Leading oncology experts are emphasizing the growing importance of molecular testing in guiding treatment decisions for endometrial cancer patients. According to Dr. Shannon Westin from MD Anderson Cancer Center, both NCCN and European guidelines now support molecular testing as a standard of care approach.
The molecular classification pathway begins with testing for POLE mutations, followed by assessment of mismatch repair status, and finally TP53 mutation analysis. This can be accomplished through either immunohistochemistry or next-generation sequencing (NGS). However, access to comprehensive molecular testing remains a challenge in some regions.
"It is still a work in progress, how we are using molecular testing to define the patient in front of us and to define the treatment," explains Dr. Westin. While the International Federation of Gynecology and Obstetrics (FIGO) has incorporated molecular testing into its staging system, accessibility concerns for NGS may limit some patients' ability to receive complete molecular profiling.
Treatment Implications of Molecular Subtypes
Emerging data suggests that tumors with different molecular profiles may require varying treatment intensities. POLE-mutated tumors potentially need minimal therapy, while TP53-mutated cases often benefit from more aggressive treatment approaches, even in early-stage disease.
For high-risk patients, the treatment landscape has evolved to include targeted approaches based on molecular findings. Immunotherapy has shown particular promise when combined with chemotherapy, especially in mismatch repair deficient (dMMR) tumors. Three immunotherapy drugs - dostarlimab, pembrolizumab, and durvalumab - have received FDA approval for endometrial cancer treatment.
Emerging Role of Targeted Therapies
The treatment arsenal has expanded with recent approvals of targeted therapies. Fam-trastuzumab deruxtecan (T-DXd) has demonstrated significant activity in HER2-positive endometrial cancers, which represent 20-30% of cases. Dr. Westin emphasizes the importance of proper HER2 testing, noting that some commercial NGS panels may miss HER2-positive cases by not including immunohistochemistry testing.
In Europe, the combination of durvalumab with olaparib has been approved for mismatch repair proficient endometrial cancer, offering new hope for this patient population. Ongoing clinical trials are exploring whether immunotherapy alone might be sufficient for certain molecular subtypes, potentially eliminating the need for chemotherapy in select patients.
Practical Considerations for Testing and Treatment
For patients experiencing disease progression after initial immunotherapy, options include alternative chemotherapy regimens such as gemcitabine and cisplatin, which have shown ability to overcome platinum resistance in some cases. The timing of molecular testing remains an important consideration, with some experts suggesting potential benefit in retesting after significant time has elapsed from initial diagnosis.
"The best bang for our buck when we give immunotherapy with chemotherapy is going to be for patients with mismatch repair deficiency," notes Dr. Westin, highlighting the importance of molecular profiling in treatment selection.
Future Directions
Research continues to refine the understanding of molecular subtypes and their treatment implications. Current clinical trials are investigating whether certain patient populations might benefit from immunotherapy alone, potentially reducing treatment-related toxicity while maintaining efficacy. Additionally, ongoing studies are exploring the role of PARP inhibitors and other targeted agents across different molecular subtypes of endometrial cancer.
