Understanding Endometrial Cancer: Risks, Treatments, and New Research

Table of Contents

• Introduction: Why Endometrial Cancer Matters
• Epidemiology and Risk Factors
• Prevention and Early Detection Options
• Racial Disparities in Endometrial Cancer
• Types of Endometrial Cancer
• Molecular Classification and Testing
• Surgical Treatment and Staging
• What This Means for Patients
• Limitations of Current Knowledge
• Patient Recommendations
• Source Information

Introduction: Why Endometrial Cancer Matters

Endometrial cancer, which develops in the lining of the uterus, represents a growing health concern in the United States. Unlike most other cancers, both the incidence and mortality rates of endometrial cancer are increasing. This rise is closely linked to the obesity epidemic, as excess weight is one of the most significant risk factors for this disease.

In recent years, treatment approaches have evolved significantly. Surgeons now use advanced techniques including sentinel lymph-node mapping alongside minimally invasive removal of the uterus, fallopian tubes, and ovaries. Groundbreaking research from the Cancer Genome Atlas (TCGA) project has revealed the biological complexity of endometrial cancer, leading to more personalized treatment options.

Despite these advances, concerning disparities persist. Black women experience disproportionately higher rates of aggressive endometrial cancer subtypes and worse outcomes even when diagnosed at similar stages. As obesity rates continue to climb, new prevention and treatment strategies are urgently needed to address this growing health challenge.

Epidemiology and Risk Factors

Endometrial cancer demonstrates a strong relationship with several modifiable risk factors. Obesity and conditions associated with metabolic syndrome, including diabetes and polycystic ovary syndrome (PCOS), significantly increase endometrial cancer risk. Additionally, conditions involving excess estrogen exposure—such as estrogen-secreting tumors and hormone replacement therapy using estrogen without progesterone—predispose women to developing this cancer.

Specific risk increases have been quantified through extensive research:

• Tamoxifen use approximately doubles the risk of both endometrioid and nonendometrioid endometrial cancers
• Using tamoxifen for more than 5 years increases risk up to four times
• Women with a normal body mass index (BMI) have a 3% lifetime risk of endometrial cancer
• For every 5-unit increase in BMI, endometrial cancer risk increases by more than 50%

Protective factors include having children (parity), with an inverse relationship between number of children and endometrial cancer risk. Oral contraceptive use reduces risk by 30-40%, with longer use providing increased protection that can persist for decades after stopping.

The average age at diagnosis is 63 years, but surveillance data shows a sustained rise in cases among women under 50. This trend is particularly concerning as younger obese women diagnosed with endometrial cancer often wish to preserve fertility, creating complex treatment decisions.

Prevention and Early Detection Options

For young obese women diagnosed with early endometrial cancer or its precursor (complex atypical hyperplasia or CAH), conservative management options exist beyond immediate hysterectomy. Many of these women experience anovulation (lack of ovulation), which causes endometrial overstimulation from excess estrogen without protective progesterone.

Treatment alternatives include oral progestin therapy or progestin-containing intrauterine devices (IUDs). Research shows varying success rates:

• Oral progestins: 65.8% complete response in CAH and 48.2% in endometrial cancer
• Recurrence rates: 23.2% for CAH and 35.4% for endometrial cancer after oral progestin treatment
• Progestin-containing IUDs: 91% complete response in CAH and 54% in endometrial cancer at 12 months

Women with higher-grade tumors or tumors invading the uterine muscle wall (myometrium) are not candidates for conservative management and require hysterectomy as standard care.

Genetic factors also play a role. Women with Lynch syndrome (caused by mutations in MLH1, MSH2, MSH6, or PMS2 genes) face a 40-60% lifetime risk of endometrial cancer, typically developing at a younger median age of 48 years compared to 63 years in the general population. Lynch syndrome accounts for approximately 3% of all endometrial cancers and 9% of cases in women under 50.

Racial Disparities in Endometrial Cancer

Concerning racial disparities have emerged in endometrial cancer outcomes. While rates are rising among all women, Black women experience the sharpest increases. Surveillance data from 1990-2017 shows:

• White women: 0.3% annual increase in incidence (P<0.05)
• Black women: 2.3% annual increase in incidence (P<0.05)
• All women combined: 0.5% annual increase (P<0.05)

These disparities become more pronounced when considering that Black women have higher hysterectomy rates. When adjusting for hysterectomy prevalence, the disproportionate rise in endometrial cancer incidence among Black women becomes even more apparent.

