Ovarian tumors comprise a heterogeneous group of lesions, displaying distinct tumor pathology and oncogenic potentiel. These tumors are subdivided into three main categories: epithelial, germ cell, and sex-cord stromal tumors. We report herein the newly described molecular abnormalities in epithelial ovarian cancers (carcinomas). Immunohistochemistry and molecular testing help pathologists to decipher the significant heterogeneity of this disease. Our better understanding of the molecular basis of ovarian carcinomas represents the first step in the development of targeted therapies in the near future.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease.

Purpose: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. Experimental Design: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction. See related commentary by Garg and Oza, p. 2957

Globally, cervical cancers continue to be one of the leading causes of cancer-related deaths. The primary treatment of patients with early-stage disease includes surgery or radiation therapy with or without chemotherapy. The main challenge in treating these patients is to maintain a curative approach and limit treatment-related morbidity. Traditionally, inoperable patients are treated with radiation therapy solely and operable patients undergo upfront surgery followed by adjuvant (chemo) radiotherapy in cases with poor histopathological prognostic features. Patients with locally advanced cervical cancers are treated with concurrent chemoradiotherapy followed by an image-guided brachytherapy boost. In these patients, the main pattern of failure is distant relapse, encouraging intensification of systemic treatments to improve disease control. Ongoing trials are evaluating immunotherapy in locally advanced tumours following its encouraging efficacy reported in the recurrent and metastatic settings. In this article, clinical evidence of neoadjuvant and adjuvant treatments in cervical cancer patients is reviewed, with a focus on potential strategies to improve patients’ outcome and minimize treatment-related morbidity.

Purpose: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. Experimental Design: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). Results: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33–0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31–0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74–1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07–0.72). Conclusions: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.

Background: The causal link between elevated systemic inflammation biomarkers and poor survival has been demonstrated in cancer patients. However, the evidence for this correlation in endometrial cancer (EC) is too weak to influence current criteria of risk assessment. Here, we examined the role of inflammatory indicators as a tool to identify EC patients at higher risk of death in a retrospective observational study. Methods: A total of 155 patients surgically diagnosed with EC stage I-III FIGO 2009 and treated with postoperative External Beam Radiotherapy (EBRT) ± brachytherapy and chemotherapy according to ESMO-ESTRO-ESGO recommendation for patients at high risk of recurrence at the Gustave Roussy Institut, France, and Hospital Clínic, Spain, between 2008 and 2017 were evaluated. The impact of pre-treatment Neutrophil-to-Lymphocyte Ratio (NLR ≥ 2.2), Monocyte-to-Lymphocyte Ratio (MLR ≥ 0.18), Systemic Immune-Inflammatory Index (SII ≥ 1100) and lymphopenia (<1.0×10⁹/L) on overall survival (OS), cancer-specific survival and progression-free survival was evaluated. Subsequently, a cohort of 142 patients within high-advanced risk groups according to ESMO-ESGO-ESTRO classification was evaluated. Results: On univariate analysis, NLR (HR = 2.2, IC 95% 1.1–4.7), SII (HR = 2.2, IC 95% 1.1–4.6), MLR (HR = 5.0, IC 95% 1.1–20.8) and lymphopenia (HR = 3.8, IC 95% 1.6–9.0) were associated with decreased OS. On multivariate analysis, NLR, MLR, SII and lymphopenia proved to be independent unfavorable prognostic factors. Conclusions: lymphopenia and lymphocytes-related ratio are associated with poorer outcome in surgically staged I-III FIGO EC patients classified as high risk and treated with adjuvant EBRT and could be considered at cancer diagnosis. External validation in an independent cohort is required before implementation for patients’ stratification.