Following the Keynote B21 trial, clinicians have become more selective with adjuvant immunotherapy in endometrial cancer. The study showed minimal benefit for pMMR patients and less impressive gains overall in its lower-risk population compared to advanced disease trials. This has led to a practice of reserving adjuvant chemo-IO primarily for stage 3 dMMR patients.

The GOG-B21 trial found that while adding pembrolizumab to chemotherapy benefits the dMMR subgroup, it paradoxically leads to worse outcomes in the pMMR subgroup. This highlights the critical need for molecular testing to avoid potential harm.

The four TCGA molecular profiles (e.g., POLE-mutated, p53-abnormal) have evolved beyond predicting outcomes to actively guiding treatment, such as de-escalating therapy for low-risk groups and escalating for high-risk ones.

Based on translational data from the RUBY trial, experts are most cautious about recommending frontline checkpoint inhibitors for patients in the "No Specific Molecular Profile" (NSMP) subgroup of pMMR endometrial cancer, suggesting this group may not benefit.

The PORTEC3 study revealed that the benefit of adding chemotherapy to pelvic radiation was concentrated in patients with p53-abnormal tumors. In contrast, those with POLE-mutated or mismatch repair deficient (dMMR) cancers saw little to no benefit, suggesting molecular subtypes should guide adjuvant therapy decisions.

Clinicians are struggling to implement the new FIGO 2023 molecular staging for endometrial cancer. While prognostically significant, it reclassifies patients (e.g., from Stage 1 to 2C) without clear, validated evidence on how to alter treatment based on the new stage. This gap between staging and evidence-based action creates clinical uncertainty.

Clinicians anecdotally report that immunotherapy is changing the pattern of recurrence in endometrial cancer. Instead of widespread disease, patients often develop isolated recurrences in a single location. This shift allows for the use of local therapies, like radiation, to treat the single spot while continuing the effective systemic immunotherapy.

While immunotherapy is transformational for DMMR endometrial cancer, its benefit is much smaller for the PMMR majority (two-thirds of patients). This reality requires more nuanced patient counseling and selective use in this population.

Mirroring success in rectal cancer, a new trial is exploring neoadjuvant immunotherapy for localized, MSI-high endometrial cancer. This strategy could potentially allow patients to avoid surgery and radiation, which is a particularly compelling option for those who wish to preserve their fertility.