Homologous recombination deficiency gene panel analysis results in synchronous endometrial and ovarian cancers.

OBJECTIVE: The objective of this study was to analyze the genetic alterations of tumors within the scope of the homologous recombination deficiency gene panel in patients diagnosed with synchronous endometrial ovarian cancer who have been followed for over 5 years using next-generation sequencing. METHODS: DNA was isolated from the patient's formalin-fixed, paraffin-embedded tissue blocks. Next-generation sequencing was performed using the Illumina capture-based sequencing method. Samples were sequenced using the Sophia HR Solution DNA Kit. RESULTS: Seven patients were included in this study. The ratios of likely pathogenic (LP)/pathogenic (P) somatic mutations in ATM (serine/threonine kinase or Ataxia-telangiectasia mutated gene), BRCA2 (breast cancer type 2 susceptibility gene), BARD1 (BRCA1 associated RING domain 1), TP53 (tumor protein p53), BIRP1 (BRCA1-interacting helicase 1 gene), PALB2 (partner and localizer of BRCA2), and CHECK2 were 21 (48.8%), 8 (18.6%), 5 (11.6%), 3 (6.9%), 2 (4.6%), 2 (4.6%), and 2 (4.6%), respectively, in endometrium, and the ratios of somatic mutations in ATM, BRCA2, TP53, BARD1, RAD54L (DNA repair/recombination protein like), BIRP1, and RAD51D (RAD51 recombinase paralog D) were 24 (60%), 6 (15%), 5 (12.5%), 2 (5%), 2 (5%), 1 (2.5%), and 1 (2.5%), respectively, in ovary. In endometrioid-synchronous endometrial ovarian cancer cases, P/LP mutations were observed in ATM and CHECK2 genes in endometrium and ATM, BRCA2, and TP53 genes in ovary. In two non-endometrioid-synchronous endometrial ovarian cancer cases, CHEK2 (checkpoint kinase 2) mutations were observed in endometrium and ATM and TP53 mutations in ovary, whereas in one case, P/LP mutations in ATM and TP53 genes were common in both tissues. CONCLUSION: Pathogenic variations confirming the diagnosis of synchronous endometrial ovarian cancer with genetic alterations were identified in all but one case. ATM gene mutation emerged as the most common alteration and has a potential association with a favorable prognosis.

Phosphokinases related to drug resistance in two cohorts from the cancer genome atlas (TCGA): uterine carcinoma and testicular cancer.

We aimed to find new therapeutic targets related to Cancer Stem Cell alterations in recurrent patients from two TCGA cohorts: Testicular Germ Cell Tumor (TGCT) and Uterine Corpus Endometrial Carcinoma (UCEC). Raw sequencing data were downloaded from the TCGA database. Datasets containing RNA expression and Methylation files were directly downloaded from cBioportal. Variant Call Format files (VCFs) were downloaded from the GDC portal. Gene enrichment analysis was performed using GSEA (Gene Set Enrichment Analysis) software. Transcriptome profiling, coexpression co-occurrence, networks, and survival analyses were performed using cBioportal tools, while mutational analysis of patients was processed using UNIX scripts. We found that cancer stem cell transcription factors were highly expressed in Testicular Germ Cell Tumor (TGCT) and Uterine Corpus Endometrial Carcinoma (UCEC) cohorts, compared to the other 29 cancer cohorts in TCGA. Patients presented a poorer diagnosis when the genes (POU5F1, NANOG, SOX2, SALL4, ABCB1, ABCC1, and ABCG2) were altered. In UCEC cohorts, recurrent patients showed the ABCG2 potentially phosphorylated by the PIM1 kinase. In the TGCT cohort, genes ABCB1 and ABCG2 only appeared in the phosphonetwork in recurrent patients potentially phosphorylated by the same kinase, PIM1, but also by PRKACA. Our data indicate that PRKACA and PIM1 may modulate POU5F1 phosphorylation.

Robotic sentinel lymph node dissection experiences in endometrial cancer at our tertiary cancer treatment institution.

