Hello. My name is Shannon Westin, and I am a Professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at the University of Texas MD Anderson Cancer Center in Houston, Texas. 

In this module, I will be talking about “Improving Provider Awareness About Healthcare Equity: Improving All Patients’ Access to Care in Endometrial Cancer.”

Let us first review some general information about endometrial cancer, which also is known as uterine or corpus cancer. Endometrial cancer is the most common gynecologic malignancy in the United States and developed nations.¹ The age-adjusted incidence for this cancer is increasing steadily, and approximately 67% of patients with endometrial cancer are diagnosed with early-stage disease. To some degree, the increasing incidence of endometrial cancer may be related to increasing weight and obesity. 

Of note, non-Hispanic Black patients have a 2-fold higher likelihood of dying from endometrial cancer  compared with non-Hispanic White patients irrespective of disease stage at diagnosis and histology.^1,2 This is important because it indicates that other factors are contributing to increased disease incidence and mortality. 

When referring to endometrial cancer by histology, one will often see classification into 2 types: endometrioid and nonendometrioid.³ The field is trying to push away from that and adopt a molecularly based classification. There is support for universal molecular testing, and current guidelines encourage genomic profiling at initial evaluation using a validated and/or FDA-approved assay. Testing for mismatch repair (MMR) protein loss not only helps us assess the potential for Lynch syndrome, but also helps guide therapy. I believe testing of POLE and P53, as well as MMR protein testing, can help stratify disease based on risk and potentially inform our treatment. The International Federation of Gynecology and Obstetrics guidelines soon may be revised to include molecular classification for all patients with newly diagnosed endometrial cancer, which definitely will help with reimbursement for molecular testing.

First, I would like to discuss why we see high rates of diagnosis at later stages of disease. To be screened for endometrial cancer, the patient needs to report abnormal bleeding, and the HCP needs to do a workup with laboratory and other testing. Moreover, a recent study showed that Black patients are less likely to report postmenopausal bleeding than White patients (70% vs 79%, respectively; P <.001).⁴ This study also found that Black patients are less likely to receive guideline-concordant care. Thus, even when Black patients do report the postmenopausal bleeding, they might not be diagnosed or worked up appropriately. This highlights a significant unmet need in following guideline-concordant care that potentially can lead to higher rates of advanced-stage endometrial cancer at diagnosis. 

The figures on the right illustrate the increasing incidence and mortality rates of endometrial cancer over time. When we separate the data by race and ethnicity, we see a noticeable increase in endometrial cancer incidence and mortality among Black patients, as well as Hispanic/Latin descent patients.^11,12 Of importance, Black race is associated with the worst overall survival (OS) compared with all other races, and this is thought to be multifactorial. 

Similar to what we see in ovarian cancer, when Black patients with endometrial cancer receive treatment at high-volume centers, they have outcomes on par with those of White patients regardless of whether they have early- or advanced-stage tumors.^20,21 The improvements in outcomes tied to treatment at high-volume centers have been attributed to decreased racial disparities, fewer complications, and better overall care.²⁰ By contrast, receiving treatment at a low-volume centers is associated with reduced survival for both early-stage type I tumors (P <.0001) and advanced-stage type I tumors (P <.0001).

As previously mentioned, the field is moving away from defining endometrial cancer by histologic subtypes and moving toward a molecular classification so that we can improve treatment decisions for these patients. Data from The Cancer Genome Atlas were used to identify 4 major subtypes of endometrial cancer: POLE ultramutated, MSI hypermutated, copy number high (associated with TP53 gene aberrations), and copy number low.²² These subgroups show distinct OS outcomes. As seen in the graph, survival is best in POLE-mutated disease, followed by the nonspecific molecular profile, mismatch repair deficient (dMMR) status, and disease with TP53 gene abnormalities.²³ One can use a series of testing approaches to divide patients into these subgroups, starting with POLE sequencing, followed by immunohistochemistry for PMS2 and MSH6, and then moving to TP53 sequencing to put patients in the last 2 groups.²²

What are the treatment implications based on these molecular subgroups? The clearest opportunity is for patients with dMMR status, which would allow for consideration of immunotherapy. As I mentioned, this can be done quite simply with immunohistochemistry testing for protein loss of one of the MMR proteins—MLH1, MSH2, MSH6, or PMS2—particularly if the patient is suspected to have Lynch syndrome.^24-30 I also will note that if you have loss of MLH1 expression, it is important to follow up on this and determine whether the loss is caused by promoter hypermethylation or genetic mutation, as those 2 characteristics may have a distinct prognosis. 

A useful handout to help inform patients about the role of molecular testing in the management of endometrial cancer can be found here.

