Ana Luzarraga Aznar

Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer

To investigate the pattern of first recurrence of disease in patients with endometrial cancer according to molecular classification, and to assess the independent role of molecular profiling in each type of failure. Retrospective single-center study including patients diagnosed with endometrial cancer stage I-IVB (International Federation of Gynecology and Obstetrics 2009) between December 1994 and May 2022, who underwent primary surgical treatment and had a complete molecular profile. First recurrence was classified as isolated or multiple, and as vaginal, pelvic, peritoneal, nodal, and distant according to its location. The log-rank test and univariate and multivariate adjusted Cox regression models were used for comparison between groups. A total of 658 patients were included. Recurrence was observed in 122 patients (18.5%) with a recurrence rate of 12.4% among mismatch-repair deficient tumors, 14.5% among non-specific molecular profile, 2.1% among POLE-mutated, and 53.7% among p53-abnormal tumors. Recurrences were found to be isolated in 80 (65.6%) and multiple in 42 (34.4%) patients, with no differences in molecular subtype (p=0.92). Patients with p53-abnormal tumors had a recurrence mainly as distant (28.4%) and peritoneal (21.1%) disease, while patients with non-specific molecular profile tumors presented predominantly with distant failures (10.3%), and mismatch-repair deficient tumors with locoregional recurrences (9.4%).On multivariate analysis, p53-abnormal molecular profile was the only independent risk factor for peritoneal failure (OR=8.54, 95% CI 2.0 to 36.3). Vaginal recurrence was independently associated with p53-abnormal molecular profile (OR=6.51, 95% CI 1.1 to 37.4) and lymphovascular space invasion. p53-abnormal and non-specific molecular profiles were independent predictors for distant recurrence (OR=3.13, 95% CI 1.1 to 8.7 and OR=2.35, 95% CI 1.1 to 5.0, respectively), along with lymphovascular space invasion and high-grade tumors. Molecular profile was not independently associated with pelvic and nodal recurrences. Endometrial cancer featured different patterns of recurrence depending on the molecular profile. p53-abnormal molecular profiling was the only independent risk factor for peritoneal relapse, while non-specific molecular profile showed a strong association with distant failures.

Endometrial adenocarcinoma recurring in the lung: impact of molecular profile and role of local therapies on prognosis

The objective of our study was to describe the characteristics of patients with endometrial cancer diagnosed with a first recurrence involving the lung, and to describe the prognostic role of the molecular profile. We also aimed to describe the prognostic outcomes after local treatment of recurrence (resection of lung metastases or stereotactic body radiation therapy) in a group of patients with isolated lung recurrence. This was a retrospective, single-center study between June 1995 and July 2021. The study included patients diagnosed with a first recurrence of endometrial cancer involving the lung. We defined two groups of patients: patients with isolated lung recurrence (confined to the lung) and patients with multisystemic recurrence (in the lung and other locations). Among 1413 patients diagnosed with endometrial cancer in stage IA to IVA of the International Federation of Gynecology and Obstetrics (FIGO) 2009, 64 (4.5%) patients had a first recurrence involving the lung. Of these, 15 (39.1%) were of a non-specific molecular profile, 16 (25%) were p53-abnormal, 15 (23.4%) were mismatch-repair deficient, and 0% POLE-mutated. P53-abnormal patients had the shortest 3 year progression-free survival after recurrence and those with mismatch-repair deficient had the longest 3 year progression-free survival (14.3% (range; 1.6-40.3) and 47.6% (range; 9.1-79.5) respectively, p=0.001). We found no differences on overall survival after recurrence by molecular profile. Thirty-one of 64 (48.4%) patients had an isolated recurrence in the lung, and 16 (25%) patients received local treatment. When comparing patients with isolated lung recurrence, locally treated patients had a longer median progression-free survival than patients treated systemically (41.9 (range, 15.4-NA) vs 7.8 (range, 7.2-10.6) months respectively, p=0.029), a complete response rate of 80% for stereotactic body radiation therapy and a complete resection of 90.9% for surgery. Although few patients will benefit from local treatment (stereotactic body radiation therapy or resection) after a recurrence involving the lung, local therapies might be considered as an option in oligometastatic lung recurrences as they achieve high local control rates and better oncological outcomes than systemic treatment alone.

