Rui Gou

Sensitivity of Platinum‐Based Chemotherapy and Efficacy of Arsenic Trioxide‐Based Non‐Platinum Chemotherapy Following the Progression of PARPi Maintenance Therapy: A Real‐World Study

ABSTRACT Background Cross‐resistance is observed between platinum and Poly (ADP‐ribose) polymerase inhibitors (PARPi). We aim to propose the definition of PARPi resistance and demonstrate the best therapeutic strategy for patients with PARPi resistance. Methods A retrospective analysis was performed on patients diagnosed with epithelial ovarian cancer from October 2015 to November 2022. Patients were treated with PARPi for more than 6 months and received chemotherapy after progression. Results Totally, 41 patients were enrolled, with 21 receiving PARPi for 6 to 12 months and 20 for more than 12 months. The median duration of PARPi was 12 months, and the median time to second progression (TTSP) was 3.45 months (range, 1.0–20.2 months). The Kaplan–Meier and Cox analysis revealed a significantly shorter TTSP for patients who received PARPi for more than 12 months compared to those for 6 to 12 months. After PARPi resistance, 34 (82.9%) received platinum‐based chemotherapy, with an overall response rate (ORR) of 26.5% (9/34). Seven patients (17.1%) received arsenic trioxide (ATO)‐based chemotherapy, with an ORR of 57.1% (4/7). During subsequent chemotherapy, 12/34 patients switched to ATO‐based chemotherapy due to progression, of which five cases were evaluated as effective (41.7%). Conclusion PARPi resistance has a negative impact on the subsequent chemotherapy. The progression of the disease beyond 6 to 12 months should be considered as acquired resistance. Non‐platinum chemotherapy, such as ATO‐based combined sequential chemotherapy, may emerge as the preferred option for patients with PARPi resistance.

Identification of immune‐enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma

Abstract Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune‐related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour‐infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.

Exosomal ANXA2 derived from ovarian cancer cells regulates epithelial‐mesenchymal plasticity of human peritoneal mesothelial cells

AbstractOvarian cancer, one of the malignant gynaecological tumours with the highest mortality rate among female reproductive system, is prone to metastasis, recurrence and chemotherapy resistance, causing a poor prognosis. Exosomes can regulate the epithelial‐mesenchymal plasticity of tumour cells, remodel surrounding tumour microenvironment, and affect tumour cell proliferation, invasion and metastasis. However, the function and mechanism of exosomes in the intraperitoneal implantation of ovarian cancer remain unclear. In this study, exosomal annexin A2 (ANXA2) derived from ovarian cancer cells was co‐cultured with human peritoneal mesothelial (HMrSV5) cells; functional experiments were conducted to explore the effects of exosomal ANXA2 on the biological behaviour of HMrSV5 and the related mechanisms. This study showed that ANXA2 in ovarian cancer cells can be transferred to HMrSV5 cells through exosomes, exosomal ANXA2 can not only promote the migration, invasion and apoptosis of HMrSV5 cells, but also regulates morphological changes and fibrosis of HMrSV5 cells. Furthermore, ANXA2 promotes the mesothelial‐mesenchymal transition (MMT) and degradation of the extracellular matrix of HMrSV5 cells through PI3K/AKT/mTOR pathway, finally affects pre‐metastasis microenvironment of ovarian cancer, which provides a new theoretical basis for the mechanism of intraperitoneal implantation and metastasis of ovarian cancer.