New approaches in the treatment of aggressive subtypes of endometrial cancer and the prognostic role of HER2 status of the tumor: A systematic review

Background. Endometrial cancer (EC) remains one of the most pressing problems in gynecological oncology. Aggressive histological subtypes of EC (serous, clear cell, carcinosarcoma) are characterized by an insufficient response to standard therapy and a poor prognosis. The above subtypes have a high rate (up to 49%) of HER2 positivity and a strong association with the p53-aberrant molecular profile, which presents potential opportunities for targeted therapy.

Aim. To review current data on approaches to the diagnosis of HER2 status, the effectiveness of anti-HER2 therapy, and the prognostic role of HER2 status of the tumor in aggressive subtypes of EC.

Materials and methods. A systematic search of publications was conducted in the PubMed, MEDLINE, Cochrane Library, and Elibrary.ru databases for 2000–2024. Key words and their combinations were used: “endometrial cancer,” “serous carcinoma,” “carcinosarcoma,” “HER2,” “ERBB2,” “targeted therapy,” “trastuzumab,” “trastuzumab deruxtecan,” “disitamab vedotin,” “endometrial cancer,” “uterine serous carcinoma,” “carcinosarcoma,” “HER2-positive,” “targeted therapy.” The inclusion criteria were met by original studies, literature reviews, meta-analyses, and case reports on the prevalence of HER2 positivity, the efficacy of anti-HER2 therapy, and the prognostic role of HER2 status in aggressive histologic subtypes of EC. Excluded from the search were articles that have not been reviewed, as well as publications that do not report data on methods for determining HER2 status (immunohistochemistry, FISH method) or response to treatment.

Results. Significant heterogeneity of HER2 expression was found with a maximum frequency in serous EC (49%) and carcinosarcoma (40%). HER2-positivity has been shown to be associated with a 45% reduction in overall survival (HR 2.1, 95% CI 1.4-3.2; p<0,001). Therapeutic studies have demonstrated the high efficacy of trastuzumab in combination with chemotherapy in the primary treatment of serous EC (median progression-free survival 17.9 months vs 9.3 months, HR 0.40; p=0.013). Trastuzumab deruxtecan showed significant activity even with expression of HER2 2+ (objective response rate 25-70% with of HER2 expression level 2+), with a median overall survival 26.0 months with HER2 expression 3+. The problems of standardization of HER2 testing and heterogeneity of expression are revealed.

Conclusion. HER2-targeted therapy has become the new standard of treatment for aggressive subtypes of EC. The greatest effectiveness was achieved when using antibody conjugates with cytostatics, especially with HER2 overexpression. The development of unified HER2 testing standards, overcoming resistance, and optimizing combined modes are critically important areas. The perspectives are related to the adaptation of therapy to molecular subtypes and the identification of response predictors.