Endometrial Cancer

Clinical Overview

Endometrial cancer represents a disease where molecular classification has become central to clinical management. Modern treatment algorithms integrate four distinct molecular subtypes—each with markedly different prognoses and treatment implications. ctDNA testing enables both molecular classification and minimal residual disease (MRD) detection, providing complementary prognostic information.

Key Clinical Context: Traditional endometrial cancer staging relies on surgical pathology (FIGO stage, grade, depth of invasion, lymph node status). However, molecular classification has emerged as a critical overlay that refines risk stratification and guides treatment decisions. The integration of molecular subtyping with ctDNA-based MRD detection is transforming endometrial cancer management.

• Molecular Classification: Four subtypes with 5-year recurrence-free survival ranging from 48% to 98%
• MMRd/MSI-H Disease (30%): Highly responsive to immune checkpoint inhibitors
• MRD Detection: Strong prognostic value with hazard ratios of 6.2-25.4 for recurrence
• Early Detection Limitations: ctDNA detection rates of 20-34% in early-stage endometrioid disease
• Clinical Validation: Interventional trials (RAINBO) ongoing to determine if molecular-guided therapy improves outcomes

Molecular Classification: PORTEC-3 Data

Four Subtypes with Distinct Prognoses

The PORTEC-3 trial validated molecular classification in high-risk endometrial cancer, demonstrating marked differences in 5-year recurrence-free survival (RFS) across four molecular subtypes. This classification has become foundational to modern endometrial cancer management and is recommended for risk stratification.

Clinical Implications: The 50-percentage-point difference in 5-year RFS between POLEmut (98%) and p53abn (48%) subtypes underscores the critical importance of molecular classification. This stratification informs decisions about adjuvant therapy intensity, surveillance frequency, and clinical trial enrollment.

Tissue Molecular Classification Remains Essential

While ctDNA testing can identify some molecular features (TP53 mutations, MSI status, PIK3CA mutations), comprehensive molecular classification currently requires tissue-based testing. Immunohistochemistry for mismatch repair proteins and sequencing for POLE mutations are standard approaches. ctDNA profiling serves as a complementary tool, particularly valuable in recurrent disease where repeat tissue biopsy may not be feasible.

ctDNA MRD Detection: Prognostic Value

Strong Risk Stratification But Not Yet Treatment-Guiding

ctDNA-based MRD detection in endometrial cancer demonstrates strong prognostic value across multiple studies. However, it is critical to distinguish between prognostic utility (predicting outcomes) and predictive utility (guiding treatment decisions that improve outcomes).

MRD Detection Performance

Prognostic vs Predictive: A Critical Distinction

Prognostic Value (Established): ctDNA MRD positivity reliably identifies patients at high risk for recurrence. The hazard ratios of 6.2-25.4 indicate that ctDNA-positive patients have substantially worse outcomes than ctDNA-negative patients. This information is valuable for risk stratification and surveillance planning.

Predictive Value (Not Yet Established): It is not yet proven that acting on ctDNA MRD results—such as intensifying therapy in ctDNA-positive patients or de-escalating in ctDNA-negative patients—improves clinical outcomes. While logical, this hypothesis requires validation in randomized interventional trials.

Stage-Specific Detection Rates

Clinical Limitation: ctDNA detection rates vary substantially by stage and histologic subtype. In early-stage endometrioid carcinoma, ctDNA detection rates are relatively low (20-34%), limiting clinical utility in this population. Detection rates are higher in advanced-stage disease, non-endometrioid histology, and recurrent disease.

Clinical Implication: ctDNA MRD testing is most informative in high-risk disease (advanced stage, high-grade, aggressive histology). In early-stage, low-grade endometrioid carcinoma, the low detection rate limits clinical utility, and a negative ctDNA result does not provide strong reassurance.

Immunotherapy in MMRd/MSI-H Disease

Established Clinical Benefit in ~30% of Patients

Mismatch repair deficient (MMRd) or microsatellite instability-high (MSI-H) endometrial cancer, representing approximately 30-33% of cases, demonstrates exceptional responsiveness to immune checkpoint inhibitors. This molecular subset is the most clearly actionable finding in endometrial cancer ctDNA profiling.

Pembrolizumab Monotherapy: KEYNOTE-158

The KEYNOTE-158 trial established pembrolizumab efficacy in previously treated MSI-H/MMRd solid tumors, with endometrial cancer showing particularly strong responses.

