Introduction
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 Around 13,030 women are estimated to die from cancers of the uterine body in 2023.4
Etiology
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
Screening and Diagnosis
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. Genomic profiling is encouraged, as well as ancillary studies of POLE mutations, mismatch repair/MSI, and aberrant p53 expression with the morphologic assessment of histologic tumor type. Consideration for NTRK gene fusion testing for metastatic or recurrent endometrial carcinoma through a validated or FDA-approved assay is also recommended. People under 50 years of age should be screened for genetic mutations, as well as individuals with Lynch syndrome since they are at a higher lifetime risk for endometrial cancer. These patients should also have yearly endometrial biopsies. In patients who are symptomatic but have a negative office endometrial biopsy, a fractional dilation and curettage under anesthesia should be performed due to a 10% rate of false negatives in these patients. A hysteroscopy can be useful for evaluating the endometrium for lesions if the patient has persistent or recurring bleeding.3
Treatment and Management
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.6
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).6
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.2,3,6
In patients with disease limited to the uterus who are suitable for primary surgery, a total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) and surgical staging is recommended. If the patient desires fertility-sparing options, continuous progestin-based therapy may be considered for those with noninvasive disease. To stage medically operable patients with endometroid histologies, the recommended surgical procedure includes removing the uterus and bilateral tubes and ovaries with lymph node and abdominal assessment. In patients not suitable for primary surgery, external bean radiation therapy (EBRT) and/or brachytherapy is recommended. Alternatively, hormone therapy, including progestin intrauterine devices, can be used in select patients.3
For patients with suspected or gross cervical involvement, a cervical biopsy or pelvic magnetic resonance imaging should be performed if not previously done. If a negative result is obtained, the primary treatment should include TH/BSO and surgical staging and appropriate adjuvant treatment after staging surgery. If a positive result is obtained and the patient is suitable for surgery, TH or radical hysterectomy and BSO and surgical staging with adjuvant treatment after staging surgery or EBRT with brachytherapy followed by TH/BSO and surgical staging should be done. In patients not suitable for primary surgery, EBRT and brachytherapy with or without platinum-based chemosensitization is recommended. If then rendered operable, surgical resection, or systemic therapy followed by surgical resection, is recommended. If the patient is still not operable, EBRT and brachytherapy are recommended.2,3
Patients with suspected extrauterine disease are recommended to undergo imaging studies along with CA-125 testing. Patients suitable for surgery with no evidence of extrauterine disease are treated using the guidelines for disease limited to the uterus. Patients with abdominal/pelvic-confined disease require TH/BSO with surgical staging/debulking, followed by adjuvant treatment. For distant metastases, systemic therapy with or without EBRT, stereotactic body radiation therapy (SBRT), and TH/BSO are recommended. If surgery is not suitable and locoregional disease is present, EBRT with or without brachytherapy and systemic therapy is recommended, followed by re-evaluation for surgery. In distant metastases with no surgery, the guidelines recommend systemic therapy followed by re-evaluation for surgical resection and/or RT based on response.2,3
The guideline-preferred systemic first-line therapy for recurrent disease includes multiagent chemotherapy regimens such as carboplatin/paclitaxel, carboplatin/paclitaxel/bevacizumab, or carboplatin/docetaxel. Second-line or subsequent-therapy options include cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, ifosfamide/paclitaxel, and cisplatin/ifosfamide.2,3
For non MSI-high/non-dMMR endometrial carcinoma, guideline-preferred second-line regimens include lenvatinib with pembrolizumab or pembrolizumab for MSI-H/dMMR or TMB-H. This is based on data from the Keynote-146 phase 1/2 trial that showed the combination of pembrolizumab and lenvatinib had promising anti-tumor activity in patients with advanced endometrial cancer regardless of their MSI status.7
Currently, FDA approved drugs for endometrial cancer include dostarlimab-gxly, pembrolizumab, lenvatinib, megestrol acetate, and carboplatin-taxol.8
Combination regimens are being explored in several ongoing trials. The phase 3 DOMENICA study is evaluating the efficacy and safety of dostarlimab versus carboplatin-paclitaxel in patients with mismatch repair deficient relapse or advanced endometrial cancer.9 This combination is also being studied in the RUBY trial.10 In the FIERCE trial, pembrolizumab combined with radiation administered to the upper part of the vagina is being explored.11
Conclusion
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.
References
1. American Cancer Society. What Is Endometrial Cancer? Updated March 27, 2019. Accessed March 9, 2023. https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html
2. Johns Hopkins Medicine. Endometrial Cancer. Published August 8, 2021. Accessed March 9, 2023. https://www.hopkinsmedicine.org/health/conditions-and-diseases/endometrial-cancer
3. Abu-Rustum N, Yashar C, Arend R, et al. Clinical practice guidelines in oncology: uterine neoplasms, version 1.2023. JNCCN. 2023;21(2):181-209. doi:110.6004/jnccn.2023.0006.
4. American Cancer Society. Key Statistics for Endometrial Cancer. Updated January 12, 2023. Accessed March 9, 2023. https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics.html
5. The American College of Obstetricians and Gynecologists. Endometrial Cancer. Published February 2019. Accessed March 9, 2023. https://www.acog.org/womens-health/faqs/endometrial-cancer
6. Mahdy H, Casey MJ, Crotzer D. Endometrial cancer. StatPearls. Updated September 26, 2022. Accessed March 9, 2023. http://www.ncbi.nlm.nih.gov/books/NBK525981/
7. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981-2992. doi:10.1200/JCO.19.02627
8. National Cancer Institute. Drugs approved for endometrial cancer. Published December 6, 2013. Updated August 12, 2021. Accessed March 9, 2023. https://www.cancer.gov/about-cancer/treatment/drugs/endometrial
9. Randomized phase III trial in MMR deficient endometrial cancer patients comparing chemotherapy alone versus dostarlimab in first line advanced/metastatic setting. ClinicalTrials.gov. Published January 21, 2022. Updated August 10, 2022. Accessed March 9, 2023. Clinicaltrials.gov identifier NCT05201547. https://clinicaltrials.gov/ct2/show/
10. NCT05201547A phase 3, randomized, double-blind, multicenter study of dostarlimab (TSR-042) plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in patients with recurrent or primary advanced endometrial cancer (RUBY). ClinicalTrials.gov. Published June 11, 2019. Updated August 12, 2022. Accessed March 9, 2023. Clinicaltrials.gov identifier NCT03981796. https://clinicaltrials.gov/ct2/show/
11. NCT03981796A phase Ib trial of vaginal cuff brachytherapy + pembrolizumab (MK3475) followed by 3 cycles of dose dense paclitaxel/q 21 day carboplatin + pembrolizumab (MK3475) in high intermediate risk endometrial cancer. ClinicalTrials.gov. Published April 30, 2019. Updated February 8, 2023. Accessed March 9, 2023. Clinicaltrials.gov identifier NCT03932409. https://clinicaltrials.gov/ct2/show/NCT03932409