Molecular Subtyping Leads to New Targeted Trials in Endometrial Cancer

Ruchi Garg, MD, chair of gynecologic oncology at City of Hope Atlanta, Chicago, and Phoenix, discusses the impact of targeted therapies studies in patients with early and recurrent endometrial cancer.

HER2-targeted therapy, which is widely used in breast cancer, has been investigated in endometrial cancer successfully. Trastuzumab (Herceptin) was effective in patients with advanced serous endometrial cancer in a randomized phase 2 trial (NCT01367002), showing profession-free survival (PFS) benefit with chemotherapy vs chemotherapy alone.

According to Garg, another focus area in targeted therapy is the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification based on the Cancer Genome Atlas (TCGA), which identifies 4 molecular subtypes of endometrial cancers: POLE [polymerase epsilon]-mutated, mismatch repair deficiency [dMMR], p53 wild-type, and p53 abnormal. These were used for prognostic purposes and predicting response to treatment.

Trials focused on finding better targeted therapies for these individual subtypes are ongoing, including the PORTEC-4a (NCT03469674) and RAINBO (NCT05255653) umbrella trials of adjuvant therapy.

TRANSCRIPTION:

0:08 | Trastuzumab is a commonly used drug for breast cancer, but it has been shown to be effective in patients with advanced serous-type endometrial cancers. The trial that was done basically showed that there was a significant progression-free survival advantage in those patients with the utilization of HER2 therapy along with chemotherapy, and then continuation of maintenance of HER2 therapy until toxicity or progression of disease. That's been one of the targeted therapies that's been utilized.

0:52 | Another targeted approach that's up and coming is in patients with early endometrial cancer where we are looking at the ProMisE classification…. This came about with TCGA studies that were undertaken, and in 2013, they looked at the genomic profile of the endometrial cancers and came up with 4 molecular subtypes which are the targets that have been identified. These 4 were: one is called POLE ɛ, dMMR, and then the other is copy-number low p53–wild-type, and then copy-number high p53 mutation. They all have shown to have a prognostic value and prediction of response to treatment and outcomes for patients.