OBJECTIVE: In endometrial cancer surgery, sentinel lymph node dissection is used instead of staging surgery, particularly in advanced disease that is limited to the uterus. The aim of this study is to evaluate our practice of robotic sentinel lymph node dissection, which is applied to endometrial cancer patients in our tertiary cancer treatment center, according to the current literature, and to share our own data. METHODS: Included in our analysis are patients who underwent robotic sentinel lymph node dissection for endometrial cancer utilizing indocyanine green in our center between January 2018 and January 2024. RESULTS: In all, of the 93 endometrial carcinoma patients who underwent sentinel lymph node biopsy, 63 were classified as low-risk, while 30 were high-risk according to the European Society of Gynaecological Oncology and National Comprehensive Cancer Network guidelines. We found sentinel lymph nodes in both low-risk and high-risk patients, with an overall sensitivity of 96.32% (95% confidence interval [CI], 85.12-99.71), specificity of 100% (95%CI, 92.20-99.8), negative predictive value of 96.72% (95%CI, 87.03-99.89), and negative likelihood ratio of 0.06 (95%CI, 0.01-0.36). CONCLUSION: After evaluating our data retrospectively, we determined that we were compatible with the current literature.

Association of insulin-like growth factor II mrna-binding protein 3 (IMP3) expression with prognostic and morphological factors in endometrial cancer.

Objective: Endometrial cancer (EC) is a heterogeneous disease with recurrence rates ranging from 15 to 20%. The discrimination of cases with a worse prognosis aims, in part, to reduce the length of surgical staging in cases with a better prognosis. This study aimed to evaluate the association between Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression and prognostic and morphological factors in EC. Methods: This retrospective, cross-sectional, analytical study included 79 EC patients - 70 endometrioid carcinoma (EEC) and 9 serous carcinoma (SC) - and 74 benign endometrium controls. IMP3 expression was evaluated by immunohistochemistry-based TMA (Tissue Microarray), and the results were associated with morphological and prognostic factors, including claudins 3 and 4, estrogen and progesterone receptors, TP53, and KI67. Results: IMP3 expression was significantly higher in SC compared to EEC in both extent (p<0.001) and intensity (p=0.044). It was also significantly associated with worse prognostic factors, including degree of differentiation (p=0.024, p<0.001), staging (p<0.001; p<0.001) and metastasis (p=0.002; p<0.001). IMP3 expression was also significant in extent (p=0.002) in endometrial tumors compared with controls. In addition, protein TP53 and KI67 showed significant associations in extent and intensity, respectively. Conclusion: IMP3 expression was associated with worse prognostic factors studied. These findings suggest that IMP3 may be a potential biomarker for EC poorer prognosis.

Sentinel node mapping decreases the risk of failed detection of isolated positive para-aortic lymph node in endometrial cancer.

BACKGROUND: Isolated positive para-aortic lymph node metastasis in endometrial cancer is an uncommon event, ranging from 1% to 3%. OBJECTIVE: Our aim was to evaluate the impact of sentinel lymph node (SLN) mapping on the risk of isolated positive para-aortic lymph node metastasis. METHODS: We retrospectively evaluated a series of 426 patients who underwent SLN mapping with at least one SLN detected from January 2013 to December 2021 (SLN group) compared with a historical series of 209 cases who underwent a systematic pelvic and para-aortic lymphadenectomy between June 2007 and April 2015 (LND group). Isolated para-aortic lymph node metastasis recurrences were included in the SLN group analysis. RESULTS: In the SLN group, 168 cases (39.4%) had backup systematic lymphadenectomy, and 56 (13.1%) had positive lymph nodes compared with 34 (16.3%) in LND group (p=0.18). The SLN group had higher rates of minimally invasive surgeries (p<0.001) and presence of lymphovascular space invasion (p<0.001). Moreover, SLN group had fewer other uterine risk factors, such as high-grade tumors (p<0.001), and deep myometrial invasion (p<0.001). We found that SLN mapped outside the pelvis at pre-sacral, common iliac areas, and para-aortic regions in 2.8% (n=12), 11.5% (n=49), and 1.6% (n=7) of cases, respectively. Overall, 52 (12.2%) patients had positive SLNs, and 3 (5.7%) positive SLNs were found outside the pelvis-one in the pre-sacral region, one in the common iliac area, and one in the para-aortic region. An isolated para-aortic lymph node was found in only 2 (0.5%) cases in the SLN group compared with 7 (3.3%) cases in the LND group (p=0.004). CONCLUSIONS: SLN protocol accurately predicts lymph node status and may decrease the risk of failed identification of isolated para-aortic lymph node metastasis compared with systematic lymphadenectomy.

