The regulatory potential of long noncoding RNA (lncRNA) FBXL19-AS1 has been highlighted in various cancers, but its effect on triple-negative breast cancer (TNBC) remains unclear. Here, we aimed to elucidate the role of FBXL19-AS1 in TNBC and its underlying mechanism. RT-qPCR was employed to detect the expressions of FBXL19-AS1 and miR-378a-3p in tissues and cells. Immunohistochemical staining and western blot were utilized to detect the expression levels of proteins. Cell activities were detected using flow cytometry, CCK-8, and transwell assay. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were deployed to investigate interactions of different molecules. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathways were used to analyze the downstream pathway. In vivo xenograft model was conducted to detect the effect of FBXL19-AS1 on tumor growth. FBXL19-AS1 was overexpressed in TNBC tissues and cell lines compared with counterparts. FBXL19-AS1 knockdown suppressed TNBC cell activities, whereas its overexpression exhibited the opposite effect. Mechanistically, FBXL19-AS1 was found to interact with miR-378a-3p. Further analysis revealed that miR-378a-3p exerted tumor-suppressive effects in TNBC cells. Additionally, miR-378a-3p targeted and downregulated the expression of ubiquitin aldehyde binding 2 (OTUB2), a deubiquitinase associated with TNBC progression. In vivo experiments substantiated the inhibitory effects of FBXL19-AS1 knockdown on TNBC tumorigenesis, and a miR-378a-3p inhibitor partially rescued these effects. The downstream pathway of the miR-378a-3p/OTUB2 axis was explored, revealing connections with proteins involved in modifying other proteins, removing ubiquitin molecules, and influencing signaling pathways, including the Hippo signaling pathway. Western blot analysis confirmed changes in YAP and TAZ expression levels, indicating a potential regulatory network. In summary, FBXL19-AS1 promotes exacerbation in TNBC by suppressing miR-378a-3p, leading to increased OTUB2 expression. The downstream mechanism may be related to the Hippo signaling pathway. These findings propose potential therapeutic targets for TNBC treatment.

BackgroundThe accurate evaluation of surgical margins holds crucial importance in determining the success of breast-conserving surgery (BCS). The aim of this study was to introduce a novel technique for the positioning of surgical margins in BCS while highlighting its advantages.MethodsThis study included a cohort of breast cancer patients who underwent BCS. The patients were categorized into two groups: one group underwent BCS with the traditional palpation-guided method, and the other with the 3D-MPT technique. The study assessed and compared the feasibility, advantages, and outcomes in terms of quality of life between the two groups.ResultsA total of 80 patients were successfully enrolled in the study. No significant differences in clinicopathological features were observed between the two groups. The 3D-MPT technique was found to be feasible and offered several advantages over the palpation-guided method. The utilization of guide wires by experienced radiologists to position the margins before surgery enabled precise and swift specimen removal, resulting in the conservation of valuable time and a reduction in the need for re-excision. Furthermore, the 3D-MPT technique exhibited the potential to enhance cosmetic outcomes and elevate patient satisfaction, particularly in cases with uncertain tumor boundaries detectable by palpation.ConclusionThe 3D-MPT technique proves to be an effective and safe approach for reducing tumor positivity rates in initial surgical margins, thereby improving the quality of life for patients undergoing breast-conserving surgery in comparison to the conventional method.

