What is the next step in management for a patient with early-stage, grade 1 endometrial adenocarcinoma, with KRAS (Kirsten rat sarcoma viral oncogene homolog) and PTEN (phosphatase and tensin homolog) mutations, and wild-type TP53 (tumor protein p53), MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6), and POLE (DNA polymerase epsilon), after standard surgery?

Management of Early-Stage Grade 1 Endometrial Adenocarcinoma with KRAS/PTEN Mutations and Wild-Type TP53, MMR, and POLE

For this patient with early-stage, grade 1 endometrioid adenocarcinoma showing KRAS and PTEN mutations with wild-type TP53, MMR proteins, and POLE, the molecular profile classifies this as "No Specific Molecular Profile" (NSMP) subtype, which carries intermediate prognosis and requires risk-stratified adjuvant therapy based on stage, depth of myometrial invasion, and lymphovascular space invasion (LVSI) status. 1, 2

Molecular Classification and Prognostic Implications

Your NGS results place this tumor in the NSMP molecular subgroup, which represents 30-40% of endometrial cancers and has intermediate prognosis 2. This classification is determined by:

• Absence of POLE hotspot mutations (ultramutated subgroup excluded - these have excellent prognosis) 1, 2
• Intact MMR proteins (MLH1, MSH2, MSH6 wild-type, excluding microsatellite unstable subgroup) 1, 2
• Wild-type TP53 (excluding p53-aberrant subgroup with poor prognosis) 1, 2
• KRAS and PTEN mutations are characteristic molecular alterations of type I endometrioid adenocarcinomas and consistent with NSMP classification 1

Risk Stratification Algorithm

The next critical step is determining the specific risk category within NSMP tumors, which depends on:

Stage IA, Grade 1 Disease with No/Focal LVSI

• Classified as LOW RISK 1
• Observation alone is the standard of care - no adjuvant therapy indicated 1
• Multiple studies demonstrate no survival benefit from adjuvant treatment in this group 1

Stage IA, Grade 1 Disease with Age ≥60 Years and/or LVSI Present

• Vaginal brachytherapy is preferred 1
• Observation can be considered if no additional risk factors 1

Stage IB, Grade 1 Disease with No Adverse Risk Factors

• Vaginal brachytherapy is preferred 1
• Observation can be considered if truly no adverse features 1

Stage IB, Grade 1 Disease with Age ≥60 Years and/or LVSI

• External beam radiation therapy (EBRT) can be considered as category 2B option 1
• Vaginal brachytherapy remains an option 1

Essential Clinical Information Still Needed

To finalize the treatment recommendation, you must determine:

1. Exact FIGO stage (IA vs IB based on depth of myometrial invasion: <50% vs ≥50%) 1
2. LVSI status (absent, focal, or substantial) - this is a critical determinant 1
3. Patient age (particularly whether ≥60 years) 1
4. Completeness of surgical staging (whether lymphadenectomy was performed) 1
5. Lower uterine segment or cervical involvement 1

Treatment Initiation Timing

• Adjuvant radiotherapy, if indicated, should begin once the vaginal cuff has healed but no later than 12 weeks after surgery 1

Critical Pitfalls to Avoid

• Do not assume low-grade histology alone determines low risk - myometrial invasion depth and LVSI status are equally important for NSMP tumors 1
• Do not overlook the importance of expert pathology review - 31% of cases initially diagnosed as low-grade may be reclassified on expert review 3
• Do not provide adjuvant therapy to true stage IA, grade 1 NSMP patients without LVSI - this represents overtreatment with no survival benefit 1
• Recognize that KRAS/PTEN mutations without TP53 abnormality do NOT confer high-risk status - these are expected molecular alterations in endometrioid carcinomas 1, 4