The role of long non-coding RNA (lncRNA) in the progression of Nasopharyngeal carcinoma (NPC) has not been fully elucidated. The study was designed to explore the functional role of NKILA, a newly identified lncRNA, in the progression of NPC. We performed a lncRNA expression profile microarray using four NPC and paired para-cancerous tissues. NKILA was identified as a potential functional lncRNA by this lncRNA expression profile. We used 107 paraffin-embedded NPC tissues with different TNM stages to detect the expression of NKILA and analyzed the survival data by Log-rank test and Cox regression. The role of NKILA and its underlying mechanisms in the progression of NPC were evaluated by a series of experiments in vitro and vivo by silencing or expressing NKILA. Compared with control tissues, NKILA expression was identified to be decreased in NPC tissues. Low NKILA expression was correlated with unfavorable clinicopathological features and predicted poor survival outcome in NPC patients. After adjusting for potential confounders, low expression of NKILA was confirmed to be an independent prognostic factor correlated with poor survival outcomes. Furthermore, we found that NKILA overexpression in high-metastatic-potential NPC cells repressed motile behavior and impaired the metastatic capacity in vitro and in vivo . In contrast, RNAi-mediated NKILA depletion increased the invasive motility of cells with lower metastatic potential. Further experiments demonstrated that NKILA regulated the metastasis of NPC through the NF-κB pathway. Taken together, NKILA plays vital roles in the pathogenesis of NPC. The unique histological characteristics of NPC indicate that local inflammation plays a vital role in carcinogenesis of nasopharyngeal carcinoma.

Rho GTPase‐activating protein 42 was identified as an inhibitor of RhoA to maintain normal blood pressure homeostasis. However, the effect of ARHGAP42 in promoting cell malignancy in nasopharyngeal carcinoma is demonstrated in this study. Microarray and real‐time quantitative PCR were used for a mRNA profiling of ARHGAP42 in nasopharyngeal primary and metastatic carcinoma tissues. Western blot and immunohistochemical staining were used for detecting the expression of ARHGAP42 protein in nasopharyngeal carcinoma tissues and cell lines. The overexpression and silence experiments of ARHGAP42 were performed in NPC cell lines using siRNA and expressive plasmid for evaluating cancer cell migration and invasion in vitro. Real‐time quantitative PCR, western blot, and transwell test were employed for with the function of ARHGAP42 and its antisense lncRNA uc010rul. We confirmed the elevated expression of ARHGAP42 in metastatic NPC tissues of mRNA and protein for the first time. Immunohistochemical analysis indicated that NPC patients with highly ARHGAP42 expression were significantly associated with shorter metastasis‐free survival. Knockdown of ARHGAP42 resulted in significant inhibition of nasopharyngeal cancer cell migration and invasion in vitro, and the overexpression of ARHGAP42 showed the opposite effects. In addition, the silence of uc010rul resulted in ARHGAP42 expression decrease and significant inhibition of nasopharyngeal cancer cell migration and invasion. High expression of ARHGAP42 is associated with poor metastasis‐free survival of nasopharyngeal carcinoma patients. ARHGAP42 promotes migration and invasion of nasopharyngeal carcinoma cells in vitro; the antisense lncRNA may be involved in this effect.

Background: The HER2-targeted drugs selection after trastuzumab failure has become a challenging issue for HER2-positive metastatic breast cancer (MBC) patients. Inetetamab is a neotype of HER2-targeted monoclonal antibody with an engineered Fc segment that optimizes the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, which was important for disease control. Moreover, HER2-targeted tyrosine kinase inhibitors, as pyrotinib, were found to further improve the ADCC effect of monoclonal antibodies in pre-clinical researches, indicating that the combination of pyrotinib and inetetamab could achieve complementarity and synergy effects in terms of short-term tumor killing effect and long-term immunotherapy benefits. Therefore, the combined treatment pattern of the two drugs has potential clinical benefits. Methods: This is a prospective, multi-center, single-arm clinical study designed to evaluate the efficacy and safety of pretreated patients with HER2-positive MBC. We recruited patients with pathologically confirmed HER2-positive MBC who had received 1-3 prior regimens for metastatic disease, which must include trastuzumab. The enrolled patients received 6 cycles of Inetetamab combined with pyrotinib and chemotherapy, subsequent maintenance therapy should be considered according to tolerability. The chemotherapy drugs were decided by physicians’ choice, and could be microtubules, anthracyclines, or antimetabolites. The primary endpoint was objective response rate (ORR) after 6 cycles of treatment, secondary endpoints included progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) and adverse events (AEs). Results: 57 patients were enrolled from October 2020 to July 2022. And 45 patients were available for response evaluation. The ORR and DCR were 53.5 % (24/45) and 86.7 % (39/45), respectively after 6 cycles treatment. The median PFS was 7.3 months. The incidence of grade Ⅲ-Ⅳ AEs was 15.8 %. The most common treatment-related AEs were diarrhea, anemia, neutropenia, leukopenia, hand and foot syndrome. No patient’ s left ventricle ejection fraction (LVEF) decreased to < 50% or decreased by >15%. And no significant decline in quality of life score was reported. Conclusion: Inetetamab combined with pyrotinib and chemotherapy showed a promising efficacy and a good tolerance in patients with HER2-positive metastatic breast cancer, confirming the synergistic effect between the ADCC optimized monoclonal antibodies and TKIs, which brings more treatment options for HER2-positive metastatic breast cancer. Citation Format: Jianli Zhao, Yangyang Cai, Linxiaoxiao Ding, Yaping Yang, Guorong Zou, Herui Yao, Ying Wang. Inetetamab combined with pyrotinib and Chemotherapy in Pretreated Patients with HER2-positive metastatic breast cancer, a single arm, multicenter phase II clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-25-02.

