A significant challenge in assessing complete response after neoadjuvant immunotherapy for rectal cancer is the presence of mucin pools. These imaging abnormalities can persist for up to two years, mimicking residual tumor and complicating decisions about non-operative management.

Even with negative biopsies, post-immunotherapy scans and scopes can show residual masses or mucin pools that are mistaken for active cancer. This makes determining a true complete clinical response difficult and can lead to unnecessary surgeries where no cancer is found, as these changes can take years to resolve.

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.

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.

Despite significant interest, circulating tumor DNA (ctDNA) is not yet an actionable tool for guiding the duration of maintenance immunotherapy in endometrial cancer. While studies like DuoE show ctDNA levels correlate with outcomes, there is no evidence to support using its clearance to decide when to stop treatment. It remains a prognostic, not a predictive, biomarker for this purpose.

The future of GYN oncology immunotherapy is diverging. For responsive cancers like endometrial, the focus is on refining biomarkers and overcoming resistance. For historically resistant cancers like ovarian, the strategy shifts to using combinatorial approaches (e.g., CAR-NKs, vaccines) to fundamentally alter the tumor microenvironment itself, making it more receptive to an immune response.

For MSI-high patients responding to immunotherapy, a lingering mass on a CT scan may not be active cancer. A negative ctDNA test can help confirm that the visible lesion is likely just scar tissue, potentially averting unnecessary surgery.

Disparate clinical trial results in endometrial cancer suggest a mechanistic difference between immunotherapy targets. PD-1 inhibitors (dostarlimab, pembrolizumab) have shown pronounced responses, whereas the PD-L1 inhibitor atezolizumab did not, indicating that targeting the PD-1 receptor may be a more robust strategy in GYN cancers.

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.