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Новые подходы в лечении агрессивных подтипов рака эндометрия, прогностическая роль HER2-статуса опухоли. Систематический обзор
Новые подходы в лечении агрессивных подтипов рака эндометрия, прогностическая роль HER2-статуса опухоли. Систематический обзор
Саевец В.В., Кузьмин Н.К., Шаманова А.Ю. Новые подходы в лечении агрессивных подтипов рака эндометрия, прогностическая роль HER2-статуса опухоли. Систематический обзор. Современная Онкология. 2025;27(3):267–274. DOI: 10.26442/18151434.2025.3.203442
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
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Аннотация
Обоснование. Рак эндометрия (РЭ) остается одной из самых актуальных проблем в онкогинекологии. Агрессивные гистологические подтипы РЭ (серозный, светлоклеточный, карциносаркома) характеризуются неудовлетворительным ответом на стандартную терапию и неблагоприятным прогнозом. Для приведенных подтипов характерны высокая частота (до 49%) HER2-позитивности и тесная связь с p53-аберрантным молекулярным профилем, что открывает возможности для таргетной терапии.
Цель. Обобщить современные данные о подходах к диагностике HER2-статуса, эффективности анти-HER2-терапии и прогностической роли HER2-статуса опухоли при агрессивных подтипах РЭ.
Материалы и методы. Для подготовки статьи проведен систематический поиск публикаций в базах данных PubMed, MEDLINE, Cochrane Library и Elibrary.ru за 2000–2024 гг. Использованы ключевые слова и их комбинации: «рак эндометрия», «серозная карцинома», «карциносаркома», «HER2», «ERBB2», «таргетная терапия», «трастузумаб», «трастузумаб дерукстекан», «диситамаб ведотин», «endometrial cancer», «uterine serous carcinoma», «carcinosarcoma», «HER2-positive», «targeted therapy». Критериям включения соответствовали оригинальные исследования, обзоры литературы, метаанализы и клинические случаи, посвященные распространенности HER2-позитивности, эффективности анти-HER2-терапии и прогностической роли HER2-статуса при агрессивных гистологических подтипах РЭ. Из поиска исключены статьи, не прошедшие рецензирование, а также публикации, не содержащие данные о методах определения HER2-статуса (иммуногистохимии, методе FISH) или ответа на лечение.
Результаты. Установлена значительная гетерогенность HER2-экспрессии с максимальной частотой при серозном РЭ (49%) и карциносаркоме (40%). Показано, что HER2-позитивность ассоциируется с сокращением общей выживаемости на 45% (ОР 2,1, 95% ДИ 1,4-3,2; p<0,001). В терапевтических исследованиях продемонстрирована высокая эффективность трастузумаба в комбинации с химиотерапией при первичном лечении серозного РЭ (медиана выживаемости без прогрессирования 17,9 мес vs 9,3 мес, ОР 0,40; p=0,013). Трастузумаб дерукстекан показал значимую активность даже при экспрессии HER2 2+ (частота объективного ответа 25–70% при HER2 2+), с медианой общей выживаемости 26,0 мес при HER2 3+. Выявлены проблемы стандартизации HER2-тестирования и гетерогенности экспрессии.
Заключение. HER2-таргетная терапия стала новым стандартом лечения агрессивных подтипов РЭ. Наибольшая эффективность достигнута при использовании конъюгатов антител с цитостатиками, особенно при HER2-гиперэкспрессии. Критически важными направлениями являются разработка единых стандартов HER2-тестирования, преодоление резистентности и оптимизация комбинированных режимов. Перспективы связаны с адаптацией терапии к молекулярным подтипам и идентификацией предикторов ответа.
Ключевые слова: рак эндометрия, агрессивные гистологические подтипы рака эндометрия, серозная карцинома, карциносаркома, HER2, экспрессия HER2, таргетная терапия, трастузумаб дерукстекан
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.
Keywords: endometrial cancer, aggressive subtypes of endometrial cancer, serous carcinoma, carcinosarcoma, HER2, HER2 expression, targeted therapy, trastuzumab deruxtecan
Цель. Обобщить современные данные о подходах к диагностике HER2-статуса, эффективности анти-HER2-терапии и прогностической роли HER2-статуса опухоли при агрессивных подтипах РЭ.
