CE / CME
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 29, 2023
Expiration: August 28, 2024
Endometrial Cancer Overview
Uterine corpus cancer, also known as endometrial cancer, unfortunately is on the rise. Approximately 66,000 women will be diagnosed with endometrial cancer in 2023 alone, and approximately 13,000 of them will die from the disease.1 Most endometrial cases (>83%) are endometrioid, where approximately 80% of the disease is confined to the uterus.2 Women diagnosed with low-grade endometrioid endometrial cancer typically have an excellent prognosis, with a 5-year survival approaching 93%.
However, there is a category of nonendometrioid endometrial cancer that is typically more aggressive and less likely to be confined to the endometrium at diagnosis.3 Aggressive endometrial cancer subtypes include serous carcinoma, carcinosarcoma, clear cell carcinoma, and undifferentiated/dedifferentiated carcinoma. Compared with low-grade endometrioid endometrial cancer, these aggressive subtypes are typically associated with poorer prognoses: Early-stage and late-stage uterine serous carcinoma have a 5-year survival rate of 74% and 33%, respectively, whereas uterine carcinosarcoma has a 5-year survival rate of approximately 35%, and clear cell carcinoma has a survival rate between 42.3% to 62.5%.4-6 Stage I/II undifferentiated endometrial cancer has a comparatively higher 5-year survival rate of 84%, although outcomes for stage III/IV disease are much worse, with 5-year survival rates of 38% and 11%, respectively.7
However, there are racial and ethnic disparities in both the incidence and outcome of endometrial cancer.3 Namely, hysterectomy-corrected endometrial cancer cases are greater in Black women than in White women, and Black women have the lowest survival rate, even when controlled for subtype and stage.
Risk Factors for Endometrial Cancer
What are the risk factors for endometrial cancer?
The biggest risk factor for endometrial cancer development is obesity. Approximately 70% of endometrial cancer cases can be attributed to excessive body weight and insufficient physical activity, whereas approximately 30% can be attributed to other factors,8 including Lynch syndrome (or genetic causes that are also associated with colon cancer and gastrointestinal cancers),9,10 type 2 diabetes, polycystic ovarian syndrome (or any other condition that results in overall above average levels of estrogen), late-onset menopause, use of postmenopausal estrogen alone, or tamoxifen use as breast cancer therapy.
Nonendometrioid Endometrial Cancer: High-Risk Histology
I would like to switch focus to high-risk histology, which we previously referred to as nonendometrioid endometrial cancer. During the past 17 years or so, the incidence of nonendometrioid endometrial cancer increased by approximately 3.1% annually, and the incidence of serous histology subtype increased by approximately 5% annually.11
Increasing rates of obesity are directly correlated with increasing rates of nonendometrioid types of endometrial cancer.12 Initially, experts believed the increase in nonendometrioid endometrial cancers was because of an excess of estrogen resulting from the additional body weight. However, new evidence suggests that obesity may create a proinflammatory microenvironment that causes increases in these high-risk subtypes.
Furthermore, there are genetic mutations and molecular markers found to be associated with more aggressive tumor phenotypes, such as the inactivation of the tumor suppression gene TP53, as well as the high-risk prevalence of other mutations in PIK3CA, ERBB2, FBXW7, and PPP2R1A.12
PIK3CA and ERBB2 are both involved in cell growth: PIK3CA encodes a key component of a signaling pathway that mediates cell growth, proliferation, and survival, whereas ERBB2 encodes a protein in the epidermal growth factor receptor family.13,14
By contrast, FBXW7 and PPP2R1A are both involved in tumor suppression.15,16 FBXW7 encodes a critical tumor suppressor and controls proteasome-mediated degradation of oncoproteins, and PPP2R1A encodes a subunit of a tumor-suppressive enzyme. In brief, mutations in these genes contribute to tumor progression by either promoting uncontrolled cell proliferation or disrupting tumor suppression. Mutations in these genes are especially prevalent in patients with serous tumors.12 Of importance, although these molecular markers are linked to more aggressive tumor phenotypes, understanding the role they have in tumor biology may lead to novel treatments and overall improvements in patient care.
