HER2 positivity is a strong negative prognostic marker even in early-stage (Stage 1) uterine cancer, associated with a 50% recurrence rate versus 17% in HER2-negative cases, despite most patients receiving chemotherapy.
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 RUBY trial surprisingly revealed that patients with p53-mutated tumors, a subset of the generally less responsive pMMR group, derive significant benefit from adding immunotherapy to chemotherapy, challenging previous assumptions about this molecular subtype.
Inconsistent methods for assessing biomarkers like PD-L1 (CPS vs. TAP scoring), p53 (IHC vs. sequencing), and HRR (different panels) across major clinical trials make it difficult to compare results and identify a reliable predictive marker for endometrial cancer.
While circulating tumor DNA (ctDNA) is currently hard to act on for escalating treatment, its most promising near-term application may be in identifying patients who can safely stop or reduce therapy, rather than determining when to start it.
Clinicians should consider re-biopsying tumors at recurrence, not upfront. Endometrial cancer can evolve, and a metastatic site may develop new targetable markers, like HER2, that were not present in the primary tumor, opening up new treatment avenues.
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.
Even when neoadjuvant immunotherapy achieves an excellent systemic response in MSI-high endometrial cancer, residual disease frequently persists within the uterus. This finding cautions against forgoing hysterectomy based on imaging or systemic response alone.
For patients on immunotherapy who develop an isolated site of progression while other lesions remain controlled, a practical strategy is to continue the checkpoint inhibitor and treat the single progressive site with localized therapy, such as radiation.
Data from DUO-E and RUBY Part 2 trials show adding a PARP inhibitor to chemo-immunotherapy provides only a small PFS benefit. Experts are not convinced of its value, citing a lack of overall survival benefit and potential for harm.
While direct comparative trials are lacking, experts note that single-agent activity appears higher for PD-1 inhibitors (pembrolizumab, dostarlimab) than PD-L1 inhibitors (avelumab, durvalumab) in endometrial cancer, leading to a clinical preference for the PD-1 class.
As various maintenance therapies (immunotherapy, ADCs) are integrated into endometrial cancer treatment, the next major clinical question is defining how long these agents need to be continued to maximize benefit while minimizing long-term toxicity and patient burden.