Материалы и методы. Для подготовки статьи проведен систематический поиск публикаций в базах данных PubMed, MEDLINE, Cochrane Library и Elibrary.ru за 2000–2024 гг. Использованы ключевые слова и их комбинации: «рак эндометрия», «серозная карцинома», «карциносаркома», «HER2», «ERBB2», «таргетная терапия», «трастузумаб», «трастузумаб дерукстекан», «диситамаб ведотин», «endometrial cancer», «uterine serous carcinoma», «carcinosarcoma», «HER2-positive», «targeted therapy». Критериям включения соответствовали оригинальные исследования, обзоры литературы, метаанализы и клинические случаи, посвященные распространенности HER2-позитивности, эффективности анти-HER2-терапии и прогностической роли HER2-статуса при агрессивных гистологических подтипах РЭ. Из поиска исключены статьи, не прошедшие рецензирование, а также публикации, не содержащие данные о методах определения HER2-статуса (иммуногистохимии, методе FISH) или ответа на лечение.
Результаты. Установлена значительная гетерогенность HER2-экспрессии с максимальной частотой при серозном РЭ (49%) и карциносаркоме (40%). Показано, что HER2-позитивность ассоциируется с сокращением общей выживаемости на 45% (ОР 2,1, 95% ДИ 1,4-3,2; p<0,001). В терапевтических исследованиях продемонстрирована высокая эффективность трастузумаба в комбинации с химиотерапией при первичном лечении серозного РЭ (медиана выживаемости без прогрессирования 17,9 мес vs 9,3 мес, ОР 0,40; p=0,013). Трастузумаб дерукстекан показал значимую активность даже при экспрессии HER2 2+ (частота объективного ответа 25–70% при HER2 2+), с медианой общей выживаемости 26,0 мес при HER2 3+. Выявлены проблемы стандартизации HER2-тестирования и гетерогенности экспрессии.
Заключение. HER2-таргетная терапия стала новым стандартом лечения агрессивных подтипов РЭ. Наибольшая эффективность достигнута при использовании конъюгатов антител с цитостатиками, особенно при HER2-гиперэкспрессии. Критически важными направлениями являются разработка единых стандартов HER2-тестирования, преодоление резистентности и оптимизация комбинированных режимов. Перспективы связаны с адаптацией терапии к молекулярным подтипам и идентификацией предикторов ответа.
Ключевые слова: рак эндометрия, агрессивные гистологические подтипы рака эндометрия, серозная карцинома, карциносаркома, HER2, экспрессия HER2, таргетная терапия, трастузумаб дерукстекан
________________________________________________
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.
Keywords: endometrial cancer, aggressive subtypes of endometrial cancer, serous carcinoma, carcinosarcoma, HER2, HER2 expression, targeted therapy, trastuzumab deruxtecan
Полный текст
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41. Moukarzel LA, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of meta-plastic breast cancers and uterine carcinosarcomas. Mol Oncol. 2021;15(4):1024-109. DOI:10.1002/1878-0261.12813
42. Crane E, Naumann W, Tait D, et al. Molecular variations in uterine carcinosarcomas identify therapeutic opportunities. Int J Gynecol Cancer. 2020;30(4):480-8. DOI:10.1136/ijgc-2019-000920
43. Rottmann D, Snir OL, Wu X, et al. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Mod Pathol. 2020;33(1):118-27. DOI:10.1038/s41379-019-0358-x
44. Buza N. HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of the ISGyP Companion Society Session at the 2020 USCAP Annual Meeting. Int J Gynecol Pathol. 2021;40(1):17-23. DOI:10.1097/PGP.0000000000000711
45. Bartley AN, Washington MK, Ventura CB, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. DOI:10.5858/arpa.2016-0331-CP
46. Завалишина Л.Э., Горбань Н.А., Вторушин С.В., и др. Руководство по тестированию HER2-статуса. Злокачественные опухоли. 2024 [Zavalishina LE, Gorban' NA, Vtorushin SV, et al. Rukovodstvo po testirovaniiu HER2-statusa. Zlokachestvennye opukholi. 2024 (in Russian)]. DOI:10.18027/2224-5057-2024-10e-36
2. Sostoianie onkologicheskoi pomoshchi naseleniiu Rossii v 2024 godu. Pod red. A.D. Kaprina, V.V. Starinskogo, A.O. Shakhzadovoi. Moscow: MNIOI im. P.A. Gertsena – filial FGBU «NMITs radiologii» Minzdrava Rossii, 2025 (in Russian).
