NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Comparison of the clinical performance of an HPV mRNA test and an HPV DNA test in triage of atypical squamous cells of undetermined significance (ASC-US).

OBJECTIVE: The effect of triaging women with atypical squamous cells of undetermined significance (ASC-US) with human papillomavirus (HPV) DNA testing has been well documented. New tests detecting HPV E6/E7 mRNA are emerging, claiming to be more specific for detecting high-grade disease. We evaluated the clinical performance of two HPV tests: the Linear Array HPV genotyping test (LA) detecting HPV DNA from 37 oncogenic and non-oncogenic HPV types and the Aptima HPV assay detecting E6/E7 mRNA from 14 oncogenic HPV types. METHODS: We identified 369 consecutive PreservCyt samples diagnosed with ASC-US tested for HPV DNA using the LA test. The Aptima HPV test was performed on residual material in the same vial. Follow-up of 325 women was available. The gold standard used was histologically confirmed cervical intraepithelial neoplasia (CIN) grade 2+ or 3+. RESULTS: LA and Aptima HPV assays were positive in 44.3% and 31.7% of the cases, respectively. The concordance was 81.2%. The two tests had identical sensitivity for detecting CIN3+ [92.6% (95% CI, 75.7-99.1)] but the Aptima HPV assay showed a significantly better specificity of 73.8% (95% CI, 68.5-78.7) versus 60.1% (95% CI, 54.3-65.7) for LA for detecting CIN3+. When using CIN2+ as the gold standard the sensitivity for LA was higher than for the Aptima HPV assay [93.8% (95% CI, 82.8-98.7) versus 87.5% (95% CI, 74.8-95.3)], but the specificity was higher for the Aptima HPV assay: 78.0% (95% CI, 72.6-82.7) versus 64.3% (95% CI, 58.3-69.9). CONCLUSIONS: Both tests showed good and equal clinical sensitivities for detecting CIN3+, but the Aptima HPV assay had significantly higher specificity for detecting CIN2+ and CIN3+ in women aged 30 years or older with ASC-US.

The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab.

OBJECTIVE: Bevacizumab, a humanized monoclonal antibody against VEGF (vascular endothelial growth factor), has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the efficacy of bevacizumab in patients with multiresistant ovarian cancer and, furthermore, to investigate the possible predictive value of serum VEGF, VEGFR1-2 and VEGF gene polymorphisms. METHODS: Patients received single-agent bevacizumab 10 mg/kg every 3 weeks. All patients were followed with CA 125 measurements and serum VEGF/VEGFR1-2 levels prior to each cycle. Endpoints were response rate (RR), progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-eight patients were included. All patients were heavily pre-treated with a median of five prior regimens. The median number of bevacizumab treatments was 4. Overall response rate was 30% according to CA 125 (GCIG criteria). Median PFS was 5.9 months (95% CI, 3.5-9.4) and median OS was 8.6 months (95% CI, 6.6-12.8). The VEGF serum level decreased during treatment in all patients. A low pre-treatment VEGF level was predictive to response. The median value was 540 pg/ml and divided the patients into two groups with a response rate of 60% and 0%, respectively (p=0.0007). The difference translated to a significant difference in PFS (p=0.047) and OS (p=0.01). VEGF gene polymorphisms -2578, -1154, -460, +405, +936 did not reveal any association with response or survival and the same applied to serum VEGFR1-2. CONCLUSIONS: Single agent bevacizumab has activity in ovarian cancer patients. Pre-treatment serum VEGF seems to have predictive value.

The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer.

OBJECTIVE: The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability of tumors. In the present study we evaluated the relation of five single nucleotide polymorphisms (SNPs) in the VEGF gene with progression-free survival. Furthermore, we evaluated the functional significance of the SNPs as determined by the influence on serum VEGF levels in ovarian cancer. METHODS: Serum from 143 consecutive ovarian cancer patients referred for first line platinum/paclitaxel treatment were analyzed for serum VEGF levels using commercially available enzyme-linked immunosorbent assay (ELISA). VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C and +936C/T) were determined by real time PCR using genomic DNA extracted from whole blood samples. RESULTS: VEGF serum levels were significantly higher in carriers of the 2578C, 460T and 405C, alleles compared to non-carriers (p=0.003, p=0.003 and p=0.001, respectively). There was no significant correlation between VEGF SNP genotypes and progression-free survival. In haplotype analysis, the multivariate survival analysis showed that progression-free survival (PFS) for the patients with the AGCGC haplotype was significantly improved compared to patients with other haplotypes (HR 1.9, p=0.036). CONCLUSIONS: VEGF polymorphisms were found to be significantly related with serum VEGF levels. The AGCGC haplotype was found to be independently associated with improved PFS.