Because health disparities in endometrial cancer outcomes cannot be attributed solely to differences in socioeconomic status or treatment, it is possible that increased prevalence of these genetic markers in certain populations may contribute to poorer outcomes, although current research finds few differences between nonendometrioid tumors in women of different races.12
Increasing Incidence and Mortality of Endometrial Cancer in the United States
The rates of both endometrioid and nonendometrioid cancer are on the rise. The figure shows rates of uterine cancer by race/ethnicity spanning approximately 16 years, illustrating the upward trend over time and demonstrating that the rate of uterine cancer is increasing among all races and ethnicities.17
Evidence suggests that increasing rates of obesity are driving the growth in endometrial cancer cases. Obesity in both young adulthood (18-20 years of age) and adulthood is positively associated with endometrial cancer risk (odds ratio [OR]: 1.26, 95% CI: 1.06-1.50; and OR: 2.85, 95% CI: 2.47-3.29, respectively).18 In fact, obesity in young adulthood is associated with endometrial cancer risk, even when accounting for adulthood BMI. This increased risk potentially may be the result of cumulative exposure to chronic inflammation, hyperinsulinemia, hyperglycemia, and heightened estrogen production.19
Disproportionate Mortality Rate Ratio in Uterine Cancer Among Black Women
The figure on the right paints a clear picture of the existing disparity in survival outcomes based on race. We see that from the years 1990-1994 and 2015-2019, the mortality rate for endometrial cancer increased for all races.20 However, the mortality rate per 100,000 individuals among Black patients is disproportionately higher, approximately double, when compared with non-Hispanic White, Asian/Pacific Islander, and Hispanic patients.
Health Disparities in Endometrial Cancer
We know that despite a 5-year overall survival (OS) rate >80% for endometrial cancer, Black patients continue to have poorer outcomes compared with patients of other races/ethnicities.21-24 The question is, why? Published reports suggest that delay in diagnosis may contribute to a decrease in OS, particularly that Black patients and those with nonprivate insurance status are more likely to present with more advanced disease.25-27 Black patients are also more likely to receive less care because of lack of insurance or low-income status. Raising awareness about healthcare disparities and promoting early recognition and diagnosis is critical to improving outcomes for Black patients with endometrial cancer.
Delay in Diagnosis and Treatment in Endometrial Cancer
A qualitative study by Doll and colleagues28 conducted semistructured interviews of 15 Black patients with endometrial cancer throughout the United States with the goal of describing the prediagnostic experiences of symptoms and symptom disclosure. During these interviews, investigators assessed what factors had a role in the delay in endometrial cancer diagnosis. Among the recurring themes that came to light from that report, it was found that the patients had an unclear definition of normal and abnormal menopause, and they were more likely to misinterpret bleeding symptoms by comparing them with similar symptoms that a relative or friend had rather than alerting their HCP or doctor about their bleeding. Nondisclosure of bleeding symptoms to families or HCPs prevented earlier diagnosis for many patients. Some patients did tell their HCP but received responses from first-line HCPs that were not in alignment with the risk of endometrial cancer among Black patients in the United States, and the “shock and awe” of receiving a cancer diagnosis extended the time interval from diagnosis to surgery and treatment.
Evaluation of Black Patients With Postmenopausal Bleeding
As demonstrated in the previous study, some factors contributing to delayed diagnosis are dependent on the patient, but successful screening for endometrial cancer also requires an appropriate workup.
