Oncoinvent (Norway)

Abstract BackgroundThe ADNEX model (Assessment of Different NEoplasias in the adnexa) is the best performing model to predict the risk of malignancy (binary) and type of malignancy (multiclass) in ovarian tumors. The immune system plays a role in the onset and progression of ovarian cancer. Preliminary research has suggested that immune-related biomarkers can help in the discrimination of ovarian tumors. We aimed to assess which proteins have the most additional diagnostic value in addition to ADNEX’ clinical and ultrasound predictors.Materials and methodsIn this exploratory diagnostic study, 1086 patients with an adnexal mass scheduled for surgery were consecutively enrolled at five oncology centers and one non- oncology center in Belgium, Italy, Czech Republic and United Kingdom between 2015 and 2019. The quantification of 33 serum proteins was carried out preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). Logistic regression analysis was performed for ADNEX’ clinical and ultrasound predictors alone (age, maximum diameter of lesion, proportion of solid tissue, presence of >10 cyst locules, number of papillary projections, acoustic shadows and ascites) and after adding proteins. We reported the AUC for benign vs malignant, Polytomous Discrimination Index (PDI; a multiclass AUC) and pairwise AUCs for pairs of tumor types. AUCs were corrected for optimism using bootstrapping.ResultsAfter applying exclusion criteria, 932/1086 patients were eligible for analysis (474 benign, 135 borderline, 84 stage I primary invasive cancer, 208 stage II-IV primary invasive cancer, 31 secondary metastatic invasive tumors). ADNEX predictors alone had an AUC of 0.909 (95% CI 0.894-0.929) to discriminate benign from malignant tumors, and a PDI of 0.532 (0.510-0.589). HE4 yielded the highest increase in AUC (+0.026), followed by CA125 (+0.017). CA125 yielded the highest increase in PDI (+0.049), followed by HE4 (+0.036). Whereas CA125 mainly improved pairwise AUCs between different types of invasive tumors (increases between 0.020-0.165 over ADNEX alone), HE4 mainly improved pairwise AUCs for benign tumors versus stage I (+0.022) and benign tumors versus stage II-IV ovarian cancers (+0.028). CA72.4 might be useful to distinguishing secondary metastatic tumors from benign, borderline, and stage I tumors. CA15.3 might be useful to discriminate borderline tumors from stage I and stage II-IV tumors. Distinguishing stage I and borderline tumors (AUCs ≤ 0.72) and stage I and secondary metastatic tumors (AUCs ≤ 0.76) remained difficult after adding proteins.ConclusionsCA125 had the highest added value over clinical and ultrasound predictors to distinguish between the five tumor types, followed by HE4. In addition, CA72.4 and CA15.3 may further improve discrimination but findings for these proteins should be confirmed. The immune-related proteins were in general not able to discriminate the groups.

A novel alpha-therapy consisting of 224Ra-labeled calcium carbonate microparticles (224Ra-CaCO3-MP) has been designed to treat micrometastatic peritoneal disease via intraperitoneal (IP) administration. This preclinical study aimed to evaluate its efficacy and tolerability when given as a single treatment or in combination with standard of care chemotherapy regimens, in a syngeneic model of ovarian cancer in immune competent mice. Female C57BL/6 mice bearing ID8-fLuc ovarian cancer were treated with 224Ra-CaCO3-MP 1 day after IP tumor cell inoculation. The activity dosages of 224Ra ranged from 14 to 39 kBq/mouse. Additionally, 224Ra-CaCO3-MP treatment was followed by either carboplatin (80 mg/kg)-pegylated liposomal doxorubicin (PLD, 1.6 mg/kg) or carboplatin (60 mg/kg)-paclitaxel (10 mg/kg) on day 14 post tumor cell inoculation. All treatments were administered via IP injections. Readouts included survival, clinical signs, and body weight development over time. There was a slight therapeutic benefit after single treatment with 224Ra-CaCO3-MP compared to the vehicle control, with median survival ratios (MSRs) ranging between 1.1 and 1.3. The sequential administration of 224Ra-CaCO3-MP with either carboplatin-paclitaxel or carboplatin-PLD indicated a synergistic effect on overall survival at certain 224Ra activities. Moreover, the combinations tested appeared well tolerated in terms of weight assessment in the first 4 weeks after treatment. Overall, this research supports the further evaluation of 224Ra-CaCO3-MP in patients with ovarian cancer. However, the most optimal chemotherapy regimen to combine with 224Ra-CaCO3-MP should be identified to fully exploit its therapeutic potential.