Zhong Ouyang

PURPOSE The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2–directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer. METHODS Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). RESULTS Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. CONCLUSION Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

Abstract Ursolic acid (UA) is a major pentacyclic triterpenoid in plants, vegetables and fruits, which has been reported to have a potential anti-diabetic activity. Despite various semi-synthetic ursolic acid derivatives already described, new derivatives still need to be designed and synthesized to further improve the anti-diabetic activity. In the present study, two series of novel UA derivatives, were synthesized and their structures were confirmed. The enzyme inhibition activities of semi-synthesized analogues against α-glucosidase were screened in vitro . The results indicated that most of UA derivatives showed a significant inhibitory activity, especially analogues UA-O-i with the IC 50 values of 0.71 ± 0.27 μM, which was more potential than other analogues and the positive control. Furthermore, molecular docking studies were also investigated to verify the in vitro study. Structure modification at the C-3 and C-2 positions of UA was an effective approach to obtain the desired ligand from UA, whose structure was in accordance with the active pocket. Besides, suitable hydrophobic group at the position of C-2 might play an important role for the docking selectivity and binding affinity between the ligand and the homology modelling protein. These results could be helpful for designing more potential α-glucosidase inhibitors from UA in the future.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC.

Importance: Preferred neoadjuvant strategies for early or locally advanced triple-negative breast cancer include a 4-drug chemotherapy regimen containing anthracyclines, cyclophosphamide, taxanes, and platinum. Blockade of the programmed death receptor 1/ligand-1 (PD-1/PD-L1) pathway may improve efficacy of classic neoadjuvant chemotherapy. Camrelizumab, an anti-PD-1 antibody, has showed antitumor activity in advanced triple-negative breast cancer. Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy for patients with early or locally advanced triple-negative breast cancer. Design, Setting, and Participants: This randomized, double-blind, phase 3 trial enrolled patients from 40 hospitals in China between November 25, 2020, and May 12, 2023 (data cutoff: September 30, 2023). A total of 441 eligible patients were enrolled. Interventions: Patients were randomized in a 1:1 ratio to receive either camrelizumab 200 mg (n = 222) or placebo (n = 219) combined with chemotherapy every 2 weeks. The chemotherapy included nab-paclitaxel (100 mg/m2) and carboplatin (area under the curve, 1.5) on days 1, 8, and 15 in 28-day cycles for the first 16 weeks followed by epirubicin (90 mg/m2) and cyclophosphamide (500 mg/m2) every 2 weeks for 8 weeks. Main Outcomes and Measures: The primary end point was pathological complete response (defined as no invasive tumor in breast and lymph nodes [ypT0/Tis ypN0]). Results: Among 441 females randomized (median age, 48 years), the median (range) follow-up duration from randomization was 14.4 (0.0-31.8) months. Pathological complete response was achieved in 126 patients (56.8% [95% CI, 50.0%-63.4%]) in the camrelizumab-chemotherapy group and 98 patients (44.7% [95% CI, 38.0%-51.6%]) in the placebo-chemotherapy group (rate difference, 12.2% [95% CI, 3.3%-21.2%]; 1-sided P = .004). In the neoadjuvant phase, adverse events of grade 3 or higher occurred in 198 patients (89.2%) in the camrelizumab-chemotherapy group and 182 (83.1%) in the placebo-chemotherapy group; serious adverse events occurred in 77 patients (34.7%) in the camrelizumab-chemotherapy group and 50 (22.8%) in the placebo-chemotherapy group, with fatal adverse events occurring in 2 patients (0.9%) in the camrelizumab-chemotherapy group. Conclusions and Relevance: Among patients with early or locally advanced triple-negative breast cancer, the addition of camrelizumab to neoadjuvant chemotherapy significantly improved pathological complete response. Trial Registration: ClinicalTrials.gov Identifier: NCT04613674.

Disassembly of intercellular junctions is a hallmark of epithelial-mesenchymal transition (EMT). However, how the junctions disassemble remains largely unknown. Here, we report that E3 ubiquitin ligase Smurf1 targets p120-catenin, a core component of adherens junction (AJ) complex, for monoubiquitination during transforming growth factor β (TGFβ)-induced EMT, thereby leading to AJ dissociation. Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. Inhibition of T900 phosphorylation or ubiquitination of p120-catenin abrogates TGFβ-induced AJ dissociation and consequent tight junction (TJ) dissociation and cytoskeleton rearrangement, hence markedly blocking lung metastasis of murine breast cancer. Moreover, the T900 phosphorylation level of p120-catenin is positively correlated with malignancy of human breast cancer. Hence, our study reveals the underlying mechanism by which TGFβ induces dissociation of AJs during EMT and provides a potential strategy to block tumor metastasis.