survival data was available for 66 patients and the median overall survival (OS) was 24.7 months. Pemetrexed-based chemo-treated patients had longer OS tendency than patients without pemetrexed-based chemo-treated (25.0 vs. 19.6 months, P=0.0769). Patients harboring A767_V769dupASV had better OS than other subtypes of EGFR ex20ins but without statistical significance (P=0.0676). Multivariate analysis revealed that histological type of NSCLC and bone-metastasis before treatment were independent prognostic factors for OS in all patients after adjusting all characteristic and treatment factors (P<0.05). CONCLUSIONS: To the best of our knowledge, it is the largest cohort study of advanced NSCLC patients with EGFR ex20ins across China. Pemetrexed-based treatment could have better control of disease than non-pemetrexed-based chemotherapies in this population. Furthermore, more effective agents are expected for patients harboring EGFR ex20ins.

Efficacy of Pyrotinib in HER2-Overexpressing Salivary Duct Carcinoma With Lung Metastasis: A Case Report.

Background: Salivary duct carcinoma (SDC), an aggressive and rare malignancy with poor prognosis, is mostly associated with the overexpression of the androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2). However, limited data are available for the targeting of both HER2 and AR in advanced/metastatic SDC. Case Presentation: A 62-year-old man with advanced SDC accompanied by lung and lymph node metastasis showed disease progression after two lines of chemotherapy and endocrine therapy. Metastatic lesions from the lung biopsy were obtained, and immunohistochemistry (IHC) indicated the overexpression of AR and HER2 (3+). The patient was administered pyrotinib (a pan-ErbB receptor tyrosine kinase inhibitor) and bicalutamide (an androgen receptor antagonist) as a third-line treatment. During the ten months of follow-up, a durable partial response was achieved with this combination. Conclusions: This is the first clinical study to report the successful application of pyrotinib in a patient with advanced SDC. We recommend that pyrotinib and bicalutamide be used as salvage therapy for AR and HER2-positive advanced metastases in SDC, given the favorable response and clinical benefit.

MET exon 14 skipping mutation, amplification and overexpression in pulmonary sarcomatoid carcinoma: A multi-center study.

BACKGROUND: High frequency of MNNG HOS transforming (MET) exon 14 skipping mutation (MET exon 14Δ) has been reported in pulmonary sarcomatoid carcinomas (PSCs). However, the frequencies differ greatly. Our study aims to investigate the frequency of MET alterations and the correlations among MET exon 14Δ, amplification, and protein overexpression in a large cohort of PSCs. MET exon 14Δ, amplification, and protein overexpression were detected in 124 surgically resected PSCs by using Sanger sequencing, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) respectively. MET exon 14Δ was identified in 9 (7.3%) of 124 cases, including 6 pleomorphic carcinomas, 2 spindle cell carcinomas and 1 carcinosarcoma. MET amplification and protein overexpression were detected in 6 PSCs (4.8%) and 25 PSCs (20.2%), respectively. MET amplification was significantly associated with overexpression (P < 0.001). However, MET exon 14Δ has no correlation with MET amplification (P = 0.370) and overexpression (P = 0.080). Multivariable analysis demonstrated that pathologic stage (hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.28-6.01; P = 0.010) and MET amplification (HR, 4.71; 95% CI, 1.31-16.98; P = 0.018) were independent prognostic factors for poor median overall survival (mOS). MET alterations including MET exon 14Δ and amplification should be recommended as routine clinical testing in PSCs patients who may benefit from MET inhibitors. MET IHC appears to be an efficient screen tool for MET amplification in PSCs.

A Novel Oncogenic Driver in a Lung Adenocarcinoma Patient Harboring an EGFR-KDD and Response to Afatinib.

Introduction: Oncogenic mutations in the epidermal growth factor receptor (EGFR) occur frequently in patients with lung cancer. These mutations may serve as critical predictive biomarkers in patients with non-small cell lung cancer (NSCLC). Among them, EGFR exon 18-25 kinase domain duplication (EGFR-KDD) mutations have been identified as a novel EGFR gene subtype in NSCLC. Case Presentation: We reported a rare case of a 59-year-old male diagnosed with adenocarcinoma. A biopsy revealed an EGFR-KDD identified by the next generation sequencing (NGS). Effective treatment outcome has been observed after administration with afatinib. Conclusion: This case highlights that comprehensive NGS technique is valuable in detecting novel genetic mutations in tumors.

