A modern approach to endometrial cancer care: molecular risk stratification, targeted therapy and team science

Oct. 08, 2021

The field of endometrial cancer — the most common female genital tract diagnosis — is shifting toward minimally invasive surgery and molecular targeted therapy, according to two experts at Mayo Clinic's campus in Rochester, Minnesota: Andrea Mariani, M.D., M.S., a gynecologic oncologist, and Saravut (John) J. Weroha, M.D., Ph.D., a medical oncologist.

Molecular risk classification

Minimally invasive surgery with sentinel lymph node biopsy — versus more-invasive open surgery used previously — is the most common and only treatment needed for approximately 70% of patients diagnosed with endometrial cancer.

The challenge is determining which patients make up the remaining 30%, those who may benefit from adjuvant therapy — chemotherapy, radiotherapy or a combination of these — due to tumor characteristics. This means identifying patients with high- and low-risk endometrial cancer. This is not always an easy task, according to Dr. Mariani. "Our goal is to limit the administration of postoperative therapy to only those patients who need it: those at higher risk," he says.

The focus of the research of Drs. Mariani and Weroha and colleagues is identifying patients at high risk so they can be treated with a targeted approach. The research team is also working toward predicting therapeutic responses to deliver personalized postoperative treatment.

Traditionally, specialists classify endometrial cancer as type 1 or 2. Risk stratification at the time of surgery is important because the opportunity to cure endometrial cancer is greatest at the time of initial diagnosis, when operations are typically performed, says Dr. Weroha. Contemporary molecular genetics-based risk classification may allow physicians to escalate a patient's care to reduce recurrence risk. "We want to treat a patient at high risk quickly and aggressively, so we don't have to see her at recurrence and tell her it's not curable," says Dr. Weroha. Conversely, if a patient's tumor is considered lower risk at surgery, physicians can de-escalate treatment, lowering complication potential.

Team science and targeted therapy

Dr. Weroha says patients with endometrial cancer may benefit greatly by being seen at a large specialty center for comprehensive risk assessment and appropriate treatment determination. He recommends a center with significant endometrial cancer research and treatment resources for women deemed to be at high-risk for recurrence and mortality.

At Mayo Clinic, surgeons and medical oncologists specializing in endometrial cancer collaborate closely to provide risk-appropriate treatment. Many patients seen in medical oncology have endometrial tumors classified as aggressive by multiple characteristics, including molecular genetics, and have experienced recurrence, says Dr. Weroha. Although all patients with recurrent endometrial cancer are eligible for immunotherapy to promote cancer regression aided by the patient's own immune system, critical decisions are not limited to whether it should be administered as monotherapy or combination therapy. Patients also need to discuss access to newer agents designed to improve the efficacy of immunotherapy in a clinical trial.

Many molecular therapies are only available in clinical trials. One such trial Dr. Weroha is particularly excited about is evaluating an immunotherapeutic standard of care versus the standard of care plus immunotherapeutic enhancement.

In another trial involving Mayo Clinic that will open soon, researchers will analyze each participant's endometrial tumors for mutations. Based on the mutations identified, investigators will assign drugs to target that patient's cancer in conjunction with immunotherapy, says Dr. Weroha.

The team is also researching potential therapeutic avenues in the laboratory, learning more about endometrial cancers and molecular-level risk. Drs. Weroha and Mariani and colleagues grow tumors in 3D cultures (ex vivo) and in animal models (in vivo).

Referral insights

According to Dr. Mariani, if surgery is performed in a tertiary care center such as Mayo Clinic, surgeons have access to resources to perform minimally invasive surgery and assess sentinel nodes when indicated. Intraoperative pathology with frozen section also is available when needed. Moreover, many endometrial cancer patients are obese and have multiple comorbidities, and surgery in a referral center allows surgeons to provide state-of-the art surgical and anesthesiologic care to these medically complex patients.

As the field moves toward a molecular-based approach, a tertiary care center may be the best place for patients requiring adjuvant therapy, says Dr. Mariani. Another key feature of a referral center such as Mayo Clinic is care directed by patient-centric team science that integrates endometrial cancer specialists from various departments and incorporates research and innovation into clinical practice. "This is a time in which we're fast moving the molecular classification into clinical practice," says Dr. Mariani. "Thus, referral to high-level cancer treatment is important, especially for patients at high risk of recurrence."

Molecular analysis helps reveal hidden tumor characteristics that are not evident at a traditional pathology evaluation. "There are certain types of endometrial cancer in which the pathologist can tell us, at first glance, 'this cancer looks aggressive,' " says Dr. Mariani. "But the molecular approach can help us see the so-called sheep in wolves' clothing, such as a DNA polymerase epsilon gene. These cancers can look aggressive, but they behave as indolent tumors.

"On the other side, the molecular approach can also help us see 'wolves in sheep's clothing,' such as L1CAM-positive tumors. Those cancers may sometimes look good under a microscope, but one could easily undertreat them without fully understanding their risk."

For more information

National Cancer Institute (NCI). Testing the Addition of the Immunotherapy Drug Pembrolizumab to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) in Stage III-IV or Recurrent Endometrial Cancer. ClinicalTrials.gov.

Alliance Foundation Trials, LLC. A Study of Targeted Agents With Atezolizumab for Patients With Recurrent or Persistent Endometrial Cancer (EndoMAP). ClinicalTrials.gov.