Andreia Cristina de Melo

Clinical Characteristics and Outcomes of a High-grade Endometrial Cancer Cohort Treated at Instituto Nacional de Câncer, Brazil

Abstract Objective To analyze the outcomes of a cohort of patients with high-risk histologies of endometrial cancer (EC) treated at Instituto Nacional de Câncer (National Cancer Institute, INCA, in Portuguese), in Brazil. Materials and Methods We reviewed the medical records of patients with high-risk histologies of EC in any stage registered at INCA between 2010 and 2016 to perform a clinical and demographic descriptive analysis and to evaluate the outcomes in terms of recurrence and survival. Results From 2010 to 2016, 2,145 EC patients were registered and treated at INCA, and 466 had high-grade histologies that met the inclusion criteria. The mean age of the patients was 65 years, 44.6% were Caucasian, and 90% had a performance status of 0 or 1. The most common histology was high-grade endometrioid (31.1%), followed by serous carcinoma (25.3%), mixed (20.0%), carcinosarcoma (13.5%), and clear cell carcinoma (9.4%). Considering the 2018 Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics, FIGO, in French) staging system, 44.8%, 12.4%, 29.8%, and 12.9% of the patient were in stages I, II, III or IV respectively. Age (> 60 years), more than 50% of myoinvasion, higher stage, poor performance status, serous and carcinosarcoma histologies, and adjuvant treatment were independent factors associated with recurrence-free survival (RFS) and overall survival (OS) in the multivariate analysis. Conclusion The current findings reinforced the international data showing poor outcomes of these tumors, especially for serous and carcinosarcomas and tumors with advanced stages, with shorter survival and high recurrence rates in distant sites, independently of the FIGO stage. Adjuvant therapy was associated with better survival.

Racial Disparities in Endometrial Cancer Incidence and Outcomes in Brazil: Insights From Population-Based Registries

PURPOSE This study aimed to examine trends in the incidence and mortality rates of endometrial cancer (EC) across ethnic groups in Brazil and to analyze the demographic and clinicopathological characteristics associated with these trends. METHODS The incidence of EC was analyzed from 2010 to 2015 using data from Brazilian Population–Based Cancer Registries (PBCRs), including crude rates and annual percentage changes (APCs). Clinical and sociodemographic information from 2000 to 2019 was gathered from Hospital-Based Cancer Registries. Mortality data between 2000 and 2021 were obtained from the National Mortality Information System, allowing for comparisons between White women and Black women. RESULTS From 2010 to 2015, a total of 32,831 new cases of EC were reported across 13 PBCRs, with Black patients accounting for 35.7% of these cases. The median age at diagnosis was 63 years, with Black women diagnosed at a younger age than White women. Black patients experienced a significant increase in incidence rate (APC +6.7% v +3.0%). A greater proportion of Black patients lived without partners (54.0%), had higher rates of alcohol consumption (15%) and smoking (25.8%), and resided in less developed regions (54.6%) with lower education levels (77.5%). From 2000 to 2021, Brazil recorded 72,189 EC-related deaths, showing higher mortality rates among White women (3.8 per 100,000) than Black women (2.4 per 100,000), although the downward trend was steeper among White women (–1.2%) than Black women (–0.6%). CONCLUSION Racial disparities in EC incidence and mortality in Brazil may be closely linked to unfavorable sociodemographic factors faced by Black women. Targeted public health initiatives are critical for improving early detection and access to equitable care for Black women.

Social inequities and clinical outcomes in young women with cervical cancer: Real-world evidence

Objective To assess the influence of social inequities and clinicopathological factors on survival outcomes in young women with cervical cancer treated at a comprehensive public cancer center in Brazil. Methods This retrospective analysis reviewed the medical records of women aged 18–39 diagnosed with cervical cancer at the Brazilian National Cancer Institute between January 2017 and December 2021, assessing demographic characteristics and survival outcomes. Results This analysis included 475 patients with a mean age of 33.6 years, with the majority being non-white (67.7%), never married women (68.0%), and having a low education level (< 8 years) (86.1%). Multivariate analysis indicated that a lower education level was associated with advanced stage (p = 0.001). Recurrence or progression occurred in 224 patients (47.2%), mainly as distant metastases (56.7%). The median progression-free survival (PFS) was 19.8 months, with two-year rates of 81.6%, 45.7%, 28.2%, and 6.2% for stages I, II, III, and IV, respectively. Shorter PFS was correlated with lower education level (p = 0.009), alcohol consumption (p = 0.026), undifferentiated carcinoma (p = 0.007), and advanced disease stage (p < 0.001). The median overall survival (OS) was 35.1 months, with five-year rates of 82.9%, 42.7%, 23.7%, and 9.7% for stages I, II, III, and IV, respectively. Factors associated with shorter OS included lower education level (p = 0.005), undifferentiated carcinoma (p = 0.006), and advanced stage (p < 0.001). Conclusion Undifferentiated carcinomas and advanced stages negatively influence the prognosis of young women with cervical cancer. Social factors may also be correlated with poorer outcomes, especially alcohol consumption and lower education levels.

