Dr Birrer on Molecular Stratification in Endometrial Cancer

Michael J. Birrer, MD, PhD, vice chancellor, the University of Arkansas for Medical Sciences, director, Winthrop P. Rockefeller Cancer Institute, director, Cancer Service Line, discusses the benefits of molecular profiling in patients with endometrial cancer, the variety of mutations that have been identified in this disease, and how stratifying patients based on the biomarkers their disease harbors allows for more individualized treatment decisions.

Groups such as The Cancer Genome Atlas (TCGA) group have worked to stratify the molecular features of endometrial cancer and correlate these features with prognosis. In 2013, TCGA group published the results of a genome characterization analysis, which identified 4 mutational subsets of endometrial cancer that correlated well with overall survival, Birrer says. These subsets were validated in tissue samples from the PORTEC-2 trial (ISRCTN16228756) biobank. PORTEC-2 was a randomized trial that aimed to improve patient selection for adjuvant therapy in patients with high- to intermediate-risk endometrial carcinoma.

The 4 molecular subgroups with distinct prognoses that were identified by TGCA were: a POLE-ultramutated subgroup, a microsatellite-unstable hypermutated/mismatch repair–deficient (dMMR) subgroup, a copy number–low subgroup, and a TP53mutation–driven copy number–high subgroup. A small subset of patients with endometrial cancer have POLE mutations, Birrer notes. These patients have high mutation levels, and their prognosis is good, Birrer explains. Researchers are investigating whether these patients require therapy at all, Birrer says.

Patients with dMMR disease have long represented a key subgroup of endometrial cancer because Lynch syndrome–associated endometrial cancer has been characterized for a long time, according to Birrer. Patients with dMMR endometrial cancer have high mutation levels but do not have as many mutations as those with POLE mutations, Birrer emphasizes.

Endometrial cancer with copy number–high differences is similar to serous tumors, shares characteristics with ovarian cancer, and has several mutations, Birrer says. Finally, the copy number–low endometrial cancer subtype is made up of disease with a non-specific molecular phenotype, Birrer explains.

Molecular classification is a method for stratifying patients that is included in the National Comprehensive Cancer Network Clinical Practice Guidelines for endometrial cancer, Birrer notes. Many oncologists stratify patients by these 4 subgroups, and this stratification influences treatment decisions and helps guide clinical trial enrollment, Birrer concludes.