Patients who receive guideline-concordant care often experience improved outcomes and survival, making it an important factor to assess when considering disparities in healthcare. Another study by Doll and colleagues29 sought to examine whether Black patients who experience postmenopausal bleeding received guideline-concordant care. Using Surveillance, Epidemiology, and End Results–Medicare, this retrospective study identified 4354 White patients and 537 Black patients diagnosed with endometrial cancer from 2001-2011 and obtained reports of postmenopausal bleeding together with procedures conducted before diagnosis. The investigators used these data to evaluate the correlation between race and appropriate diagnostic workup. The study demonstrates that 79% of White vs 70% of Black patients (P <.001) who reported postmenopausal bleeding received guideline-concordant care, indicating that there is a discrepancy between those 2 populations in receiving guideline-concordant care. Moreover, nonguideline-concordant pathways have been associated with higher rates of advanced-stage endometrial cancer at diagnosis (with an adjusted OR: 1.90-2.88).
Suboptimal Receipt of Guideline-Based Treatment in Black Patients Compared With White Patients
After diagnosis, another factor that could be contributing to the disparity in survival outcomes for Black patients compared with White patients with endometrial cancer is the receipt of guideline-based treatment. A study published in the American Journal of Obstetrics and Gynecology sought to determine if better adherence to evidence-based treatment recommendations could improve survival outcomes for Black patients.30 In this study, investigators used the National Cancer Database to identify 35,035 Black patients and 275,173 White patients (N = 310,208) in the United States with a diagnosis of endometrial cancer, who received treatment from 2004-2016. To determine how adherence to evidence-based treatment influenced survival outcomes, investigators established 5 quality metrics: surgical treatment in less than 6 weeks after diagnosis, use of minimally invasive surgery, pelvic lymphadenectomy, adjuvant radiation, and systemic chemotherapy for stage III/IV disease.
When compared with perfectly adherent White patients, Black patients had a higher relative risk (RR) of mortality at 30 days (adjusted RR [aRR]: 1.56; 95% CI: 1.30-1.88), 90 days (aRR: 1.29; 95% CI: 1.13-1.46), and 5 years (aRR: 1.27; 95% CI: 1.23-1.31).
In stage I disease, Black women with perfect adherence to all quality metrics experienced improved outcomes relative to other Black women, although they remained at higher risk of mortality at 30 days (aRR: 2.25; 95% CI: 1.30-3.90), 90 days (aRR: 1.84; 95% CI: 1.23-2.76), and 5 years (aRR: 1.42; 95% CI: 1.26-1.59), when compared with perfectly adherent White patients. In patients with stage III disease, perfect adherence also improved outcomes for Black patients. However, Black patients still experienced a higher risk of mortality at 30 days (aRR: 1.86; 95% CI: 1.01-3.44), 90 days (aRR:1.37; 95% CI: 0.89-2.11), and at 5 years (aRR: 1.35; 95% CI: 1.22-1.50) when compared with perfectly adherent White patients.
Taken together, adherence to the quality metrics correlated with improved survival for Black patients. However, Black patients were less likely to receive each level of guideline-based treatment. Moreover, receiving evidence-based care improved outcomes for Black women but did not fully resolve disparities in survival observed for this population, suggesting that other factors may be contributing to lower survival outcomes.
Structural Racism/Bias Promote Disparity
In addition to disparities in the receipt of care, we have to think about structural racism or HCP bias experienced by patients of color. A qualitative study from 5 cancer centers in the United States conducted 91 interviews with cancer center leaders, principal investigators, referring HCPs, study coordinators, and research staff regarding how they interacted with underserved patients of color.31 Investigators analyzed the content of these interviews to assess interviewee biases. What emerged from the analysis of the interviews was that underserved patients of color were perceived as more challenging to interact with. Underserved patients of color also were not perceived to be ideal patients for clinical research studies (clinical trials) and thus were not approached for available clinical trials. Limited clinic time with these patients and a negative perception of underserved patients of color led to withholding available clinical trial information. Of importance, a few site investigators also indicated that race was not relevant to clinical trial improvement.