Epidemiology of Cervical Cancer in Brazil: Age-Specific Trends From 2000 to 2018

PURPOSE Cervical cancer (CC) remains a significant public health challenge in low- and middle-income countries (LMICs), including Brazil. While global incidence has declined, age-specific variations may mask emerging trends among younger women. This study aimed to evaluate trends and age-specific changes in CC incidence in Brazil between 2000 and 2018. MATERIALS AND METHODS Incidence data and age at diagnosis were obtained from Brazilian Population-Based Cancer Registries (PBCRs) for the period 2000-2018. Temporal trends were evaluated using Joinpoint regression to estimate annual percent changes (APCs) and average APCs (AAPCs). RESULTS Between 2000 and 2018, 66,358 CC cases were identified across 33 PBCRs. The median age at diagnosis was 51 years (IQR, 40-63), declining from 52 years in 2000 to 48 years in 2018. The overall adjusted incidence showed a significant decline between 2000 and 2013 (APC: –4.5% [95% CI, –5.3 to –3.7]; P < .001) followed by a nonsignificant increase from 2013 to 2018 (APC: 3.1 [95% CI, –1.6 to 8.1]; P = .20). Age-stratified analyses revealed rising trends among women age 25-44 years, suggesting a transition to younger age at diagnosis. CONCLUSION The observed decrease in median age and rising incidence among women younger than 45 years indicate a potential epidemiologic shift in CC in Brazil. These findings highlight the need to strengthen national screening programs, expand human papillomavirus (HPV) vaccination coverage, and incorporate molecular HPV testing into prevention strategies.

Epidermal growth factor receptor regulates fibrinolytic pathway elements in cervical cancer: functional and prognostic implications

Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model.

Advanced Cervical Cancer: Leveraging the Historical Threshold of Overall Survival

Survival with Cemiplimab in Recurrent Cervical Cancer

Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Population-Based Trends in Cervical Cancer Incidence and Mortality in Brazil: Focusing on Black and Indigenous Population Disparities

This study aimed to explore trends in cervical cancer (CC) incidence and mortality rates according to race/skin color in Brazil focusing on the seriousness of the racial disparity. Data from Brazilian Population-Based Cancer Registries (PBCRs) were analyzed for trends in incidence between 2010 and 2015. For mortality, data from the National Mortality Information System were retrieved between 2000 and 2020. A self-declaration on race/skin color was collected following the classification proposed by the Brazilian Institute of Geography and Statistics - white, black, brown/mixed race, yellow, or indigenous. For the analysis, black and brown/mixed race were grouped as black. Between 2010 and 2015, 10,844 new cases of CC were registered in the participating PBCRs, distributed among white women (49.6%), black (48.0%), and other race/skin color (2.3%). Compared with white counterparts, black women had a 44% higher risk of incident CC. As for mortality, between 2000 and 2020, 108,590 deaths from CC occurred nationwide. The mean age-adjusted mortality rates according to race/skin color were 3.7/100,000 for white, 4.2/100,000 for black, 2.8 for yellow, and 6.7 for indigenous women. Taking the mortality rates in white women as a reference, there was a 27% increase in death risk in black women (RR = 1.27) and 82% in indigenous women (RR = 1.82). These findings suggest that the higher rates of incidence and mortality from CC in vulnerable populations of black and more impactfully indigenous women in Brazil remain alarming. More efficient HPV vaccination strategies synchronized with well-conducted Pap smear-based screening should be prioritized in these more vulnerable populations.

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)–deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P &lt; .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1–positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

A Phase II Study of Utidelone With Toripalimab in Advanced Cervical Cancer

This is a Phase II clinical trial to evaluate the safety and efficacy of Utidelone, a genetically engineered epothilone derivative, combined with Toripalimab, a PD-1 inhibitor, in patients with recurrent or metastatic cervical cancer who have progressed after standard treatments. The study will also assess the safety profile of this combination therapy. The primary objectives of this study include: (1) to determine the objective response rate (ORR), meaning whether the treatment can reduce the size of tumors or make them disappear, according to the RECIST 1.1 criteria; (2) to evaluate the safety of the treatment and document the side effects experienced by participants. This study is for individuals who: (1) are between 18 and 75 years old; (2) have a confirmed diagnosis of recurrent or metastatic cervical cancer; (3) have previously received at least one standard chemotherapy regimen that is no longer controlling the cancer; (4) are in generally good health, as determined by the study investigators. In this single-arm study, all participants will receive the same treatment: Utidelone will be administered by intravenous (IV) infusion over 1.5 hours, once a day for 5 consecutive days, in each 21-day treatment cycle; Toripalimab will be administered by IV infusion over 1.5 hours, once on Day 6 of each 21-day cycle. Participants may continue receiving the study drugs as long as they are benefiting from the treatment and side effects are manageable. Doctors will assess tumor size using imaging scans (like CT or MRI) every 6 weeks to monitor how the cancer responds to treatment. The study will take place at Zhongnan Hospital of Wuhan University and plans to include approximately 32 participants.

Study of Cemiplimab in Adults With Cervical Cancer

The primary objective is to compare overall survival (OS) for patients with recurrent or metastatic cervical cancer who have histology of squamous cell carcinoma (SCC) and who have any eligible histology treated with either cemiplimab or investigator's choice (IC) chemotherapy. The secondary objectives performed among SCC patients and among all eligible histologies (SCC and adenocarcinoma/adenosquamous carcinoma (AC) are: * To compare progression-free survival (PFS) of cemiplimab versus IC chemotherapy * To compare objective response rate (ORR) (partial response \[PR\] + complete response \[CR\]) of cemiplimab versus IC chemotherapy per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * To compare the duration of response (DOR) of cemiplimab versus IC chemotherapy * To compare the safety profiles of cemiplimab versus IC chemotherapy by describing adverse events (AE) * To compare quality of life (QOL) for patients treated with cemiplimab versus IC chemotherapy using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)