The evaluation of biomarkers by molecular techniques and immunohistochemistry has become increasingly relevant to the diagnosis and treatment of endometrial cancer. Biomarkers enable a more accurate disease prognosis and may help predict which therapies a patient is likely to respond to.

We previously divided endometrial cancer into types 1 and 2 roughly based on histology to denote lower- and higher-risk patient groups. However, with the release of The Cancer Genome Atlas (TCGA), endometrial cancers are now divided into 4 prognostic groups, which we are learning also can be diagnostic classifications and predictive in terms of identifying potential therapies. One group of patients who seem to do very well are those whose endometrial cancer is characterized by POLE mutations. This has raised the question of whether we could potentially de-escalate treatment, particularly adjuvant treatment, in some cases.

There is also an intermediate-prognosis group characterized by mismatch repair deficiency and microsatellite instability. These characteristics are not only seen in the inherited tumors, such as with Lynch syndrome, but also appear to indicate who would be more sensitive to immunotherapies, particularly ICIs. Another intermediate-prognosis group of patients are those with no specific molecular profile, and these individuals tend to have wild-type TP53. In this group of patients, we have some evidence supporting the use of the SINE selinexor.

Patients who have mutated TP53 seem to have the worst prognosis. This includes many of those with serous tumors and those who are more likely to have metastatic disease or recurrence. We have seen that some patients with TP53 mutations have HER2 overexpression. Patients with HER2 overexpression may be candidates for HER2-directed therapies such as trastuzumab, as well as several other new drugs in development. Patients whose tumors have hormone receptors (HRs) are somewhat more likely to respond to hormonal therapy than patients whose tumors do not have HRs. Most gynecologic oncologists typically test their patients for the TCGA-indicated biomarkers, HRs, and HER2. So, many of the diagnostic and prognostic biomarkers are also predictive for response to therapy.

In terms of biomarkers that might be on the horizon, one of them is CA125. While we typically think of CA125 as a prognostic biomarker for ovarian cancer, it may also be prognostic for endometrial cancer. An elevated CA125 level makes us concerned that the disease has spread beyond the uterus. In addition, the CA125 level may be predictive of the response to systemic therapy in patients with advanced or metastatic endometrial cancer, and we frequently use it in our practice. Finally, a variety of proteomic biomarkers that can be excreted or expressed from the cancer and pass into the vagina could potentially be used for diagnosis.