Clinical Significance: A 48% objective response rate to single-agent immunotherapy in previously treated endometrial cancer represents a substantial improvement over historical chemotherapy response rates (15-25%). The 16% complete response rate is particularly notable, with many CRs demonstrating durable benefit exceeding 2 years.

Dostarlimab: GARNET Trial

The GARNET trial evaluated dostarlimab in MMRd recurrent or advanced endometrial cancer, confirming the predictive value of MMR status.

The 3-fold difference in response rates between MMRd (42.3%) and MMRp (13.3%) disease confirms that MMR/MSI status is a predictive biomarker—identifying patients likely to benefit from immunotherapy.

Dostarlimab Plus Chemotherapy: RUBY Trial

The RUBY trial evaluated combination dostarlimab plus carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer, demonstrating substantial survival benefit.

Clinical Impact: The RUBY trial established dostarlimab plus chemotherapy as a standard first-line treatment for advanced MMRd/MSI-H endometrial cancer. An HR of 0.28 represents a 72% reduction in progression risk, translating to substantial improvement in median PFS (not reached vs 7.7 months).

HER2 Amplification: Emerging Target

Subset of Serous Carcinoma with Actionable Alteration

HER2 (ERBB2) amplification occurs in 13-31% of uterine serous carcinomas, an aggressive histologic subtype that typically falls within the p53abn molecular category. Recent data with HER2-directed antibody-drug conjugates demonstrate clinical benefit in this molecularly defined subset.

Trastuzumab Deruxtecan

Trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate approved in breast and gastric cancers, has shown activity in HER2-amplified endometrial cancer.

Clinical Significance: Uterine serous carcinoma has historically poor prognosis with limited treatment options. An ORR of 57.5% with trastuzumab deruxtecan in HER2-amplified disease represents a major therapeutic advance for this subset.

Testing Strategy

HER2 Testing Recommendations: HER2 amplification should be assessed in uterine serous carcinoma, particularly in the p53abn molecular subtype. Testing can be performed on tissue (IHC and FISH) or identified through comprehensive genomic profiling including ctDNA-based sequencing. Given the 13-31% prevalence and availability of effective HER2-directed therapy, HER2 testing should be considered in all serous carcinomas.

PI3K Pathway Alterations: Common but Limited Options

PTEN and PIK3CA Mutations Highly Prevalent

The PI3K/AKT/mTOR pathway is altered in the majority of endometrial cancers, primarily through PTEN loss (83%) and PIK3CA activating mutations (39%). While this pathway represents an attractive therapeutic target, clinical development of PI3K pathway inhibitors has been challenging.

PIK3CA Mutations

Alpelisib: PI3K Inhibitor

Alpelisib, a PI3K-alpha inhibitor with established efficacy in PIK3CA-mutant breast cancer, has shown preliminary activity in endometrial cancer.

Clinical Limitation: While PI3K pathway alterations are highly prevalent and the ORR of 35% with alpelisib is clinically meaningful, PI3K inhibitors have not yet received regulatory approval for endometrial cancer. Additionally, these agents are associated with significant toxicities (hyperglycemia, rash, diarrhea) that limit clinical use. Further trials are needed to establish optimal dosing, combinations, and patient selection strategies.

PTEN Loss

PTEN loss, detected in 83% of endometrial cancers, leads to constitutive PI3K pathway activation. However, PTEN loss is challenging to target therapeutically, as it represents loss of a tumor suppressor rather than an oncogenic driver amenable to small molecule inhibition. Clinical trials are evaluating AKT inhibitors, mTOR inhibitors, and combination strategies in PTEN-deficient endometrial cancer.

Clinical Summary

Integration of Molecular Classification and ctDNA Testing

Endometrial cancer management is increasingly driven by molecular classification, with ctDNA testing providing complementary prognostic information. The integration of molecular subtyping with MRD detection is transforming risk stratification and treatment selection.

Bottom Line: Endometrial cancer management is driven by molecular classification, with four subtypes demonstrating 5-year RFS ranging from 48% to 98%. MMRd/MSI-H disease (~30% of cases) is highly responsive to immunotherapy, with pembrolizumab achieving 48% ORR and dostarlimab plus chemotherapy achieving HR 0.28 in first-line treatment. ctDNA MRD detection demonstrates strong prognostic value (HR 6.2-25.4) but is not yet proven predictive—interventional trials (RAINBO, results 2028) will determine whether ctDNA-guided treatment improves outcomes. Clinical limitations include low detection rates (20-34%) in early-stage endometrioid disease. Tissue-based molecular classification remains essential for comprehensive risk stratification and treatment planning.