Trastuzumab (H) plus Pertuzumab (P) combined with cytotoxic agents has been the SOC for Her2+BC across perioperative to late stage. Even with high efficacy, optimized treatment strategy still needs to be explored. KN026 is a bispecific monoclonal antibody that targets domain II and IV of HER2. KN026 showed comparable or better efficacy with H+P in preclinical study. The superior efficacy had also been validated in a series of clinical trials in late line Her2+ solid tumors as well as the first-line Her2+ breast cancer and gastric cancer. Here we report the results of KN026 plus docetaxel as neoadjuvant treatment in HER2+ BC pts. Treatment naive pts with HER2+ early or LABC were enrolled to receive 4 cycles of KN026 (30mg/kg, ivgtt d1, q3w) and docetaxel (75 mg/m2, ivgtt d1, q3w) as neoadjuvant treatment. The primary endpoint was tpCR rate. Secondary endpoints were bpCR, ORR, safety, etc. This study is registered in ClinicalTrials.gov, number NCT04881929. From August 9th, 2021, to July 29th, 2022, a total of 30 pts were enrolled from 5 sites. 16 pts (53.3%) were stage II, and 14 pts (46.7%) were stage III; 26 (86.7%) pts with biopsy-confirmed lymph node metastases; 15 (50.0%) pts were hormone receptor positive. As of Nov 21st, 2022, the study completed the primary outcome. 28 pts completed the surgery followed by pathological evaluation, and 2 pts discontinued from the study earlier due to AEs. In FAS, tpCR rate was 56.7% (17/30, 95% CI: 37.43%-74.53%), bpCR rate was 60% (18/30, 95% CI:40.60%-77.34%), ORR was 90.0% (27/30, 95% CI: 73.47%-97.89%). The incidence of TEAEs and CTCAE Grade ≥3 TEAEs were 100% (30/30) and 53.3% (16/30), respectively. The most common (≥5%）Grade ≥3 TEAEs were neutrophil count decreased (50%, 15/30), white blood cell count decreased (40.0%, 12/30), and lymphocyte count decreased (10%, 3/30). 7 (23.3%）pts required docetaxel dose reduction due to AEs. KN026 and docetaxel related SAEs occurred in only one patient. No Grade 5 TEAEs occurred. KN026 plus docetaxel as neoadjuvant treatment has shown promising clinical benefit and acceptable safety for pts with HER2+ early or LABC. Further validation in a large-scale randomized controlled trial is warranted.

Background: Despite the use of targeted therapy has revolutionized the treatment in the neoadjuvant setting for early, locally advanced, HER2-positive breast cancer, these approaches still have limited efficacy, which calls for persistent exploration for optimized treatment strategy. KN026 is a bispecific monoclonal antibody that targets the distinct extra-cellular domains II (Pertuzumab binding site) and IV (Trastuzumab binding site) of HER2. KN026 has better anti-tumor activity than either Trastuzumab or Pertuzumab used alone, and also aimed to demonstrate similar or better anti-tumor response than Trastuzumab in combination with Pertuzumab. Here we report the preliminary results of KN026 and docetaxel as neoadjuvant treatment in patients with HER2-positive early or locally advanced breast cancer (LABC). Methods: Treatment naive patients with HER2-positive early (T1c or 2, N1, M0; T2 or 3, N0, M0) or locally advanced breast cancer (T1c or 2 or 3, N2, M0; T3N1M0; T1c or 2 or 3, N3a or 3b, M0) were enrolled to receive 4 cycles of KN026 (30mg/kg, ivgtt d1, q3w) and docetaxel (75 mg/m2 ivgtt d1, q3w) neoadjuvant treatment. The primary endpoint was total pCR rate (tpCR; defined as absence of any residual invasive cancer in the breast and lymph nodes) [ypT0/is, ypN0]). Secondary endpoints were pCR in the breast (bpCR, defined as absence of any residual invasive cancer in the breast [ypT0/is]), ORR (objective response rate), safety, PK (pharmacokinetics) and immunogenicity. The study is still ongoing, and the planned enrollment number is 30. This study is registered in ClinicalTrials.gov, number NCT04881929. The data cutoff date was April 15, 2022. Results: Between August 8, 2021, and April 15, 2022, a total of 15 patients were enrolled from 5 sites. 7 (46.7%) patients were stage II, and 8 (53.3%) patients were stage III; 12 (80%) patients with lymph node metastases, and 3 (20%) patients without lymph node metastases; 7 (46.7%) patients were hormone receptor positive, and 8 (53.3%) patients were hormone receptor negative. As of April 15, 2022, 4 patients are still under neoadjuvant therapy, 1 patient withdrew from the study earlier due to AE during neoadjuvant treatment period, and 10 patients completed the surgery. Of the 10 patients who completed surgery, tpCR rate were 50% (5/10, 95% CI: 18.7%-81.3%), bpCR rate were 50% (5/10, 95% CI:18.7%-81.3%), and ORR were 100% (10/10, 95% CI: 69.2%-100%). The incidence of TRAE and Grade ≥3 TRAEs were 100% (15/15) and 53.3% (8/15) respectively. The most common TRAE were alopecia (14/15, 93.3%), white blood cell decreased (10/15, 66.7%), anemia (10/15, 66.7%), diarrhea (9/15, 60.0%), neutrophil count decreased (9/15, 60.0%), alanine aminotransferase increased (8/15, 53.3%) and hypoalbuminemia (8/15, 53.3%). The Grade ≥3 TRAE include neutrophil count decreased (8/15, 53.3%), white blood cell decreased (5/15, 33.3%), alanine aminotransferase increased (1/15, 6.7%), and lymphocyte count decreased (1/15, 6.7%). No Grade 5 TRAEs occurred. 3 TRAEs (Alanine aminotransferase increased, blood bilirubin increased and neutrophil count decreased) leading to KN026 interruption, and no TRAE leading to KN026 discontinuation. 1 SAE (hepatitis E-not TRAE; outcome: recovered) occurred in 1 patient, without other SAE or death throughout the study. Conclusions: KN026 and docetaxel as neoadjuvant treatment has shown promising clinical benefit for patients with HER2-positive early or locally advanced breast cancer with an acceptable and manageable safety profile. Further validation in a large-scale randomized controlled trial is warranted. Citation Format: Jiong Wu, Benlong Yang, Linxiaoxi Ma, Mingliang Zhang, Kun Wang, Yiding Chen, Zhimin Fan, Jing Zhang, Summer Xia. KN026 in combination with docetaxel as neoadjuvant treatment for HER2-positive early or locally advanced breast cancer: A single arm, multicenter, phase 2 study [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 OT2-16-04.

