Molecular Subtyping Is Shaping Uterine Cancer Treatment

Until the 2000s, cancer treatment decisions were based on histological subtypes and cancer stage. In recent years, however, molecular subtypes have also begun to influence these decisions, enabling more personalized and targeted approaches. Breast and lung cancer are among the best-known examples of how molecular subtypes affect treatment decisions. For instance, in HER2-positive breast cancer HER2-targeted therapies, or, in EGFR-mutant lung cancer, EGFR inhibitors, have been developed to target specific molecular features. These strategies improve treatment success and patients' quality of life.

Endometrial cancer begins in the inner lining of the uterus and is the most common type of uterine cancer. Treatment generally includes surgery, radiotherapy and chemotherapy, with immunotherapy added in recent years. However, the approaches vary according to factors such as disease stage, histological grade and subtype.

Molecular biology has played an increasing role in cancer treatment in recent years. Identifying molecular subtypes of endometrial cancer has enabled more personalized treatment plans. This article examines these molecular subtypes and their influence on treatment strategies.

Molecular Subtypes and Biomarkers

Molecular subtypes of endometrial cancer are classified according to their genetic and biochemical characteristics. This classification is important for predicting the disease course and determining treatment options. The main molecular subtypes are:

• POLE-Mutant (POLE mut): This subtype contains mutations in the exonuclease domain of the POLE gene and is generally characterized by a high mutation burden. POLE-mutant endometrial cancer generally has good patient outcomes despite adjuvant treatment and a favorable prognosis (disease course). Patients with this subtype have a good prognosis even without adjuvant treatment. Approximately 7-12% of endometrial cancers belong to this group.

• Microsatellite Instability-High (MSI-high) / Mismatch Repair-Deficient (MMRd): This subtype has high microsatellite instability and mutations in mismatch repair (MMR) genes, such as MLH1 and MSH2. These cancers generally respond well to immunotherapy. Approximately 20-30% of endometrial cancers belong to this group.

• p53-Abnormal (p53 abn): This subtype contains TP53 gene mutations and resembles high-grade serous ovarian cancer; treatment strategies may overlap between the two cancers. p53-abnormal endometrial cancer generally has an aggressive course and a high mortality rate. This subtype accounts for approximately 15% of endometrial cancers.

• Non-Specific Molecular Profile (NSMP): This subtype includes cancers without a distinct molecular profile and generally comprises hormone receptor-positive endometrioid cancers. Hormonal treatment is an attractive option for these cancers. NSMP accounts for approximately 40-50% of endometrial cancers.

Molecular Subtyping Has Refined Staging, Particularly in FIGO Stage I-II Endometrial Cancer

Molecular classifications are used to help patients at these stages receive more accurate, personalized treatment. The molecular classification of FIGO stage I-II endometrial cancer is shown below:

• Stage IAm-POLEmut: POLE-mutant endometrial carcinoma is confined to the uterine corpus or extends to the cervix and has a favorable prognosis regardless of lymphovascular space invasion (LVSI) or histological type.
• Stage IICm-p53abn: p53-abnormal endometrial carcinoma is confined to the uterine corpus with any myometrial invasion, with or without cervical invasion, and has a poor prognosis regardless of LVSI or histological type.

These classifications aim to establish more specific treatment strategies based on molecular features. Identifying molecular subtypes is important not only for FIGO stage I-II endometrial cancer but for treatment planning in endometrial cancer at all stages. However, FIGO's formal inclusion of these molecular classifications has accelerated their integration into clinical practice, particularly in the management of early-stage (I-II) cancer.

Treatment Strategies

Identifying molecular subtypes enables more targeted and personalized endometrial cancer treatment. For example, patients with POLE-mutant endometrial cancer may have a favorable prognosis even without adjuvant treatment, whereas chemotherapy combined with radiotherapy may be more effective in the p53-abnormal subtype.

Adjuvant Treatment Options

• Chemotherapy: The effectiveness of chemotherapy differs between POLE-mutant and p53-abnormal subtypes. While it substantially improves prognosis in the p53-abnormal subtype, it may provide no additional benefit in the POLE-mutant subtype.
• Radiotherapy: In the MSI-high/MMRd subtype, radiotherapy can be used alone or combined with immunotherapy to improve effectiveness.
• Immunotherapy: PD-1/PD-L1 inhibitors have high response rates, particularly in MSI-high/MMRd subtypes, and can make an important contribution to treatment.
• Hormonal Therapy: In the NSMP subtype, hormonal therapy may be an effective option for hormone receptor-positive endometrial cancer.

Conclusion

Identifying molecular subtypes of endometrial cancer enables more personalized, targeted treatment plans. This approach helps patients avoid unnecessary treatment while supporting the use of effective options. Future research and clinical trials will further clarify how molecular subtypes affect treatment strategies and enable new options to be developed.