Colombian consensus for the molecular diagnosis of endometrial cancer / Consenso colombiano para el diagnóstico molecular del cáncer de endometrio.

Objective: The Cancer Genome Atlas research program (TCGA) developed the molecular classification for endometrial cancer with prognostic and therapeutic utility, which was replaced by the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification by consensus and international guidelines due to its high cost. This article aims to present national recommendations from an expert consensus that allows unification and implementation of the molecular classification for women with endometrial cancer nationwide, with a rational use of resources and technology. Methods: Consensus of 36 experts in clinical oncology, oncological gynecology, pathology, and genetics, with clinical practice in the national territory. The leader group performed a literature review and structuring of questions rated 1 to 9 points. A modified nominal group technique was used. There was a face-to-face meeting with master presentations, deliberative dialogue, and Google Forms (Google LLC, Mountain View, CA, USA) questionnaire voting with analysis and discussion of responses. The non-consensual responses led to a second round of voting. The final manuscript was finally prepared and revised. Results: Seven recommendations were formulated integrating the panelist responses based on evidence, but adjusted to the Colombian context and reality. Recommendation 1. The molecular classification is recommended in all the endometrial cancers using the immunohistochemistry markers as subrogated results from the molecular profile initially proposed in the TCGA classification. Recommendation 2. The sequential test strategy is recommended, starting with the immunohistochemistry markers (p53, MLH1, MSH 2, MSH6, PMS2) simultaneously in all the patients, defining to request POLE (DNA polymerase epsilon) (if available) according to the risk classification based on the surgical piece. Recommendation 3. It is recommended, that the gynecologist oncologist should be the one to request the POLE (if available) according to the final pathology report. This test must be requested for all endometrial cancers stage I-II, except in low risk (stage IA low grade endometrioid histology without linfovascular invasion normal p53) and, stages III-IV without residual disease, without affecting the request of subrogated immunohistochemistry molecular markers upon histology. The consensus proposes that the POLE is requested after the immunohistochemistry and according to the categories in the risk classification established by the 2020 ESGO/ESTRO/ESP guidelines. Recommendation 4. It is recommended to perform immunohistochemistry for hormonal receptors for all women with endometrial cancer and the HER2 in patients with p53abn, simultaneously with the others immunohistochemistry markers. Recommendation 5. It is recommended to perform the immunohistochemistry markers (p53, MLH1, MSH2, MSH6 y PMS2) in an initial endometrial biopsy or curettage when the specimen is adequate and available. In case the initial immunohistochemistry is inconclusive, or there are histological discrepancies between the initial and definitive pathology, it is recommended to repeat the molecular profile in the surgical pathology. The immunohistochemistry markers must be reported in the pathology report according to the CAP (College of American Pathologists) recommendations, independently of the type of sample. Recommendation 6. It is recommended to perform MLH1 promoter methylation testing in patients who exhibit loss of expression of MLH1 in immunohistochemistry whether it is accompanied or not with loss of expression of PMS2. All the patients with deficient MMR (mismatch repair), should be sent for genetic counseling to rule out Lynch syndrome. Recommendation 7. It is recommended to consider the molecular classification in addition to the classical histopathological criteria when making adjuvant judgments, as incorporated by the classification of prognostic groups of the 2020 ESGO/ESTRO/ESP guidelines. Conclusions: It is necessary to implement the molecular classification of endometrial cancer in clinical practice in accordance to the Colombian context, due to its prognostic and probably predictive value. This will enable the characterization of the Colombian population in order to offer individualized guided treatments. This is an academic and nonregulatory document.