Another actionable biomarker for patients with endometrial cancer is HER2 gene overexpression or amplification, which occurs in approximately 30% of endometrial cancers—more so in serous and carcinoma histologies.^31,32 HER protein‒positive status has been associated with a benefit from the addition of trastuzumab to chemotherapy in stage III/IV or recurrent disease.³³ In general, HER2 protein staining of 3+ by immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization is indicative of a positive result and should be used to guide patient care.^31,32

Now, let us talk about how we can individualize care for patients with endometrial cancer. The figure on the right depicts various approaches to treatment based on the stage of disease and line of treatment.^26,32-35 Patients with early-stage endometrial cancer may receive only surgery. As the disease stage increases, we may add radiotherapy and chemotherapy. Patients with stage IV or recurrent disease often receive systemic therapy and the addition of targeted agents. More recently, the NCCN guidelines incorporated new data for the use of immunotherapy in combination with standard of care platinum-based chemotherapy in the frontline setting.³³ We will cover that in more detail later in this module.

An important question to ask is whether HCPs comply with treatment guidelines like those I just showed you and ensure that patients receive guideline-concordant care. This study by Huang and colleagues³⁶ identified lower adherence to guideline-based treatment for Black patients compared with White patients. As shown in the table on the right, when optimal guideline-based care is delivered, it can improve outcomes for Black patients but does not overcome all disparities, suggesting that multiple factors contribute to these disparities.

If your patient receives molecular testing, how can you use that information? If your patient has recurrent disease featuring MSI‒high status, there is a clear benefit from the use of single-agent immunotherapy. Both pembrolizumab and dostarlimab have been shown to yield very high response rates in patients with dMMR disease, with impressive durations of response in the recurrent setting.^37,38 However, this treatment approach will apply to only approximately 25% to 30% of our patients.

An option for patients with disease that is MMR proficient (pMMR) or microsatellite stable is supported by data from the KEYNOTE-775 trial, which evaluated the combination of lenvatinib, a nonspecific tyrosine kinase, and pembrolizumab, an immune checkpoint inhibitor.³⁹ Patients in this trial received either lenvatinib/pembrolizumab or the investigator’s choice of chemotherapy, which was either doxorubicin or weekly paclitaxel. The primary endpoint was PFS by blinded independent central review. The results of this trial led to the confirmation of an accelerated approval of the lenvatinib/pembrolizumab regimen by the FDA in May 2021.

The tables on the right show the baseline characteristics for the patient population in KEYNOTE-775.³⁹ The study population looked very similar to the usual population of patients with endometrial cancer whom we see in clinic. However, I want to highlight that the population enrolled on this trial was predominantly White (59%-63%) and Asian (21%-22%), with a very low proportion of Black patients (3%-4%). This raises the question of how representative this population may be of the general population in the United States and other developed countries. That said, there was a good mix of histologies (endometrioid: 13%-23%; serous: 25%-28%; clear cell: 4%-7%; mixed: 4%-5%) and prior lines of therapy (1 line: 67%-79%; ≥2 lines: 28%-33%).

In patients with pMMR disease, lenvatinib/pembrolizumab demonstrated a 30% overall response rate vs 15% with chemotherapy, which was similar to what we saw in the overall population (31.9% vs 14.7%).³⁹

The combination also improved both median PFS (6.7 vs 3.8 months; HR: 0.60; P <.0001) and median OS (18.0 vs 12.2 months; HR: 0.70; P <.0001) in patients with pMMR disease.³⁹ These findings confirmed and yielded the indication for lenvatinib/pembrolizumab in patients with endometrial cancer who do not have MSI‒high or dMMR disease.

The combination of lenvatinib/pembrolizumab can be challenging for some patients. This combination is associated with high rates of AEs, as well as high-grade AEs.³⁹ That being said, these toxicities can be managed―you just have to be aware of them and plan accordingly. Hypertension (64%), diarrhea (54%), and fatigue (33%) are quite common. Regarding immune-related AEs, hypothyroidism (57%) and arthralgia (30.5%) are the most common, and other immune-related AEs are less common.

There are some considerations to keep in mind for managing these AEs. Of most importance, make sure you educate patients about what could happen and prepare them to report any AEs to you so that you can help manage them. Performance status matters—you want to ensure that your patients are at the optimal dose of lenvatinib based on their performance status. The recommended dose of lenvatinib is 20 mg. However, if you have a patient with comorbidities or who perhaps already has encountered multiple AEs, you may want to consider reducing the dose to allow the patient to better tolerate lenvatinib. You should have a low threshold for dose interruptions and dose reductions. Ideally, you or a member of your team should reach out to patients during the first few weeks of treatment to monitor for hypertension and diarrhea, among other AEs, and intervene with prophylaxis (as appropriate) before the AEs become severe and the drug must be discontinued. For example, we often will send our patients home with a prescription for an antihypertensive (hydralazine); we also send them home with a blood pressure monitor so they can track their blood pressure and act accordingly.