Oncologist implicit bias also has been demonstrated to affect the care underserved patients of color receive.32 For instance, non-Black oncologists with high implicit bias scores had shorter interaction time and less communication with patients who were Black. Ultimately, less communication can potentially result in less confidence in treatment recommendations from the HCP, contributing to disparities in care for Black patients.
Oncology Clinical Trial Enrollment Racial Composition
There is a pressing need to improve clinical trial enrollment among underserved patients of color. Results from a study of 230 oncology trials leading to approvals from the FDA spanning a 10-year period showed that only 63% of these trials reported at least 1 race.33 Although investigators are mandated to include that data, approximately 37% of trials had no mention of race. Furthermore, Black and Hispanic patients were underrepresented in landmark clinical trials.33 The figure on the right compares the incidence and mortality of patients with cancer and their relative enrollment on clinical trials. In the White population, the rate of incidence and mortality are essentially equivalent to clinical trial enrollment. In the Asian population, the enrollment rate is higher than the incidence and mortality rate. By contrast, there is much lower enrollment for Black and Hispanic patients on clinical trials compared with the incidence and mortality observed in those populations.
Why is evaluation of diversity in clinical trial enrollment necessary? A retrospective study by Morton and colleagues presented at the Society of Gynecologic Oncology in 2023 underscores the importance of access to clinical trials for vulnerable patients.34 This study compared patients with ovarian cancer who received standard-of-care treatment outside a clinical trial (n = 259) vs patients who were patients in clinical trials (n = 46) and found a 50% improvement in 3-year OS in favor of clinical trial patients. In another retrospective study presented by Patel and colleagues35 in 2018,of patients who had never enrolled on a clinical trial, White patients were reported to have a noticeably higher OS rate when compared with patients of underrepresented ethnic or racial groups. However, among patients who had enrolled on one or more clinical trials, there was no difference in OS rates between White patients and women from underrepresented ethnic or racial groups. Thus, boosting the participation of underrepresented patients of color and promoting access to guideline-concordant care could help further validate study outcomes, increase overall patient survival, and meaningfully contribute to a reduction in inequality in oncologic care.
Improving Clinical Trial Engagement
To improve clinical trial engagement, we must first recognize that Black patients are a vulnerable population. Incidences like the Tuskegee experiment, where patients were not given adequate information on what the study was about, created a historic vulnerability and mistrust.33 Now, there are many safeguards in place because of those historic trials that took advantage of these vulnerable populations. It is important to educate patients on the safety mandates and to practice transparency regarding the safety of clinical trials, what the trial is about, and letting the patient know that they can unenroll if they feel uncomfortable.
In addition, cancer centers must intentionally engage in underserved patient of color recruitment, such as having nurse navigators or research coordinators who can help a patient navigate through screening and clinical trial enrollment.36 Community outreach is a great way to let patients know that there are clinical trials within the area, through direct patient referrals, oncologist communications, or primary care physician engagement.
Another barrier to clinical trial enrollment is transportation and access to clinical trials in the local community.37 Recently, clinical trial sponsors have started providing transportation for patients who may have difficulty getting to the cancer center. However, the identification of transportation challenges is not easy. In my practice, I have not always been able to identify it early on, but once I have determined that a patient has difficulty getting to the cancer center, I engage our social workers at the cancer institute to look for resources that may help patients get to their appointments.
High-Volume Treatment Centers Are Associated With Better Outcomes for Black Patients With EC
Another way to improve health disparities is to increase patient access to high-volume treatment centers. All patients, not just those with endometrial cancer, do better in a high-volume treatment center.38,39 For example, if a cancer center provides care for 50-100 patients per year with a particular type of cancer, the care team might be more familiar with the required treatments and patient management.