Objetivos: el programa Cancer Genome Atlas Research (TCGA) desarrolló la clasificación molecular para cáncer endometrial con utilidad pronóstica y terapéutica, la cual ha sido reemplazada por consensos y guías internacionales por la clasificación ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) debido a su alto costo. El objetivo de este artículo es presentar recomendaciones a nivel nacional derivadas de un consenso de expertos que permitan unificar e implementar la clasificación molecular para mujeres con cáncer endometrial, mediante un uso racional de recursos y tecnología. Materiales y métodos: consenso de 36 expertos en oncología clínica, ginecología oncológica, patología y genética con práctica clínica en el territorio nacional. El grupo líder realizó una revisión de la literatura y estructuración de preguntas calificadas de 1 a 9 puntos. Se utilizó la técnica de grupo nominal modificada. Se efectuaron reuniones presenciales con presentaciones magistrales, diálogo deliberativo y votación de cuestionario Google Forms (Google LLC, Mountain View, CA, USA) con análisis y discusión de respuestas. Las respuestas no consensuadas se llevaron a una segunda ronda de votación. Finalmente, se elaboró y revisó el manuscrito final. Resultados: se formularon siete recomendaciones integrando las respuestas de las panelistas basadas en evidencia, pero ajustadas al contexto y a la realidad colombiana. Recomendación 1. Se recomienda realizar la clasificación molecular en todos los carcinomas endometriales utilizando los marcadores de inmunohistoquímica como resultados subrogados del perfil molecular inicialmente propuesto en la clasificación del TCGA. Recomendación 2. Se recomienda la estrategia secuencial de testeo iniciando por los marcadores de inmunohistoquímica (p53, MLH1, MSH 2, MSH6, PMS2) simultáneamente en todas las pacientes, y definir la solicitud del POLE (polimerasa épsilon del DNA) (si se encuentra disponible) de forma diferida de acuerdo con la clasificación de riesgo basado en la pieza quirúrgica. Recomendación 3. Se recomienda que sea el ginecólogo oncólogo quien solicite el POLE (si se encuentra disponible) de acuerdo con el reporte de patología definitivo. Esta prueba se debe solicitar a todos los cánceres endometriales de estadio I-II, excepto los de bajo riesgo (estadio IA endometrioide de bajo grado sin invasión linfovascular p53 normal) y estadio III-IV sin enfermedad residual, sin afectar la solicitud de los marcadores moleculares subrogados por inmunohistoquímica de acuerdo con la histología. El consenso propone que la solicitud del POLE se realice posterior a la inmunohistoquímica y de acuerdo con la clasificación del riesgo según las categorías establecidas por la guía ESGO/ESTRO/ESP del 2020. Recomendación 4. Se recomienda realizar simultáneamente con los otros marcadores de inmunohistoquímica la prueba para receptores hormonales en todas las pacientes con cáncer endometrial y el HER2 en pacientes con p53abn. Recomendación 5. Se recomienda que los marcadores de inmunohistoquímica (p53, MLH1, MSH2, MSH6 y PMS2) se realicen en la biopsia/legrado endometrial inicial cuando la muestra es adecuada y está disponible. En caso de inmunohistoquímica inicial no concluyente, o discrepancias histológicas entre la patología inicial y definitiva, se recomienda repetir el perfil molecular en la patología quirúrgica. Los marcadores de inmunohistoquímica deben reportarse en el informe de patología de acuerdo con las recomendaciones del CAP (College of American Pathologists), independientemente del tipo de muestra. Recomendación 6. Se recomienda realizar estudio de metilación de promotor de MLH1 en pacientes con pérdida de expresión de MLH1 en la inmunohistoquímica, acompañado o no de pérdida de expresión de PMS2. Todas las pacientes con déficit de MMR (mismatch repair), deben ser enviadas a genética para descartar síndrome de Lynch. Recomendación 7. Se recomienda tener en cuenta la clasificación molecular, además de los criterios histopatológicos clásicos para la toma de decisiones de adyuvancia, tal como los incorpora la clasificación de los grupos pronósticos de la guía ESGO/ ESTRO/ESP del 2020. Conclusiones: es necesario implementar la clasificación molecular de cáncer de endometrio en la práctica clínica acorde al contexto colombiano, dado su valor pronóstico y posiblemente predictivo. Esto permitirá la caracterización de la población colombiana para ofrecer tratamientos guiados de manera individualizada. Se trata de un documento académico y no regulatorio.