Molecular Characteristics and Clinical Outcomes of EGFR Exon 19 C-Helix Deletion in Non-Small Cell Lung Cancer and Response to EGFR TKIs.

Epidermal growth factor receptor (EGFR) exon 19 deletion (E19del) is the most common activating mutation in advanced non-small cell lung cancer (NSCLC) and associates with the sensitivity of EGFR tyrosine kinase inhibitors (TKIs) treatment. However, not all mutant patterns of E19del have been well studied for the limited coverage of regular EGFR mutation testing. Here, we performed a retrospective cohort study of the C-helix E19del in advanced NSCLC patients based on the screening data by the next-generation sequencing (NGS) platform. From May 2012 to December 2019, clinical information and specimen from 7544 consecutive advanced (IIIB/IV) NSCLC patients were collected and screened for EGFR gene mutations by NGS from multicenters in China. The molecular characteristics and responsiveness to first-line EGFR TKIs therapy in NSCLC patients with C-helix E19del were analyzed. The clinical characteristics were also compared between patients with classical E19del and C-helix E19del. Thirty-eight (2.6%) patients with C-helix E19del and 1400 (97.4%) patients with classical E19dels were identified from 1438 patients with E19del. No significant difference in clinical characteristics was observed between the C-helix E19del and classical E19del groups (P > .05), except for histology (P < .001). All 22 patients with C-helix E19del as p.S752_I759del, p.A750_E758del, p.A750_E758delinsP, p.T751_A755delinsNY, p.T751_I759delinsG, p.T751_I759delinsLD, p.T751_I759delinsN, p.T751_L760delinsNL, and p.T751_D761delinsLY reached the best response as partial response rate (72.7%), and the progression-free survival (PFS) was 12.0 months. The PFS after EGFR TKIs in patients with C-helix E19del tended to be longer than patients with classical E19del but has no statistical significance (12.0 months vs 8.5 months, P = .06). The C-helix E19del could be a positive biomarker for predicting response to EGFR TKIs in advanced NSCLC patients. NGS should be the appropriate platform to identify this rare population, especially when patients harbor no actionable driver mutation initially and are reluctant to accept chemotherapy as first-line therapy.

PD-L1 expression level in different thymoma stages and thymic carcinoma: a meta-analysis.

BACKGROUND: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. METHODS: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. RESULTS: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high (I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity (I2 = 55%). CONCLUSION: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.

A novel SOS1-ALK fusion variant in a patient with metastatic lung adenocarcinoma and a remarkable response to crizotinib.

OBJECTIVES: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. MATERIALS AND METHODS: With advances in detection methods, more and more uncommon ALK fusion partners have been identified. Herein we present a novel SOS1-ALK fusion and the efficacy of crizotinib in an advanced NSCLC patient harboring this type of fusion. RESULTS: A 52-year-old Chinese man had left upper lobe primary NSCLC and synchronous multiple lung metastases (cT2N3M1, stage IV). The ultrasound-guided fine-needle aspiration cytology of palpable left supraclavicular lymph nodes and the results of immunohistochemistry staining supported the diagnosis of metastatic lung adenocarcinoma. Using a next-generation sequencing assay (NGS), we showed that the tumor had a SOS1-ALK fusion which the breakpoints was (S2, A20) rather than other actionable mutations. Therefore, the patient received first-line crizotinib and experienced a remarkable tumor response and has tolerated crizotinib well until this writing. CONCLUSION: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice.

Eye metastasis in lung adenocarcinoma mimicking anterior scleritis: A case report.

BACKGROUND: The eye is a rare site for lung cancer metastasis. Indeed, ocular metastasis is one of the greatest challenges to quality of life in a cancer patient. Here we present a patient with lung adenocarcinoma and ocular metastasis. CASE SUMMARY: The patient was a 70-year-old man diagnosed with lung adenocarcinoma who developed eye metastasis mimicking anterior scleritis. Brain magnetic resonance imaging showed an abnormal signal in the right eye. Based on next generation sequencing of the surgical specimen, the patient was shown to have a KRAS point mutation (p.G12D). CONCLUSION: Multidiscipline expertise collaboration is needed to make the early diagnosis and determine the prompt treatment in patients. We hope to increase the awareness of the possibility of lung cancer metastasizing to the eye.