Of particular concern is the higher rate of aggressive nonendometrioid tumors among Black women. Population studies show that Black women under 50 are more likely to present with higher-grade, nonendometrioid tumors at later stages compared to White women of the same age. Even after adjusting for stage and tumor characteristics, young Black women with early-stage tumors had a 24% higher likelihood of dying compared to their White counterparts.

The causes of these disparities are multifactorial, potentially involving biological differences, access to appropriate care, and systemic healthcare inequities. Urgent attention is needed to understand and address these concerning disparities in endometrial cancer outcomes.

Types of Endometrial Cancer

Endometrial cancers are broadly classified into two main types with distinct characteristics and outcomes. Endometrioid carcinomas account for approximately 80% of cases and typically arise from complex atypical hyperplasia (CAH) with epithelial atypia. These tumors are often hormone-driven and associated with estrogen excess from obesity, unopposed estrogen therapy, or estrogen-producing tumors.

Nonendometrioid tumors comprise about 20% of cases and include three main subtypes:

• Endometrial serous carcinoma (most common nonendometrioid type)
• Clear-cell carcinoma
• Carcinosarcoma (malignant mixed müllerian tumors)

These aggressive tumors have hormone-independent development patterns and no known precursor lesions. They typically occur in older postmenopausal women and carry worse prognoses. Endometrial serous carcinoma shows extrauterine disease spread in up to 37% of patients without evidence of invasion into the uterine wall.

Endometrioid tumors are graded using the International Federation of Gynecology and Obstetrics (FIGO) system:

1. Grade 1: less than 6% solid tumor component
2. Grade 2: 6-50% solid tumor component
3. Grade 3: more than 50% solid tumor component

Grades 1 and 2 are considered low-grade with generally good prognosis, while grade 3 tumors have intermediate-to-poor outcomes. Prognosis is typically worst with carcinosarcomas, followed by clear-cell and serous carcinomas.

Molecular Classification and Testing

The Cancer Genome Atlas (TCGA) project has revolutionized our understanding of endometrial cancer biology by comprehensively analyzing cancer genomes. This research identified four distinct molecular subgroups with different clinical behaviors and treatment responses:

1. Ultramutated group: Characterized by POLE mutations, highest mutation numbers, and significantly longer survival
2. Hypermutated group: Primarily endometrioid carcinomas with high microsatellite instability (MSI) and high mutation rates
3. Copy-number-low group: Largest category, mainly microsatellite-stable endometrioid carcinomas
4. Copy-number-high group: Characterized by TP53 mutations, low mutation rates, and frequent copy-number alterations (mainly serous carcinomas)

This molecular classification refutes the previous assumption that all young, obese women have hormone-driven disease with good prognosis. Some patients have endometrioid cancers driven by WNT-β-catenin signaling pathway activation rather than hormones.

Specific genetic alterations carry prognostic significance:

• TP53 mutations: Associated with poorer survival, especially in grade 3 tumors
• CTNNB1 mutations: Associated with poorer outcomes in endometrioid tumors
• POLE mutations: Associated with prolonged survival
• Mismatch-repair deficiency: Impacts prognosis and treatment options

Molecular testing has important clinical implications, particularly for identifying Lynch syndrome patients who have increased colon cancer risk and family members who may benefit from predictive genetic testing and enhanced screening.

Surgical Treatment and Staging

Surgery remains the cornerstone of initial endometrial cancer management. Current standard approaches involve laparoscopic or robotic removal of the uterus, cervix, fallopian tubes, and ovaries combined with sentinel lymph-node evaluation. This represents a significant advancement from previous surgical practices.