Comparative Assessment of miR-185-5p and miR-191-5p Expression: From Normal Endometrium to High-Grade Endometrial Cancer.

Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.

Tailoring Endometrial Cancer Treatment Based on Molecular Pathology: Current Status and Possible Impacts on Systemic and Local Treatment.

Endometrial cancer (EC) is a heterogeneous disease with a rising incidence worldwide. The understanding of its molecular pathways has evolved substantially since The Cancer Genome Atlas (TCGA) stratified endometrial cancer into four subgroups regarding molecular features: POLE ultra-mutated, microsatellite instability (MSI) hypermutated, copy-number high with TP53 mutations, and copy-number low with microsatellite stability, also known as nonspecific molecular subtype (NSMP). More recently, the International Federation of Gynecology and Obstetrics (FIGO) updated their staging classification to include information about POLE mutation and p53 status, as the prognosis differs according to these characteristics. Other biomarkers are being identified and their prognostic and predictive role in response to therapies are being evaluated. However, the incorporation of molecular aspects into treatment decision-making is challenging. This review explores the available data and future directions on tailoring treatment based on molecular subtypes, alongside the challenges associated with their testing.

The incidence risk of gynecological cancer by antipsychotic use: a meta-analysis of 50,402 patients.

BACKGROUND: Female gynecological cancers represent a serious public health problem, with 1,398,601 new diagnoses and 671,875 deaths per year worldwide. Antipsychotics are often used in psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. It is estimated that the prescription of these drugs is linked to 1,800 deaths a year in the United States, but their association with cancer remains controversial. METHODS: We searched PubMed, Scopus, and Web of Science databases for studies reporting the correlation in the incidence risk of gynecological cancer by antipsychotic use. We used DerSimonian and Laird random-effect models to compute logit transformed odds ratio (OR) for the primary binary endpoint with 95% confidence interval (CI). Heterogeneity was assessed through effect size width along with I-squared and Tau-squared statistics. Review Manager 5.4.1. was used for statistical analyses. A p-value of < 0.05 denoted statistically significant. RESULTS: 50,402 patients were included, of whom 778 (1,54%) took antipsychotic medication for at least 1 year. 1,086 (2,15%) with ovarian cancer and 49,316 (97,85%) with endometrial cancer. Antipsychotic use (OR 1.50; 1.06 to 2.13 95% CI; p-value 0.02), hypertension (OR 1.50; 95% CI 1.06 to 2.13; p-value < 0.01), nulliparity (OR 1.98; 95% CI 1.53 to 2.57; p-value < 0.01) and multiparity (OR 0.53; 95% CI 0.41 to 0.69; p-value < 0.01) showed significantly different distributions between groups of cancer and cancer-free patients. The primary endpoint of incidence risk of gynecological cancer by antipsychotic therapy showed a statistically significant difference (OR 1.67; 95% CI 1.02 to 2.73; p-value < 0.05) against the use of antipsychotic drugs. CONCLUSIONS: Our meta-analysis showed that the use of antipsychotic drugs increases the risk of gynecological cancers, particularly endometrial cancer. This result should be weighed against the potential effects of treatment for a balanced prescribing decision.

Sociodemographic, clinical characteristics, and treatment patterns of endometrial cancer cases in Puerto Rico during the period 2009 to 2015: A retrospective study.