Sentinel SENECA risk factors for unsuccessful bi-lateral sentinel lymph node mapping in endometrial cancer

Our study aims to assess the risk factors associated with bi-lateral sentinel lymph node (SLN) mapping failure in endometrial cancer. The SENECA study was a retrospective multi-center international observational study that reviewed data from 2139 women with clinical stage I-to-II endometrial cancer across 64 centers in 17 countries. Between January 2021 and December 2022, patients underwent surgical treatment with SLN assessment, following the guidelines of the European Society of Gynaecological Oncology. Risk factors associated with the absence of bi-lateral mapping were analyzed using χ Among the 2139 patients, the bi-lateral lymph node detection rate was 82.7%, whereas the unilateral detection rate was 97.3%. In multi-variate analysis, 5 risk factors remained statistically associated with unsuccessful bi-lateral lymph node mapping: high-grade histology (OR 1.35, 95% CI 1.02 to 1.79, p=.03), myometrial invasion >50% (OR 1.37, 95% CI 1.07 to 1.75, p=.012), low-volume surgeon <20 cases/year (OR 2.11, 95% CI 1.55 to 2.89, p<.01), open surgical approach (OR 1.72, 95% CI 1.06 to 2.78 , p=.03), and non-indocyanine green tracer (OR 4.59, 95% CI 2.64 to 7.99, p<.01). The addition of bi-lateral pelvic lymphadenectomy and/or paraaortic lymphadenectomy to SLN biopsy caused an increased rate of intra-operative complications (2% vs 8.4%, p<.01) and all-grade post-operative complications (4.1% vs 11.2%, p<.01). Our study identifies 5 risk factors associated with unsuccessful lymph node mapping in endometrial cancer. Efforts should be made to perform this technique with indocyanine green, through minimally invasive surgery, and performed or supervised by an experienced surgeon with ≥20 endometrial cancer cases per year.

Correspondence on ‘Predicting the risk of nodal disease with histological and molecular features in endometrial cancer: the prospective PROME trial’ by Bogani et al

Response to: Correspondence on 'Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer' by Zhang and Sun

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Current challenges and emerging tools in endometrial cancer diagnosis

The diagnostic process of endometrial cancer includes imaging methods such as trans-vaginal ultrasound, along with procedures to obtain endometrial tissue for histologic evaluation. Common techniques for tissue sampling include Pipelle endometrial biopsy, hysteroscopy, and dilation and curettage, which are used to confirm the diagnosis, determine tumor histology, grade, and molecular profile. However, diagnostic algorithms for endometrial cancer differ significantly across countries, influenced by local resources, protocols, and the availability of diagnostic methods. These variations include differences in the endometrial thickness threshold for recommending a biopsy and the choice of the initial diagnostic test. Moreover, patients often have multiple tests and appointments before a definitive diagnosis, although only 5%-10% of women with post-menopausal bleeding are diagnosed with endometrial cancer. Current diagnostic techniques have limitations. Pipelle endometrial biopsy has a significant false-negative rate (10%-20%) and may fail to provide adequate diagnostic material in up to 30% of cases. Hysteroscopy, while useful, is associated with pain in up to 65% of patients and can delay diagnosis because of limited availability. Dilation and curettage is an invasive procedure requiring general anesthesia and has a higher complication rate. In response to these challenges, there is growing interest in developing new diagnostic tools that are less invasive and provide 1-step diagnoses, including liquid biopsies from urine, blood, cervico-vaginal and endometrial fluid samples by means of genomics and proteomics. This review will examine the current diagnostic algorithms in European and American guidelines, evaluate the sensitivity, specificity, and accuracy of current techniques, and explore new diagnostic tools under development.

SENECA study: staging endometrial cancer based on molecular classification

Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.