Risk-reducing mastectomy and salpingo-oophorectomy in unaffected BRCA mutation carriers: uptake and timing.

Once female carriers of a BRCA mutation are identified they have to make decisions on risk management. The aim of this study is to outline the uptake of risk-reducing surgery in the Danish population of BRCA mutation positive women and to search for factors affecting this decision. We analysed data from 306 healthy BRCA carriers with no personal history of ovarian or breast cancer. We found a 10-year uptake of 75% for risk-reducing salpingo-oophorectomy and 50% for risk-reducing mastectomy by time to event analysis. Age and childbirth influenced this decision. The uptake rate has not changed significantly over the last decade. Risk-reducing surgeries are widely acceptable among Danish BRCA mutation positive women and the uptake of prophylactic mastectomy is higher than in most other countries.

Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer.

The response of tumor cells to platinum-based chemotherapy involves DNA repair mechanisms. Excision repair cross-complementation group 1 (ercc1) is one of the leading genes involved in DNA repair, and several studies have linked ercc1 to platinum resistance in cell lines and in human cancers. A common single nucleotide polymorphism (SNP) of ercc1 at codon 118 has been proposed to impair ercc1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum-based chemotherapy. The primary aim of the present study was to evaluate ERCC1 expression and ercc1 codon 118 polymorphism in epithelial ovarian cancer (EOC) and their possible predictive value in patients treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded tissue sections from 159 patients with advanced EOC were used for immunohistochemistry. Ercc1 codon 118 SNP genotyping was performed by real-time polymerase chain reaction. ERCC1 protein overexpression was found in 37.7% of the tumors. The CA-125 response rate was 94.5% (52/55) in patients with ERCC1-negative tumors compared to 80% (36/45) in patients with ERCC1-positive tumors (P = 0.026, chi(2)). The T/T genotype (44%) signalized a better response to chemotherapy than C/C (15%) + C/T (41%) variants (P = 0.045, trend test). Patients with ERCC1-negative tumors appear to have significantly better response to platinum-based chemotherapy compared to patients with ERCC1-positive tumors, but the differences in response rates did not translate into differences in survival. In addition, the TT genotype seems to be favorable toward better response to platinum-based chemotherapy.

The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer.

Both cyclooxygenase 2 (COX2) and human epidermal growth factor receptor 2 (HER2, also called c-erbB-2) overexpression have been related to a worse prognosis in epithelial ovarian cancer (EOC), but the data are conflicting and the percentage of tumors with overexpression varies widely in different studies. The aim of this study was to investigate the potential prognostic value of COX2 and HER2 expression in EOC. A further purpose was to investigate a possible coexpression of the two markers, and finally, to elucidate the agreement between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for evaluation of the HER2 status in EOC. Immunostaining was performed for COX2/HER2 together with FISH analysis for HER2 gene amplification in 160 patients with EOC, FIGO stages IIB-IV. Follow-up was more than 10 years. COX2 overexpression was found in 20.0% of the tumors. With HER2 staining, 64.4% were scored as 0, 24.4% as 1+, 6.9% as 2+, and 4.4% as 3+. Median survival time for COX2-negative tumors was 21.6 versus 36 months for COX2-positive tumors. The longer survival for COX2 positive was significant by both univariate analysis (P= 0.015) and multivariate analysis (P= 0.025). Positive immunostaining for HER2 was associated with poor overall survival (P= 0.03). Agreement between IHC and FISH was seen in all cases (P < 0.0000001). With long-term observation, patients with negative COX2 expression had significantly shorter survival compared to patients with COX2-positive tumors. Positive HER2 expression also notified a grave prognosis, but the low rate of overexpression reduces its potential clinical application.