Endometrial cancer begins when the cells of the inner lining of the uterus, known as the endometrium, become malignant. It is the most common type of cancer in the uterus and is divided into different types based on cell histology. The types of endometrial cancer include adenocarcinoma, uterine carcinosarcoma, squamous cell carcinoma, small cell carcinoma, transitional carcinoma, and serous carcinoma. Most endometrial cancers are adenocarcinomas, and endometrial cancer is the most common type of adenocarcinoma.¹ Endometrial cancers are grouped into one of the following molecular subtypes: microsatellite instability-high (MSI-H), polymerase-epsilon (POLE) mutation, copy number high, and copy number low.^2,3

Approximately 50,000 women in the United States are diagnosed with endometrial cancer each year, making it the most commonly diagnosed gynecologic cancer.² In 2024, the American Cancer Society estimates that around 67,880 new cases of cancer of the uterus will be diagnosed, and around 13,250 women are estimated to die from cancers of the uterus.⁴

Endometrial cancer, also called endometrial carcinoma, occurs when the cells of the endometrium grow rapidly. The uterus may thicken, and the areas of thickness may form a tumor.⁵ Around 95% of endometrial cancer is caused by somatic mutations and 5% is caused by genetic mutations. Endometrial cancer caused by genetic mutations occurs 10 to 20 years before cancer caused by somatic mutations. Both types of mutations have similar histopathologic features, so molecular analysis and subtype classification is used to select therapies.³

Each molecular subtype differs in clinical prognosis. Tumors that result from the POLE mutations are usually high grade with deep myometrial invasion and lymphovascular space invasion and have good prognosis. Cancer with the p53 mutation (copy number high) is the most aggressive subtype and requires multiple treatment types. Tumors resulting from the MSI-H mutation have an intermediate prognosis and are associated with genetic cancer predisposition.³

The risk for endometrial cancer increases as women get older, and it is most common in White women. Other risk factors include overweight and obesity, a high fat diet, family history, starting the menstrual cycle before age 12 years, never having children, hormonal imbalance, estrogen replacement therapy, and polycystic ovary syndrome, among others.²

No validated screening tests are currently available for endometrial carcinoma. Approximately 90% of patients with endometrial cancer have postmenopausal bleeding. If a uterine neoplasm is suspected, the initial evaluation should include patient history and physical examination, a complete blood count, liver and renal function tests, an endometrial biopsy, and imaging.³

For diagnosing endometrial cancer, histologic evaluation is essential, with other laboratory and imaging studies aiding in excluding differential diagnoses and guiding preoperative staging. In postmenopausal women, transvaginal ultrasound (TVU) or endometrial sampling is recommended as first-line tests, but TVU is not advised for premenopausal women due to the lack of reliable endometrial thickness thresholds.⁴ Laboratory tests, such as urine pregnancy tests and complete blood counts, are important for assessing abnormal uterine bleeding and differential diagnoses. Endometrial biopsy is indicated for postmenopausal bleeding, persistent or irregular bleeding in premenopausal women with risk factors, and abnormal endometrial findings on imaging. Common biopsy techniques include endometrial aspiration, dilatation, and curettage (D&C) with or without hysteroscopy.⁴ Histological and molecular studies are conducted on biopsy samples, and molecular subtyping is recommended for accurate cancer staging. Imaging studies like TVU can evaluate postmenopausal bleeding, while CT and MRI are used for presurgical planning and assessing metastasis in high-grade cases. Persistent postmenopausal bleeding requires further assessment, even if initial ultrasound results are normal. For premenopausal women, a thorough evaluation of symptoms and risk factors is necessary before deciding on a biopsy, as ultrasound is less effective for diagnosis in this group.⁴

Diagnosing, treating, and managing endometrial cancer are best handled by a multidisciplinary team. This is largely due to the many risk factors involved in the disease’s development. Thus, a team that includes dietitians, oncology and gynecology physicians and nurses, pharmacists, and bariatric surgeons is necessary.⁴

