What is the recommended management for a patient with early-stage endometrial adenocarcinoma and a Next-Generation Sequencing (NGS) panel showing clinically significant pathogenic mutations in Phosphatase and Tensin Homolog (PTEN) (exon 3) and Kirsten Rat Sarcoma viral oncogene homolog (KRAS) (exon 2), with wild-type status for Tumor Protein p53 (TP53), MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and DNA Polymerase Epsilon (POLE)?

Management of Endometrial Adenocarcinoma with PTEN and KRAS Mutations

Molecular Classification

This tumor should be classified 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 status. 1

The molecular profile you describe—PTEN (exon 3) and KRAS (exon 2) mutations with wild-type TP53, intact MMR proteins (MLH1, MSH2, MSH6), and wild-type POLE—definitively places this tumor in the NSMP molecular subgroup. 1, 2 This subgroup represents 30-40% of endometrial cancers and is characterized by the absence of POLE hotspot mutations, intact MMR proteins, and wild-type TP53. 2

Critical point: KRAS and PTEN mutations are expected molecular alterations in endometrioid carcinomas and do NOT confer high-risk status in the absence of TP53 abnormality. 1 These mutations are extremely common in endometrial cancer, with PTEN mutations occurring in 57-61% and KRAS mutations in 23% of cases. 3, 4

Essential Information Required Before Treatment Decision

Before proceeding with treatment recommendations, you must obtain the following specific information:

• FIGO stage with precise depth of myometrial invasion: Determine if this is stage IA (<50% myometrial invasion) versus stage IB (≥50% myometrial invasion). 1, 5

• Lymphovascular space invasion (LVSI) status: Classify as absent, focal, or substantial LVSI, as this directly impacts treatment decisions. 6, 1

• Histologic grade: Confirm whether this is grade 1,2, or 3 endometrioid adenocarcinoma. 6

• Patient age: Specifically determine if the patient is ≥60 years old, as this influences adjuvant therapy recommendations. 1

• Cervical stromal involvement: Confirm stage II disease if present. 6, 5

Risk Stratification Algorithm for NSMP Tumors

Once you have the above information, apply the following ESMO 2022 risk stratification framework for NSMP molecular subtype:

Low-Risk NSMP Disease (No Adjuvant Therapy Required)

• Stage IA (G1-G2) endometrioid type with no or focal LVSI 6
• Management: Observation alone; no adjuvant therapy indicated 6, 1

Intermediate-Risk NSMP Disease

• Stage IA G3 endometrioid with no or focal LVSI 6
• Stage IB (G1-G2) endometrioid with no or focal LVSI 6
• Stage II G1 endometrioid with no or focal LVSI 6
• Management: Vaginal brachytherapy is preferred; observation is an option if no additional risk factors present 1

High-Intermediate-Risk NSMP Disease

• Stage I endometrioid (any grade, any depth of invasion) with substantial LVSI 6
• Stage IB G3 endometrioid regardless of LVSI 6
• Stage II G1 endometrioid with substantial LVSI 6
• Stage II G2-G3 endometrioid 6
• Management: External beam radiotherapy (EBRT) with or without vaginal brachytherapy boost, or vaginal brachytherapy alone 5

Treatment Timing

If adjuvant radiotherapy is indicated based on the risk stratification above, it should begin once the vaginal cuff has healed but no later than 12 weeks after surgery. 1

Prognostic Implications of Specific Mutations

PTEN mutations in endometrial cancer are associated with younger age (<60 years), early-stage disease, endometrioid histology, non-recurrence, and better overall survival. 4 KRAS mutations occur in approximately 23% of endometrial cancers and are common in the NSMP subgroup. 4 The combination of PTEN and KRAS mutations without TP53 abnormality confirms the intermediate-prognosis NSMP classification rather than high-risk disease. 1, 2

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 misclassify this as high-risk disease: The presence of KRAS/PTEN mutations without TP53 abnormality does NOT confer high-risk status. 1

• Do not rely on clinical staging alone: It underestimates disease extent in some cases; surgical staging provides accurate information for treatment decisions. 5

• Never perform uterine morcellation: This risks spreading cancerous tissue and compromises pathological assessment. 5