Two randomized trials demonstrated that minimally invasive surgery provides important benefits compared to traditional open abdominal surgery:

• Significantly lower rates of postoperative complications
• Improved short-term quality of life
• Equivalent long-term survival outcomes

The evolution of lymph node assessment represents another major advance. Previously, standard lymphadenectomy (removal of pelvic and paraaortic nodes) caused lymphedema in over 30% of patients along with increased surgical time and blood loss. The current sentinel-node approach involves:

1. Injecting indocyanine green dye into the cervix
2. Identifying and removing bilateral sentinel lymph nodes
3. Performing side-specific lymphadenectomy if no sentinel node is identified
4. Conducting pathological ultrastaging of sentinel nodes

This approach has proven highly accurate in clinical studies. A multicenter prospective trial showed 86% successful mapping of at least one sentinel node with a false negative rate of only 2.8%. Even in higher-risk patients (grade 3 tumors or serous histology), success rates reached 89% with a 4.3% false negative rate.

After surgery, endometrial cancer is staged using the FIGO system based on pathological evaluation of the removed tissues, determining the extent of disease spread and guiding further treatment decisions.

What This Means for Patients

This research has significant implications for endometrial cancer prevention, detection, and treatment. The strong link with obesity (accounting for 57% of cases) highlights the importance of weight management as a preventive strategy. Women should be aware that every 5-unit BMI increase raises endometrial cancer risk by more than 50%.

For young women diagnosed with early-stage disease who wish to preserve fertility, progestin-based treatments offer viable alternatives to immediate hysterectomy. Success rates of 54-91% depending on treatment method and condition (CAH vs. cancer) provide realistic expectations for conservative management.

The molecular classification system enables more personalized treatment approaches, particularly for recurrent disease. Patients with mismatch repair deficiency may be candidates for immune checkpoint inhibitors, while those with specific genetic mutations might benefit from targeted therapies.

Black women and their healthcare providers should be particularly vigilant about endometrial cancer symptoms, given the disproportionate increase in incidence and mortality rates in this population. Early detection and appropriate treatment are crucial for addressing these disparities.

Limitations of Current Knowledge

While significant progress has been made in understanding endometrial cancer, important knowledge gaps remain. The reasons behind the increasing racial disparities, particularly why Black women develop more aggressive nonendometrioid tumors, are not fully understood. Larger studies are needed to examine biological differences according to race and socioeconomic factors.

The translation of molecular classification into routine clinical practice has lagged behind the research findings. While TCGA identified four distinct molecular subgroups, implementing comprehensive genomic analysis in everyday patient care remains challenging due to cost and complexity.

Simplified biomarker testing approaches are being evaluated in clinical trials like the European PORTEC-4a study, which is assessing molecular risk profiling to guide adjuvant treatment decisions. However, these approaches are not yet standard practice in most clinical settings.

More research is needed to understand the molecular changes in certain endometrial cancer subtypes, particularly clear-cell carcinoma, which appears to be genomically heterogeneous with subsets resembling both endometrioid and serous carcinomas.

Patient Recommendations

Based on this comprehensive research, patients should consider the following recommendations:

1. Weight management: Maintain a healthy BMI, as obesity is the strongest modifiable risk factor for endometrial cancer
2. Regular check-ups: Be aware of symptoms including abnormal bleeding and discuss concerns promptly with your healthcare provider
3. Genetic counseling: Consider genetic testing if you have a personal or family history of endometrial or colon cancer, especially if diagnosed before age 50
4. Treatment discussions: For young women wishing to preserve fertility, discuss conservative management options with your gynecologic oncologist
5. Second opinions: Seek care from specialists experienced with sentinel lymph-node mapping and minimally invasive surgical techniques
6. Advocacy: Be proactive in discussing racial disparities in care with your healthcare team if you belong to a minority group
7. Molecular testing: Inquire about tumor molecular profiling, especially for recurrent or advanced disease, to identify targeted treatment options

Patients should also be aware that oral contraceptive use provides significant protection against endometrial cancer (30-40% risk reduction), with longer use offering greater protection that persists for years after discontinuation.

Source Information

Original Article Title: Endometrial Cancer
Authors: Karen H. Lu, M.D., and Russell R. Broaddus, M.D., Ph.D.
Publication: The New England Journal of Medicine
Date: November 19, 2020
Volume and Issue: 383;21
Pages: 2053-2064
DOI: 10.1056/NEJMra1514010

This patient-friendly article is based on peer-reviewed research originally published in The New England Journal of Medicine. It maintains all significant findings, statistics, and clinical information from the original scientific review while making the content accessible to educated patients.