M. Lopez-Yurda

Neo-adjuvant pembrolizumab in stage IV high-grade serous ovarian cancer: the phase II Neo-Pembro trial

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC patients, who were scheduled for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation using multiplexed immunofluorescence and immune-related gene expression. Our findings show immune activation, evidenced by an increase in CD3 + , CD8 + , CD8 + /FOXP3+ ratio, TNF-α and interferon-γ signaling. Treatment was well-tolerated. We observed major pathologic responses in 9/33 patients (27%, 95%CI 14-46), with pathologic response strongly associated with immune activation and OS. At a median follow-up of 52.8 months, 8/9 major responders were alive, with 6 patients recurrence-free. In contrast, 4/24 minor responders survived, including one recurrence-free. ctDNA clearance was observed in all major responders and was associated with prolonged PFS and OS. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as biomarkers, warranting further exploration. These results suggest major responders may benefit from neo-adjuvant pembro.

Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1)

Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial. Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models. While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence. Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation. NCT00426257.

MRI in advanced ovarian cancer: multicentre MISSION trial.

For patients with advanced ovarian cancer, complete cytoreductive surgery (CRS) offers the best chance for long-term survival and cure. Currently, staging relies on CT and, in selected cases, diagnostic laparoscopy, both of which have important limitations. This study assessed the diagnostic performance of MRI for predicting complete interval CRS. This prospective multicentre cohort study included FIGO stage III-IV ovarian cancer patients scheduled for interval CRS. Radiologists, blinded to surgical findings, independently scored the MRI-derived Peritoneal Cancer Index (mriPCI). Gynaecologic oncologists recorded the surgical PCI (sPCI) before and after intraoperative disclosure of MRI findings (revised-sPCI). The primary endpoint was the ability of mriPCI to predict complete interval CRS (no macroscopic residual disease). Secondary endpoints included concordance between mriPCI and sPCI, diagnostic yield from MRI disclosure, and inter-reader agreement. Sample size calculations indicated that 189 patients undergoing interval CRS should be included. Between 2018 and 2023, 270 patients were recruited, of whom 194 were eligible for analysis. Complete interval CRS was achieved in 149/194 patients (77%). The diagnostic performance of mriPCI showed an AUC of 0.76 for predicting a complete CRS. The revised-SPCI, after intraoperative disclosure of MRI led to an AUC of 0.88. MRI findings led to a change in sPCI in 19% of patients. Interobserver reliability for mriPCI was substantial (Interclass correlation coefficient 0.81, 95% CI 0.67-0.88). MRI enables accurate, non-invasive prediction of complete interval CRS feasibility in advanced ovarian cancer. Integration of MRI into surgical planning enhances intraoperative detection of lesions and can facilitate decision-making, supporting its role as a non-invasive staging tool. NCT03399344.