Keren Levanon

De-escalating first-line treatment in stage IVB or recurrent cervical cancer: outcomes of immunotherapy alone and systemic review

Abstract Introduction Chemo-immunotherapy (IO) is the preferred first-line treatment for stage IVB or recurrent cervical cancer. However, limited data exist on the efficacy and safety of using IO-alone as a de-escalation strategy. We report outcomes from a case series of selected patients treated with IO-alone and review the feasibility of de-escalating first-line treatment. Methods The authors conducted a literature review using Google Scholar and PubMed to identify reports using IO-alone as a de-escalation strategy across malignancies published between 1999 and December 2024 and also reviewed a cervical cancer database from a tertiary academic to identify patients with stage IVB or recurrent disease treated with IO-alone. The authors used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS). Results Among 582 patients treated between 2015 and 2021, 18 met the inclusion criteria. The median age was 43 years (range 28-84); 67% had squamous cell carcinoma, 11% adenocarcinoma, and 80% expressed PD-L1. CPS scores were <1 in 20%, 1--10 in 33%, and >10 in 47%. Most patients had oligo-metastatic disease (83%). Treatment with IO-alone began a median of 7 months after platinum-based chemotherapy. Indications included prior adjuvant (44%) or neoadjuvant (22%) chemotherapy, clinical trial participation (11%), or patient preference (22%). Median PFS and OS were 27 months and 82 months, respectively. Conclusions These findings support the need for clinical trials evaluating IO-alone as a first-line treatment option for de-escalation in stage IVB or recurrent cervical cancer. Biomarker development is needed to better identify candidates for personalized therapy.

NF-κB-miR-155 axis activation mediates ovulation-induced oncogenic effects in fallopian tube epithelium

Abstract The fallopian tube secretory epithelial cells (FTSECs) are the cell-of-origin of most high-grade serous ovarian carcinomas (HGSOC). FTSECs are repeatedly exposed to inflammation induced by follicular fluid (FF) that is released with every ovulation cycle throughout a woman’s reproductive years. Uninterrupted ovulation cycles are an established risk factor for HGSOC. Stimuli present in the FF induce an inflammatory environment which may cause DNA damage eventually leading to serous tumorigenesis. With the aim of elucidating possible mechanistic pathways, we established an ‘ex vivo persistent ovulation model’ mimicking the repeated exposure of human benign fallopian tube epithelium (FTE) to FF. We performed mass spectrometry analysis of the secretome of the ex vivo cultures as well as confirmatory targeted expressional and functional analyses. We demonstrated activation of the NF-κB pathway and upregulation of miR-155 following short-term exposure of FTE to human FF. Increased expression of miR-155 was also detected in primary HGSOC tumors compared with benign primary human FTE and corresponded with changes in the expression of miR-155 target genes. The phenotype of miR-155 overexpression in FTSEC cell line is of increased migratory and altered adhesion capacities. Overall, activation of the NF-κB-miR-155 axis in FTE may represent a possible link between ovulation-induced inflammation, DNA damage, and transcriptional changes that may eventually lead to serious carcinogenesis.

Proteomic signature for detection of high‐grade ovarian cancer in germline BRCA mutation carriers

AbstractNo current screening methods for high‐grade ovarian cancer (HGOC) guarantee effective early detection for high‐risk women such as germline BRCA mutation carriers. Therefore, the standard‐of‐care remains risk‐reducing salpingo‐oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high‐risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7‐protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high‐risk for HGOC and the application of the BRCA‐specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average‐risk population is warranted.

Biomarkers for Early Detection of Ovarian Cancer Using Uterine Lavage

Screening programs for high-grade ovarian carcinoma failed to reduce disease-specific mortality, since they do not offer early enough detection of the disease. Most cases of high grade ovarian cancer develop in the fallopian tubes, hence the universal recommendation for high-risk populations (e.g., BRCA1/2 mutation carriers) is to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) around the age of 40. The aims of this trial are: (1) to identify novel early-stage disease biomarkers using liquid biopsies obtained through uterine lavage, and (2) to optimize the technique a of uterine lavage and the processing of the samples for ultimate implementation as a routine diagnostic test for high risk populations.