The randomized phase III ENGOT-EN6/GOG-3031/RUBY trial evaluated carboplatin and paclitaxel with or without dostarlimab followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced or recurrent endometrial cancer. The coprimary endpoints of the study are progression-free survival (PFS) by investigator and overall survival.⁴⁰ 

Data presented at 2023 SGO and ASCO annual meetings showed the primary endpoint of PFS was met with a clinically significant 2-year PFS improvement for the dostarlimab arm vs the chemotherapy-alone arm in the overall population (36% vs 18%; HR: 0.64; P <.001), deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H; HR: 0.28; range: 0.16-0.50; P <.001), and proficient mismatch repair (pMMR)/microsatellite stable (MSS) population (HR: 0.76; range: 0.59-0.98).⁴⁰

The NRG GY018 trial also was a randomized phase III study of carboplatin and paclitaxel with or without pembrolizumab followed by pembrolizumab or placebo maintenance for 2 years in patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer. The primary endpoint was PFS per RECIST v1.1 by investigator in pMMR and dMMR popilations.⁴¹ 

Similar to the RUBY trial, the primary endpoint of PFS per RECIST v1.1 by investigator in the pMMR and dMMR population was met. Data presented at SGO 2023 showed a clinically significant improvement in median PFS for the pembrolizumab-containing arm vs chemotherapy-alone arm for the dMMR cohort (not reached vs 7.6 months; HR: 0.30; P <.001) and pMMR cohort (13.1 vs 8.7 months; HR: 0.54; P <.001).⁴¹

Regarding AEs related to immune checkpoint inhibitors—whether used as single-agent immunotherapy or in combination with lenvatinib—be aware that inflammation can arise in any organ, and it is important to address it quickly. An Interactive Decision Support Tool based on the National Comprehensive Cancer Network guidelines is available on the Clinical Care Options website to help you manage patients experiencing immune checkpoint inhibitor‒related toxicities in real time. You can find the most recent version of this tool here.

Additional helpful resources for endometrial cancer can be found here.

In addition to targeting HER2 and immune checkpoint pathways in endometrial cancer, there has been interest in targeting the P53 gene. Selinexor is a selective inhibitor of nuclear export that keeps tumor suppressor proteins in the cell nucleus, and keeping a functioning tumor suppressor such as the P53 protein in the nucleus might help kill the cancer cell and improve OS and PFS. The randomized, double-blind phase III SIENDO study compared selinexor with placebo maintenance in patients with stage IV or first-relapse endometrial cancer who had achieved a partial or complete response after 12 weeks of taxane/carboplatin (prior to surgery, radiotherapy, or hormonal therapy). That study demonstrated an improvement with selinexor in the intention-to-treat population vs placebo (median PFS: 5.7 vs 3.8 months; P = .024) (NCT03555422).⁴² However, the improvement was more pronounced in patients who had wild-type P53 gene (median PFS: 13.7 vs 3.7 months; P = .0003). This was a very exciting outcome for a maintenance therapy in endometrial cancer and led to the ongoing phase III XPORT-EC clinical trial, which is looking to improve outcomes specifically in patients with P53 wild-type disease (NCT05611931).

Diverse enrollment on clinical trials improves underrepresented racial and ethnic minority patients’ ability to access standard of care treatments and helps ensure timely access to healthcare services.^41,42 Clinical trials also help patients gain access to novel therapies and increase adherence to diagnostics and follow-up care, which ultimately will help us understand the true racial differences in gynecologic malignancies.^43,45 All HCPs should endeavor to inform patients about available resources and clinical trials and find positive ways to address patient skepticism and misconceptions about clinical trial participation. 

A useful handout to help inform patients about available resources and information on clinical trials can be found here.

Several ongoing trials in the frontline setting are evaluating promising therapies as treatment or maintenance therapy for endometrial cancer, such as dostarlimab in combination with either platinum-based chemotherapy or a PARP inhibitor (ENGOT-EN6/RUBY, NCT03981796); atezolizumab in combination with platinum-based chemotherapy vs platinum-based chemotherapy alone (AtTEnd, NCT03603184); durvalumab plus platinum-based chemotherapy followed by maintenance durvalumab with or without olaparib (DUO-E, NCT4269200); lenvatinib/pembrolizumab vs platinum-based chemotherapy (LEAP-001, NCT03884101); and maintenance selinexor vs placebo (XPORT-EC, NCT05611931). Visit ClinicalTrials.gov for enrolling clinical trials near you.

Regarding communication, we need to improve communication between patients and HCPs, acknowledge patients’ beliefs and values, minimize HCP bias, ensure that we are offering clinical trials to all patients, and work on having the medical care team be representative of the patients they are treating.^47-48 Regarding costs, we must work on reducing treatment costs and provide support for costs unrelated to medications, such as transportation and missed wages. Regarding gaps in outcomes research, we need to increase participation of underrepresented groups in clinical trials and understand not only the social differences, but also the genetic and potential molecular differences in tumor biology based on race. Oncology pharmacists, nurses, patient navigators, and other members of the healthcare team can help empower patients and ensure that they have adequate resources and education so they can make the right treatment choices for themselves. 

A useful handout to help inform patients about improving patient‒HCP communication and treatment choices can be found here.