An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway.

In clinical practice, some breast cancer (BC) patients carry a rare ERBB2 in-frame insertion (p. Pro780_Tyr781insGlySerPro) and are resistant to anti-ERBB2 therapy. To explore the potential procarcinogenic role of this ERBB2 mutation, we conducted the present study using BC cells overexpressing wild-type (WT) ERBB2 or P780-Y781 ERBB2 [mutated (MT)]. MDA-MB-231 and MCF-7 cells were transfected with the following plasmids using a lentivirus system: negative control (ERBB2-NC), WT ERBB2 overexpression (ERBB2-WT), and P780-Y781 ERBB2 overexpression (ERBB2-MT). P780-Y781 ERBB2 conferred significant resistance to lapatinib, as assessed by cell viability and colony counts. Analysis of the cell cycle showed that the P780-Y781 ERBB2 group showed an elevated proportion of cells in S, G2, and M phases compared with WT ERBB2 when exposed to lapatinib. Following lapatinib treatment, phosphorylated AKT (p-AKT) was strongly upregulated in the P780-Y781 ERBB2 group. Among ERBB2+ patients, the P780-Y781 ERBB2 group showed increased levels of p-AKT. Furthermore, the AKT inhibitor perifosine effectively suppressed lapatinib resistance, as indicated by the lapatinib inhibition curve and results of the colony formation assay, and decreased AKT phosphorylation. Altogether, we discovered a procarcinogenic mutation of ERBB2 that enhances BC cell growth through AKT signaling and causes resistance to lapatinib. Patients with this in-frame insertion mutation of ERBB2 should be recommended other therapeutic strategies apart from ERBB2 tyrosine kinase inhibitors, in particular lapatinib.

Association between BRAF mutant classification and the efficacy of pemetrexed-based chemotherapy in Chinese advanced non-small cell lung cancer patients: a multicenter retrospective study.

BACKGROUND: BRAF mutation plays a rare but aggressive oncogenic role in non-small cell lung cancer (NSCLC) patients. The controversy of first-line chemotherapy in patients with different BRAF mutations exists. Here, we identified 41 stage IIIB/IV NSCLC patients with BRAF mutation from 3,669 NSCLC patients by next-generation sequencing (NGS) testing of ctDNA in plasma or tumor tissues. METHODS: Kaplan-Meier survival curves were used to compare the prognostic difference of progression-free survival (PFS) and overall survival (OS) in different classes of BRAF mutations. Multivariate Cox proportional-hazards regression was used to determine the hazard ratio (HR) of different prognostic factors in survival. RESULTS: A total of 40 stage IIIB/IV NSCLC patients with BRAF mutation were further divided into four groups according to the updated functional classification of BRAF mutations, 56.1% (23/41) of class 1, 12.2% (5/41) of class 2, 12.2% (5/41) of class 3 and 19.5% (8/41) of others. The median PFS of patients after first-line pemetrexed-based chemotherapy was longer than other regimens of chemotherapy (7.0 vs. 4.0 months, P<0.001). The patients with class 1 BRAF mutation treated with pemetrexed-based first-line chemotherapy had a better OS than other regimens of chemotherapy (30 vs. 22 months, P<0.001). A significant improvement of OS was observed in patients with class 1 BRAF mutation than other groups (25 vs. 12, 15 and 14 months, P<0.0001). Multivariate analysis showed that first-line pemetrexed-based chemotherapy was associated with better PFS and OS (HR =0.16 and 0.31, respectively; P<0.001 and 0.02, respectively), as well as improved OS in patients with class 1 BRAF mutation than other classes (HR =2.15, P<0.001). CONCLUSIONS: Pemetrexed-based regimen could be considered as first-line chemotherapy in advanced NSCLC patients with BRAF mutants when target therapy is unavailable, especially in patients harboring class 1 mutations compared with other classes.