Purpose To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib’s treatment response and outcome were also explored. Results A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.

Long noncoding RNA (LncRNA) dysregulation has been shown to exhibit a regulatory effect in various cancers. However, the effect of LINC01287 on breast cancer (BC) has not been illustrated. The aim of this research was to explore the expression and function of LncRNA LINC01287 in BC. LINC01287 expression in clinical tissues and BC cell lines was detected. The luciferase reporter assay was performed to verify the correlation between LINC01287, microRNA 98 (miR-98), and the insulin-like growth factor 1 receptor (IGF1R). The CCK-8 assay was performed to examine cell viability. Cell invasion and migration capacity was determined by transwell and wound healing assays. The protein level of IGF1R, phosphorylated mitogen-activated protein kinase 1 and 2 (p-MEK1/2), and phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) was analyzed by western blotting. LINC01287 expression markedly increased in BC cell lines. Subsequent studies identified LINC01287 as a downstream target of miR-98. In addition, LINC01287 knockdown and miR-98 overexpression significantly stagnated progression of BC cells. LINC01287 knockdown also downregulated IGF1R levels. Moreover, LINC01287 knockdown notably downregulated the phosphorylation of MEK1/2 and ERK1/2. The in vivo assay verified that LINC01287 can regulate tumorigenesis of BC. Our findings showed that LINC01287 was overexpressed in BC cells and tissues. LINC01287 promoted the malignant characteristics of BC cells and acted as an oncogene. Its regulatory effect may be associated with the miR-98/IGF1R/MEK/ERK signaling pathway. Therefore, LINC01287 has potential for use as a biomarker or therapeutic target for the treatment of BC.

BACKGROUND:Lymph or chyle leak (LL/CL) is severe complications after lateral cervical lymph node dissection (LLND), mainly due to iatrogenic injury of the lymphatic duct. Efficient and well-operated methods to reduce postoperative drainage are still lacking. This was a feasibility study to evaluate a new method of preventing LL/CL compared to conventional treatment. METHOD:We retrospectively analyzed 20 consecutive patients who used the "pedicled omohyoid flap covering (POFC)" method during LLND from January 2019 to December 2021 in our center as an observation group. Another 20 consecutive patients used the conventional method during LLND in this period as a control group. The clinical and pathological features of the two groups were compared, and the related factors that affected postoperative lymphatic drainage were analyzed with Cox proportional hazards models. RESULTS:The drainage volume per 24 h and the incidence of LL/CL in the control group were both higher than that in the observation group (all P < 0.05), and the number of lymph nodes dissected in the IV region > 10 and the use of the POFC method were the independent risk factors that significantly affected the incidence of LL/CL post LLND (all P < 0.05). CONCLUSIONS:POFC is a safe and useful method for reducing drainage and preventing LL/CL post-LLND, especially for patients with heavy metastasis of the lymph nodes in the IV region.

