Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. The main challenge in EC management is to correctly estimate the risk of metastases at diagnosis and the risk to develop recurrences in the future. Risk stratification determines the need for surgical staging and adjuvant treatment. Detection of occult, microscopic metastases upstages patients, provides important prognostic information and guides adjuvant treatment. The molecular classification subdivides EC into four prognostic subgroups: POLE ultramutated; mismatch repair deficient (MMRd); nonspecific molecular profile (NSMP); and TP53 mutated (p53abn). How surgical staging should be adjusted based on preoperative molecular profiling is currently unknown. Moreover, little is known whether and how other known prognostic biomarkers affect prognosis prediction independent of or in addition to these molecular subgroups. This review summarizes the factors incorporated in surgical staging (i.e., peritoneal washing, lymph node dissection, omentectomy and peritoneal biopsies), and its impact on prognosis and adjuvant treatment decisions in an era of molecular classification of EC. Moreover, the relation between FIGO stage and molecular classification is evaluated including the current gaps in knowledge and future perspectives.

PIK3CA belongs to the phosphatidylinositol 3‐kinases (PI3Ks) family, which play an important role in proliferation, adherence, transformation and cell survival through the PI3K/AKT signaling pathway. Somatic activating mutations of this gene have recently been detected in several types of cancers. In the present study, 109 advanced ovarian carcinomas were analyzed for PIK3CA mutations in exon 9 and exon 20 by direct sequencing. Activating missense mutations were observed in 4 of the 109 tumors in addition to one variant leading no change of the PIK3CA protein. Two of the cases with mutations were mucinous and clear cell tumors, suggesting that PIK3CA mutations are more common in these rare histological types.

In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage I-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed. The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored.

Tumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences but are not easily assessable in patients. Here we present a method based on diagnostic dynamic contrast enhanced (DCE) MRI that reflects a continuous range of hypoxia levels in patients with tumors of cervical cancer. Hypoxia images were generated using an established approach based on pixel-wise combination of DCE-MRI parameters νe and Ktrans, representing oxygen consumption and supply, respectively. Using two tumor models, an algorithm to retrieve surrogate measures of hypoxia levels from the images was developed and validated by comparing the MRI-defined levels with hypoxia levels reflected in pimonidazole-stained histologic sections. An additional indicator of hypoxia levels in patient tumors was established on the basis of expression of nine hypoxia-responsive genes; a strong correlation was found between these indicator values and MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2–M checkpoint were associated with moderate hypoxia, epithelial-to-mesenchymal transition, and inflammatory responses with significantly more severe levels. At the mildest levels, IFN response hallmarks together with HIF1A protein expression by IHC appeared significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance. Significance: These findings present an approach to image a continuous range of hypoxia levels in tumors and demonstrate the combination of imaging with molecular data to better understand the biology behind these different levels.

PURPOSE: To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS: In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890 ), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m² plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS: Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION: Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.