BACKGROUND: Over the past decades, the rising incidence rates of endometrial cancer have made it a significant public health concern for women worldwide. Treatment strategies for endometrial cancer vary based on several factors such as stage, histology, the patient's overall health, and preferences. However, limited amount of research on treatment patterns and potential correlations with sociodemographic characteristics among Hispanics is available. This study analyzes the treatment patterns for patients diagnosed with endometrial cancer in Puerto Rico. METHODS: A secondary database analysis was performed on endometrial cancer cases reported to the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database from 2009 to 2015 (n = 2,488). The study population's sociodemographic and clinical characteristics were described, along with an overview of the therapy options provided to patients receiving care on the island. Logistic regression models were used to evaluate the association of sociodemographic/clinical characteristics with treatment patterns stratified by risk of recurrence. RESULTS: In our cohort, most patients were insured through Medicaid and had a median age of 60 years. Almost 90% of patients received surgery as the first course of treatment. Surgery alone was the most common treatment for low-risk patients (80.2%). High-risk patients were more likely to receive surgery with radiotherapy and chemotherapy (24.4%). Patients with Medicare insurance were five times (HR: 4.84; 95% CI: 2.45-9.58; p < 0.001) more likely to receive surgery when compared with patients insured with Medicaid. In contrast, those with private insurance were twice as likely to receive surgery (HR: 2.38; 95% CI: 1.40-4.04; p = 0.001) when compared to those with Medicaid. CONCLUSION: These findings provide insight into the treatment patterns for endometrial cancer in Puerto Rico and highlight the importance of considering factors such as disease risk when making treatment decisions. Addressing these gaps in treatment patterns can contribute to effective management of endometrial cancer.

Preoperative cancer antigen-125 levels as a predictor of recurrence in early-stage endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynecological cancer in developed countries, with a majority of cases being low-grade endometrioid endometrial cancer. Identifying risk factors for disease recurrence and poor prognosis is critical. This study aimed to assess the correlation between preoperative cancer antigen-125 levels and disease recurrence in early-stage endometrioid endometrial cancer patients. METHODS: The study was a retrospective analysis of 217 patients diagnosed with endometrioid endometrial cancer who underwent surgical treatment at a university-affiliated tertiary hospital between 2016 and 2022. Patients were divided into two groups based on their preoperative cancer antigen-125 levels and compared with clinicopathological findings and disease recurrence. Disease-free survival rates were calculated, and logistic regression analysis was performed to determine independent factors affecting disease-free survival. RESULTS: The mean age of patients was 61.59±0.75 years, and the mean follow-up time was 36.95±1.18 months. The mean cancer antigen-125 level was 27.80±37.81 IU/mL. The recurrence rate was significantly higher in the group with elevated cancer antigen-125 levels (p=0.025). Disease-free survival was lower in patients with elevated cancer antigen-125 compared with those with normal levels (p=0.005). Logistic regression analysis revealed that elevated cancer antigen-125 levels were associated with disease recurrence (OR: 3.43, 95%CI 1.13-10.37, p=0.029). CONCLUSION: The findings of this study suggest that preoperative cancer antigen-125 levels can be used as a predictor of disease recurrence in early-stage endometrioid endometrial cancer patients. cancer antigen-125 levels may be a useful tool for risk stratification and patient management in endometrial cancer.

Is p53 immunohistochemistry alone useful for delineating adjuvant endometrial treatment in low-middle-income countries?

OBJECTIVE: Endometrial cancer (EC) treatment changed substantially with the introduction of molecular classification. Low-middle income (LMIC) countries will face barriers to including molecular classification to guide treatment. This study aims to analyse the value of p53 immunohistochemistry to delineate adjuvant treatment in FIGO stages I and II. METHODS: Patients with EC treated between 2010 and 2016 were retrospectively evaluated. Patients included in this analysis must have reviewed FIGO stage I/II high-grade histologies (endometrioid grade 3, serous, clear cell, carcinosarcoma, mixed and undifferentiated). Samples were subjected to p53 immunohistochemistry. Recurrence-free and overall survival were analysed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was performed for multivariable analysis. RESULTS: From 2010 to 2016, 265 patients met the inclusion criteria. Patients with aberrant p53 (71.4 %) were associated with older age (59.7 % vs 77.8 % with more than 60 years), relapse (12.5 vs 29.6 %) and death (22.2 vs 46.7 %). The pattern of relapse was not different, with most being at extrapelvic sites (55.5 % vs 62.3 % for p53 wild type and aberrant, respectively). The median overall survival was not reached versus 92.2 months for p53 wild type and aberrant, respectively (p = 0.003). In multivariate analysis, chemotherapy decreased death (p = 0.014) in p53 aberrant tumours, a benefit not seen in the wild-type cohort (p = 0.22). CONCLUSION: This retrospective analysis corroborates the finding of worse outcomes for p53 aberrant tumours in stage I/II EC and the benefit of more aggressive adjuvant treatment (systemic therapy and radiotherapy). Although not ideal as a sole molecular marker, p53 immunohistochemistry could complement the classical anatomopathological features and be part of the decision-making process with patients in LMIC.