The table on the right shows data from a study using the National Cancer Database to identify 243,422 White patients and 27,764 Black patients with endometrial cancer (N = 271,186) treated at 1059 different hospitals from 1998-2012.38 The study investigators assessed whether hospital volume influenced race-based outcomes in patients with endometrial cancer. Investigators also stratified hospitals into categories based on annual procedural volume and assessed the 5-year survival rates of Black vs White patients across these categories. Of note, the 2-year survival differential between Black and White patients decreased at high-volume hospitals, in both early-stage (-0.5; 95% CI: -0.9 to 0.0) and advanced-stage disease (1.2; 95% CI: -2.9 to 5.3). By contrast, receipt of care at low-volume treatment centers was associated with reduced 2-year survival for Black vs White patients with early-stage (-1.4; 95% CI: -2.4 to -0.5) and advanced-stage tumors (-12.4; 95% CI: -24.0 to -0.9).
In an ideal world, all patients would have access to equal gynecologic cancer care at high-volume treatment centers. However, even if HCPs refer their patients to high-volume treatment centers, the reality is that there are many factors that determine whether this is feasible for an individual. Other ways to make care at high-volume centers more accessible include virtual tumor boards and offering consultations for people in the community, although patient privacy concerns and state licensing also may place limitations on overcoming these barriers to care.
COVID-19 Highlighted Healthcare Disparities: Lessons Learned
COVID-19 placed a magnifying glass over the healthcare disparities in the United States. In particular, we saw that patients who were Black, Latino/a, of indigenous descent, immigrants, and those with lower socioeconomic status were disproportionately affected by the COVID-19 pandemic.40
A major factor contributing to these disparities continues to be access to insurance and healthcare centers.40 To improve patient health status, we must improve access to healthcare. Washington, DC, is a great example of what can be done to improve healthcare access. In the city, residents have access to healthcare regardless of their documentation status. In my practice, I often receive patients who are not aware that they have access to healthcare because of their status as residents of the city. In those cases, social workers are typically able to get them coverage within 1 month.
We must also address structural racism and its impact on healthcare outcomes. Implicit bias training is necessary for all, regardless of who the HCPs are or what their racial background is. Having diverse and representative medical staff is also important for patients to be able to interact with and trust someone who looks like them. Primary care and cancer care centers must intentionally hire trainees from disadvantaged/underrepresented backgrounds.
Finally, we must improve communication with disadvantaged and underserved populations. It is crucial to ensure translator availability in person through communication with peer or nurse navigators and provide written content in their native language. For patient-friendly materials on endometrial cancer and enrolling clinical trials, I recommend these online sources: The American Cancer Society, Endometrial Cancer Foundation for Women’s Cancer, and ClinicalTrials.gov.
Real-world Case Study
I would like to end my discussion with a real-world case study of a 65-year-old Black woman who has never been pregnant. This patient initially presented with postmenopausal bleeding. She was unable to recall the age of menopause onset. She stated that she had heavy vaginal bleeding approximately 6 months before her presentation for workup and was not able to get a swift appointment as a new patient in the area. When she did see an obstetrics and gynecology specialist, a pap smear demonstrated atypical glandular cells. She ultimately underwent an endometrial biopsy, which was consistent with serous carcinoma. The patient underwent minimally invasive surgery for diagnosis and staging and was found to have stage IV serous carcinoma: noted at the time of surgery. She underwent guideline-concordant treatment. Surveillance imaging 6 months after treatment revealed likely recurrent disease in the omentum and peritoneal lining. An interventional radiology-guided biopsy confirmed endometrial cancer disease recurrence.
This case study highlights recurrent themes of delay in diagnosis and disparity in endometrial cancer care. The patient is a Black woman, a high-risk population, who presented with postmenopausal bleeding and is unable to recall her age of menopause onset. She did not have access to care in a timely manner. She did undergo guideline-concordant care, but her prognosis is highly dependent on her stage at diagnosis (stage IV).
Ultimately, she underwent guideline-concordant care, and the next step was to consider her for any clinical trial opportunities in her community. This case study also presents an opportunity to think about where we can improve in this scenario. I ask you, what could you offer her next?
Back