Treatment options should be determined based on the individual characteristics of the patient (age, reproductive status, health, other acute and chronic diseases, and others) and tumor status (histotype, grade, tumor size, uterine, local/regional, nodal status, and intraperitoneal and/or extra-abdominal metastasis presence).⁴

The National Comprehensive Cancer Network guidelines divide endometrial cancer into three categories for treatments: 1) disease limited to the uterus; 2) suspected or gross cervical involvement; and 3) suspected extrauterine disease. Type 1 and grades 1 and 2 endometrial cancers are the most common and are confined to the uterus. They generally have excellent prognosis. On the other hand, type 2, serous, clear cell and grade 3 carcinomas are aggressive cancers and invade the lymphatic system and metastasize and are associated with poor prognosis. Thus, treatment approaches differ in these instances.^2-4

The primary treatment for endometrial cancer localized to the uterus involves surgical intervention, usually a total hysterectomy with bilateral salpingo-oophorectomy, preferably via a minimally invasive approach. This procedure includes surgical staging to assess the extent of the disease and determine the necessity for adjuvant therapies. Sentinel lymph node biopsy is recommended for all patients to evaluate lymph node metastasis, and lymphadenectomy may be performed in patients with intermediate-high and high-risk disease. Additionally, peritoneal washings for cytology can be obtained, although they are no longer a standard component of staging guidelines.^3,4

In cases of high-risk endometrial cancer, such as stage 1 endometrial serous carcinoma, omentectomy is recommended due to the frequent association with peritoneal dissemination and omental metastases. Hysterectomy alone can provide a 95% probability of relapse-free survival over five years for stage 1, low-risk endometrial cancer, but postsurgical adjuvant therapy may be necessary for cancers with high-risk factors.⁴

Adjuvant therapies include radiation and chemotherapy. Radiation therapy, which can be either external beam radiation or brachytherapy (internal radiation), is recommended after surgery for early-stage or high-risk tumors. Chemotherapy is generally advised for advanced or high-risk endometrial cancers, including those that have spread beyond the uterus or have high-grade histology.⁴ A common chemotherapy regimen includes carboplatin and paclitaxel, which can be administered concurrently or sequentially with radiation therapy. In some cases, chemotherapy alone is used.³

Several clinical trials have demonstrated the efficacy of adjuvant therapies in endometrial cancer. For instance, the PORTEC-2 trial compared external beam radiation therapy (EBRT) with vaginal brachytherapy alone for stage I endometrial cancer and found that both treatments provided excellent pelvic control, with vaginal brachytherapy associated with significantly less toxicity.⁵ The GOG-249 trial, which evaluated pelvic radiation versus vaginal cuff brachytherapy combined with chemotherapy in high-risk early-stage patients, found no significant difference in recurrence-free survival between the two groups but noted higher toxicity in the chemotherapy arm.⁶

Hormone therapy, such as high-dose progesterone, may be considered for women with early-stage, low-grade endometrial cancer who wish to preserve fertility or are not suitable surgical candidates. However, recurrence rates are high, making hormone therapy typically a temporary measure until childbearing is complete. Other endocrine therapies, including progestins, aromatase inhibitors, and tamoxifen, are used for estrogen receptor-positive metastatic disease, although their efficacy is not well established.⁴

Targeted therapies, including immune checkpoint inhibitors (e.g., pembrolizumab and atezolizumab), DNA repair inhibitors, and cellular pathway inhibitors, are used as monotherapy or in combination for recurrent or advanced endometrial cancers with specific molecular abnormalities. Checkpoint inhibitors are effective for tumors with mismatch repair deficiency, while DNA repair inhibitors are being studied for their efficacy in copy-number-high endometrial cancers. For serous endometrial cancers with HER2 overexpression, anti-HER2 medications are often added to standard chemotherapy to improve survival outcomes.⁴