Management of endometrial cancer in Latin America: raising the standard of care and optimizing outcomes.

Molecular characterization of endometrial cancer is allowing for increased understanding of the natural history of tumors and paving a more solid pathway for novel therapies. It is becoming increasingly apparent that molecular classification is superior to histological classification in terms of reproducibility and prognostic discrimination. In particular, the Proactive Molecular Risk Classifier for Endometrial Cancer allows classification of endometrial cancer into groups very close to those determined by the Cancer Genome Atlas Research Network-that is, DNA polymerase epsilon-mutated, mismatch repair-deficient, p53 abnormal, and non-specific molecular profile tumors. The transition from the chemotherapy era to the age of targeted agents and immunotherapy, which started later in endometrial cancer than in many other tumor types, requires widespread availability of specialized pathology and access to novel agents. Likewise, surgical expertise and state-of-the-art radiotherapy modalities are required to ensure adequate care. Nevertheless, Latin American countries still face considerable barriers to implementation of international guidelines. As we witness the dawn of precision medicine as applied to endometrial cancer, we must make continued efforts towards improving the quality of care in this region. The current article discusses some of these challenges and possible solutions.

Perfil molecular de cáncer de endometrio en mujeres de Bogotá DC, Colombia / Molecular profile of endometrial cancer in women from Bogota DC, Colombia

Introducción: El cáncer de endometrio ocupa el sexto lugar en incidencia del cáncer en mujeres. La caracterización molecular de este cáncer permite optimizar la estratificación de riesgo para mejorar el tratamiento de las pacientes. Objetivo: Determinar el perfil molecular TCGA de pacientes con cáncer de endometrio en Bogotá, D.C., Colombia. Método: Estudio descriptivo en una cohorte de pacientes con cáncer de endometrio. Las mutaciones en los exones 9 a 14 del gen POLE fueron identificadas mediante amplificación por reacción en cadena de la polimerasa, seguida de secuenciación Sanger y análisis bioinformático. La expresión de las proteínas MMR y p53 se identificó mediante inmunohistoquímica. Resultados: Se incluyeron 40 pacientes con una mediana de edad de 66 años. El 15% presentaron mutaciones en el dominio exonucleasa de POLE. El 32% de las pacientes que no presentaron mutaciones manifestaron deficiencia en el sistema MMR. El 43,47% de las pacientes sin mutaciones en POLE ni alteración del sistema MMR presentaron alteración de la proteína p53. Conclusiones: La población de cáncer de endometrio analizada presenta un perfil molecular TCGA similar a lo reportado para otras poblaciones.

Introduction: Endometrial cancer ranks sixth in cancer incidence among women. Its molecular characterization allows for a more precise risk stratification with the aim of improving patient treatment. Objective: To determine the TCGA molecular profile of patients with endometrial cancer in Bogota, Colombia. Method: A descriptive study of a cohort of patients with endometrial cancer. The expression of MMR proteins and p53 was identified through immunohistochemistry. Mutations in exons 9 to 14 of the POLE gene were identified through polymerase chain reaction amplification, followed by Sanger sequencing and bioinformatic analysis. Results: Forty patients were included in the study, with a median age of 66 years, 15% of them exhibited mutations in the exonuclease domain of POLE, while 32% of patients without mutations showed deficiency in the MMR system. Forty three percent of patients without mutations in POLE or MMR alterations showed aberrant p53 protein expression. Conclusions: The analyzed population of endometrial cancer presents a TCGA molecular profile similar to that reported for other populations.