Background and Aim: IGF1R and HER2 are both members of the growth factor receptor family which is known to play a different role in breast cancer. However, correlation between IGF1R and HER2 has created a controversial situation that need to be fully delineated in development of Herceptin resistance. The aim of this study was to investigate the mechanism of Herceptin resistance through the IGF1R pathway in HER2 positive breast cancer. Materials and Methods: Clinical data were obtained from TCGA database and archived documents from The First Affiliated Hospital of Bengbu Medical College. Western blot and immunohistochemistry were used to detect proteins and their phosphorylation. Cell transfection were constructed using shRNA lentivirus vectors. RNAs were analyzed by RT-qPCR. Proteins in serum were analyzed by ELISA assay. Cell proliferation was analyzed by MTS method. Luciferase report experiment was conducted to verify RNA’s inter-reaction. Results: Western blot showed IGF2 protein was significantly increased in Herceptin resistant SKBR3-R cells (P<0.01), and IGF1R/HER2 heterodimer level was significantly increased (P<0.01). Luciferase reporter assay verified miR-98-5p could bind to 3 ‘UTR of IGF2 mRNA. When miR-98-5p was upregulated, the expression level of IGF2 was decreased(P<0.01), the cell invasive ability was reduced(P<0.01), and ultimately, Herceptin resistant cells regained their sensitivity to Herceptin. In clinical research, we found that decreased miR-98-5p level or increased IGF2 level significantly associated with poor treatment response and poor overall survival (OS), poor recurrence free survival (RFS) and poor distant metastasis-free survival (DMFS) in HER2-positive breast cancer. Conclusion: MiR-98-5p and IGF2 might potential candidates for predicting Herceptin sensitivity and provides a new way to overcome Herceptin resistance in clinic.

Treatment of breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) has undergone a prosperous development with the advent of emerging small molecule tyrosine kinase inhibitors (TKIs). However, their efficacy in brain metastases (BMs) requires further investigation in both clinical trials and practice by specifically targeting this population. We herein reported a HER2-positive metastatic bilateral BC case with symptomatic diffusion of parenchymal BM after first-line treatment with trastuzumab-based regimen. She then received pyrotinib (with a disease-free survival of 5.7 months) followed by whole brain radiotherapy. Unexpectedly, under satisfactory control of intracranial parenchymal lesions, the patient based on clinical manifestations, auxiliary examinations and exclusive diagnosis was diagnosed with meningeal progression, and soon died of tumor progression. Thus, pyrotinib response differed from meningeal to parenchymal BM in BC patients, and the need of comprehensive and systematic evaluation of TKIs in some particular clinical scenarios has become a critical issue.

OBJECTIVE:The aim of this retrospectively study was to assess the clinical efficacy and toxicity of Herceptin as a single agent in the treatment of patients with metastatic breast cancer (MBC). METHODS:We retrospectively included and analyzed 31 metastasis breast cancer patients in our patient database. All of the included 31 patients were pathology confirmed of breast carcinoma with remote metastases and treated with Herceptin as a single agent. The clinical efficacy and drug-related toxicity were analyzed. RESULTS:No complete response patients were observed for 31 cases. And 8 (26%) reached partial response 16 (52%) with stable disease. The objective response rate of the 31 patients was 23%. We further divided the 31 cases into three subgroups according to the treatment modality. The objective response rate was 36%, 14%, and 17% for the first-line, second-line, and third-line treatment modality, respectively. The objective response rate was not statistical different among the three subgroups (P > 0.05). The main drug-related adverse event were asthenia, chills, diarrhea, nausea, hypotension and dizziness with their incidence of 68%, 26%, 13%, 10%, 10%, and 6%, respectively, for each patients. CONCLUSION:Herceptin as a single agent was effective and safe in the treatment of patients with MBC.