Several clinical trials have provided robust evidence for the efficacy of these treatments. The NRG-GY018 trial demonstrated that the combination of pembrolizumab with carboplatin and paclitaxel significantly improved progression-free survival (PFS) and overall survival (OS) in patients with stage III or IV endometrial carcinoma with measurable disease. The trial showed a PFS of 74% versus 38% in the dMMR cohort and a median PFS of 13.1 months versus 8.7 months in the pMMR cohort, favoring the pembrolizumab arm.⁷ Similarly, the RUBY trial showed that adding dostarlimab to the carboplatin/paclitaxel regimen improved 24-month PFS (36.1% versus 18.1%) and OS (71.3% versus 56%) in patients with advanced or recurrent disease, with significant benefits observed in patients with dMMR/MSI-H tumors.⁸

For advanced and recurrent endometrial cancers, treatment involves a combination of surgery, chemotherapy, radiation, and targeted therapies tailored to the individual patient's disease characteristics and overall health. Localized recurrences may be managed with surgical and radiation approaches, while metastatic disease typically requires systemic therapies. Chemotherapy with carboplatin and paclitaxel remains the preferred treatment for advanced or recurrent disease, with neoadjuvant chemotherapy becoming more common for initial stage 4B endometrial cancer treatment.⁴

The GOG-209 phase III trial compared carboplatin/paclitaxel with the more intensive cisplatin regimen, doxorubicin, and paclitaxel plus filgrastim (G-CSF). It found similar oncologic outcomes but favored carboplatin/paclitaxel due to a better toxicity and tolerability profile.⁹ Additionally, a phase II study showed that adding bevacizumab to carboplatin/paclitaxel improved median PFS and OS, with an overall response rate of 82.8%.¹⁰

Hormone therapy can be used for hormone receptor-positive recurrent disease, and targeted therapies are being investigated for earlier use in the clinical course of advanced and recurrent endometrial cancer.⁴ Systemic therapies, including pembrolizumab/carboplatin/paclitaxel and dostarlimab/carboplatin/paclitaxel, are recommended for stage III or IV disease based on recent clinical trial data, showing improved progression-free and overall survival rates.³

Currently, FDA-approved drugs for endometrial cancer include dostarlimab-gxly, durvalumab, pembrolizumab, lenvatinib, megestrol acetate, and carboplatin-taxol.¹¹

The key to a successful outcome for endometrial cancer is prevention. Lifestyle changes, weight reductions, and a healthy diet can play a role in preventing the disease from starting. Once the disease has started, the ideal treatment is complete excision of the uterus. This is often not ideal, especially for women who have fertility concerns. Endometrial cancer is a complex and challenging disease that requires the expertise of a multidisciplinary team who are familiar with all aspects of the disease to improve outcomes.

1. American Cancer Society. What Is Endometrial Cancer? Updated March 27, 2019. Accessed July 24, 2024. https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html
2. Johns Hopkins Medicine. Endometrial Cancer. Accessed July 24, 2024. https://www.hopkinsmedicine.org/health/conditions-and-diseases/endometrial-cancer
3. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Uterine Neoplasms, version 2.2024. Accessed July 24, 2024. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf   
4. Mahdy H, Casey MJ, Crotzer D. Endometrial cancer. StatPearls. Updated April 20, 2024. Accessed July 29, 2024. http://www.ncbi.nlm.nih.gov/books/NBK525981/
5. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816-823. doi:10.1016/S0140-6736(09)62163-2
6. Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: Adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer. J Clin Oncol. 2019;37(21):1810-1818. doi:10.1200/JCO.18.01575
7. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312
8. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334
9. Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33):3841-3850. doi:10.1200/JCO.20.01076
10. Rose PG, Ali S, Moslemi-Kebria M, Simpkins F. Paclitaxel, Carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma. Int J Gynecol Cancer. 2017;27(3):452-458. doi:10.1097/IGC.0000000000000891
11. National Cancer Institute. Drugs approved for endometrial cancer. Updated June 24, 2024. Accessed July 29, 2024. https://www.cancer.gov/about-cancer/treatment/drugs/endometrial