Background: The overall survival (OS) among patients with advanced breast cancer (ABC) varies greatly.Although molecular subtype is known as the most important factor in OS differentiation, significant differences in OS among patients with the same molecular subtype still occur, leading to the need for a more accurate prognostic prediction model. This study aimed to develop a prediction model (nomogram) based on current diagnosis and treatment to predict the OS of newly diagnosed ABC patients in China.Methods: From the institution's database, we collected data of 368 ABC patients from Sun Yat-sen Memorial Hospital (national hospital) as a training set to establish a nomogram with prognostic risk factors that calculated the predicted probability of survival. Nomograms were independently validated with 278 patients with ABC from two other institutions using the concordance index (C-index), calibration plots and risk group stratifications. Results:The initial primary tumor stage, molecular subtype, disease-free survival (DFS), presence of brain metastasis, and the tumor burden of metastasis disease (local recurrence, oligo-metastatic disease, or multiple-metastatic disease) were included in the prognostic nomogram. The nomogram had a C-index of 0.77 and 0.71 in the training and the validation sets, respectively. The nomogram was able to stratify patients into different risk groups, respectively (HR 6.81, 95% CI: 4.69 to 9.89, P<0.001). In the lower risk score group (risk score <11), there was no significant difference between the OS with chemotherapy and hormone therapy (HR 0.81, 95% CI: 0.44 to 1.47, P=0.48). Conclusions:We have constructed a novel prediction nomogram that can guide the physicians to select personalized treatment options. Furthermore, our study is the first to add oligo-metastatic disease and primary endocrine/trastuzumab resistance into the prognostic models.

The Genomic Landscape of Chinese Breast CancerBackground : The comprehensive genomic profiling (CGP) through next-generation sequencing (NGS) brought a new understanding of breast cancer and provided more information about further clinical treatment. However, the genomic features in Chinese breast cancer group are limited to date, which might offer both prognostic and predictive values. Patients and Methods: Hybrid capture-based CGP was performed on 126 primary and 38 relapsed/metastatic breast cancer patients using a 324-gene panel assay (FoundationOne CDx) to identify all classes of genomic alterations, including base substitutions, insertions and deletions, rearrangement and copy number changes. Tissue samples were obtained by surgery or biopsy. Results:There was no sample with unstable microsatellite status both in primary and relapsed/metastatic breast cancer patients. The tumor mutational burden was higher in Relapsed/metastatic breast cancer than in primary breast cancer (2.91±0.29 for primary, 5.10±0.50 for relapsed/metastatic breast cancer, respectively, p&lt;0.001). There were 11 genes detected more than 10% incidence across all samples, including TP53(63.69%), PIK3CA(38.85%), ERBB2(22.29%), RAD21(17.20%), CCND1(15.29%), FGF3(14.01%), FGF19(14.01%), MYC(13.38%), NSD3(WHSC1L1)(11.36%), ZNF703(10.83%), among which RAD21, NSD3(WHSC1L1) were novel significantly mutated genes in Chinese breast cancer patients other than the previous genes identified in other ethnic groups and might be related to poor prognosis. The 10 top genes with greater difference mutational incidence between primary and relapsed/metastatic breast cancer were mostly identified in relapsed/metastatic group frequently (TP53, MYC, RAD21, PTEN, MLL2, CCND1, RB1), only 3 gene occurred more often in primary group (PIK3CA, FGFR1, MDM2). Relapsed/metastatic breast cancer patients were probably to get instruction in targeted therapies than primary group from CGP, the proportion of relapsed/metastatic breast cancer patients getting instruction in one or more targeted therapies was 94.74%, whereas the proportion of primary group was 76.98%(p=0.014). Conclusions:There was significant molecular heterogeneity between primary and relapsed/metastatic breast cancer in Chinese patients and between Chinese and other ethic group. Fig The mutational landscape of top 21 most frequently mutated genes (mutational incidence &gt;5%) in Chinese breast cancers (n=184). The upper histogram showed the total number of mutations in every patient. The bottom bars indicated the clinical characteristics, samples were grouped by primary breast cancers (n=141) and relapsed/metastatic breast cancers (n=43). Sidebar on the left summarized the mutational incidence of each gene and listed the separate frequencies of primary and R/M patients. Sidebar on the right classified different mutation types. Citation Format: Qiuting You, Jianli Zhao, Kai Chen, Yi Chen, Minhua Zeng, Biaolin Wen, Linxiaoxiao Ding, Fengxi Su. The genomic landscape of Chinese breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-40.