Copy number signatures and CCNE1 amplification reveal the involvement of replication stress in high-grade endometrial tumors oncogenesis.

PURPOSE: Managing high-grade endometrial cancer in Martinique poses significant challenges. The diversity of copy number alterations in high-grade endometrial tumors, often associated with a TP53 mutation, is a key factor complicating treatment. Due to the high incidence of high-grade tumors with poor prognosis, our study aimed to characterize the molecular signature of these tumors within a cohort of 25 high-grade endometrial cases. METHODS: We conducted a comprehensive pangenomic analysis to categorize the copy number alterations involved in these tumors. Whole-Exome Sequencing (WES) and Homologous Recombination (HR) analysis were performed. The alterations obtained from the WES were classified into various signatures using the Copy Number Signatures tool available in COSMIC. RESULTS: We identified several signatures that correlated with tumor stage and disctinct prognoses. These signatures all seem to be linked to replication stress, with CCNE1 amplification identified as the primary driver of oncogenesis in over 70% of tumors analyzed. CONCLUSION: The identification of CCNE1 amplification, which is currently being explored as a therapeutic target in clinical trials, suggests new treatment strategies for high-grade endometrial cancer. This finding holds particular significance for Martinique, where access to care is challenging.

Molecular profile in endometrial carcinoma: can we predict the lymph node status? A systematic review and meta-analysis.

PURPOSE: Molecular classification of endometrial cancer (EC) has become a promising information to tailor preoperatively the surgical treatment. We aimed to evaluate the rate of lymph node metastases (LNM) in patients with EC according to molecular profile. METHODS: A systematic review and meta-analysis were performed according to PRISMA guidelines by searching in two major electronic databases (PubMed and Scopus), including original articles reporting lymph node metastases according to the molecular classification of EC as categorized in the ESGO-ESMO-ESP guidelines. RESULTS: Fifteen studies enrolling 3056 patients were included. Pooled prevalence LNM when considering only patients undergoing lymph node assessment was 4% for POLE-mutated (95%CI: 0-12%), 22% for no specific molecular profile (95% CI: 9-39%), 23% for Mismatch repair-deficiency (95%CI: 10-40%) and 31% for p53-abnormal (95%CI: 24-39%). CONCLUSIONS: The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Factors Associated with Parametrial Involvement in Endometrial Carcinoma in Patients Treated with Radical Hysterectomy.

INTRODUCTION: Describe factors associated with parametrial involvement, and how these factors modify the prognosis of patients with endometrial carcinoma treated with radical hysterectomy. METHODS: Observational study in which categorized patients according to those with and without parametrial involvement. A descriptive analysis and comparative analysis were performed for associations between parametrial spread and clinical, surgical, and pathology variables. RESULTS: We analyzed 85 patients, which 18 (21%) had parametrial involvement. Pathology factors associated with parametrial involvement were the endometrioid subtype, grade 3, and variants of poor prognosis (odds ratio (OR) 3.41, 95% CI 1.09-10.64; P = 0.035), myometrial invasion of over 50% (OR 7.76, 95% CI 1.65-36.44; P = 0.009), serosal involvement (OR 17.07, 95% CI 3.87-75.35; P < 0.001), ovarian metastasis (OR 5.15, 95% CI 1.36-19.46; P = 0.016), positive peritoneal cytology (OR 3.9, 95% CI 1.04-14.77; P = 0.044), and lymph node metastasis (OR 3.4; 95% CI 1.16-9.97; P = 0.026). Five-year disease-free survival was 74% (95% CI 57.4-85.4) for the group without parametrial spread and 50.8% (95% CI 22.7-73.4) for the group with parametrial spread (P = 0.001). Similarly, 5-year overall survival was 85.2% (95% CI 67.9-93.6) for the group without parametrial spread and 47.5% (95% CI 8.1-80.2) for the group with parametrial spread (P = 0.002). CONCLUSION: Factors associated with parametrial involvement were histologies of poor prognosis, tumors affecting uterine serosa, cervix, or spread beyond the uterus. Additionally, parametrial involvement directly affects prognosis by reducing overall survival, disease-free survival and increasing odds for recurrence.