3. Baker-Rand H, Kitson SJ. Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment. Cancers (Basel). 2024;16(5):1028. DOI:10.3390/cancers16051028
4. Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27(1):16-41. DOI:10.1093/annonc/mdv484
5. McGunigal M, Liu J, Kalir T, et al. Survival Differences Among Uterine Papillary Serous, Clear Cell and Grade 3 Endometrioid Adenocarcinoma Endometrial Cancers: A National Cancer Database Analysis. Int J Gynecol Cancer. 2017;27(1):85-92. DOI:10.1097/IGC.0000000000000844
6. Li R, Yue Q. A nomogram for predicting overall survival in patients with endometrial carcinoma: A SEER-based study. Int J Gynaecol Obstet. 2023;161(3):744-50. DOI:10.1002/ijgo.14580
7. Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33):3841-80. DOI:10.1200/JCO.20.01076
8. Matulonis UA, Filiaci VL, Huang HQ, et al. Analysis of patient-reported outcomes (PROs) for GOG-258, a randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel (Cis-RT+CP) vs. carboplatin and paclitaxel (CP) for optimally debulked, locally advanced endometrial carcinoma: A Gynecologic Oncology Group/NRG study. JCO. 2018;36(Suppl. 15):5589-59. DOI:10.1200/jco.2018.36.15_suppl.5589
9. Powell MA, Cibula D, O'Malley DM, et al. Efficacy and safety of dostarlimab in combination with chemotherapy in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer in a phase 3, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Gynecol Oncol. 2025;192:40-9. DOI:10.1016/j.ygyno.2024.10.022
10. Westin SN, Moore KN, Guy M, et al. Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer: Longitudinal changes in circulating tumor DNA. JCO. 2025;43(16_suppl):5512-52. DOI:10.1200/jco.2025.43.16_suppl.5512
11. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-48. DOI:10.1056/NEJMoa2108330
12. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309. DOI:10.1016/S1470-2045(18)30079-2
13. Vermij L, Horeweg N, Leon-Castillo A, et al. HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes. Cancers (Basel). 2020;13(1):44. DOI:10.3390/cancers13010044
14. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469-87. DOI:10.1038/sj.onc.1210477
15. Talia KL, Banet N, Buza N. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18. DOI:10.1016/j.pathol.2022.11.004
16. Giordano SH, Franzoi MAB, Temin S, et al. Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2022;40(23):2612-65. DOI:10.1200/JCO.22.00519
17. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-97. DOI:10.1016/S0140-6736(10)61121-X
18. Diver EJ, Foster R, Rueda BR, Growdon WB. The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer. Oncologist. 2015;20(9):1058-68. DOI:10.1634/theoncologist.2015-0149
19. Aro K, Loukovaara M, Bützow R, Pasanen A. HER2 amplification and HER2 low expression in endometrial carcinoma: prevalence across molecular, histological and clinicopathological risk groups. BJC Rep. 2025;3(1):8. DOI:10.1038/s44276-025-00125-6
20. Gupta S, Bhati P, Nair I, et al. Study of frequency and prognostic significance of HER2 overexpression by immunohistochemistry in high-risk endometrial cancer: A retrospective cohort study. Cancer Res Stat Treat. 2024;7(3):281-9.
21. Halle MK, Tangen IL, Berg HF, et al. HER2 expression patterns in paired primary and metastatic endometrial cancer lesions. Br J Cancer. 2018;118(3):378-87. DOI:10.1038/bjc.2017.422
22. Erickson BK, Najjar O, Damast S, et al. Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study. Gynecol Oncol. 2020;159(1):17-22. DOI:10.1016/j.ygyno.2020.07.016
23. Maadi H, Soheilifar MH, Choi WS, et al. Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma. Cancers (Basel). 2021;13(14):3540. DOI:10.3390/cancers13143540
24. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117-27. DOI:10.1016/j.ccr.2004.06.022
25. Tsang RY, Sadeghi S, Finn RS. Lapatinib, a Dual-Targeted Small Molecule Inhibitor of EGFR and HER2, in HER2-Amplified Breast Cancer: From Bench to Bedside. Clinical Medicine Insights: Therapeutics. 2011;3. DOI:10.4137/cmt.s3783
26. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol. 2018;36(20):2044-101. DOI:10.1200/JCO.2017.76.5966
27. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res. 2020;26(15):3928-95. DOI:10.1158/1078-0432.CCR-20-0953
28. Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(1):15-20. DOI:10.1016/j.ygyno.2009.09.025
29. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-30. DOI:10.1016/S1470-2045(19)30863-0
30. Kulukian A, Lee P, Taylor J, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020;19(4):976-87. DOI:10.1158/1535-7163.MCT-19-0873
31. Erickson BK, Enserro D, Lankes HA, et al. Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026). JCO. 2024;42(16_suppl):TPS5641-P5641. DOI:10.1200/jco.2024.42.16_suppl.tps5641
32. O'Brien NA, Huang HKT, McDermott MSJ, et al. Tucatinib has Selective Activity in HER2-Positive Cancers and Significant Combined Activity with Approved and Novel Breast Cancer-Targeted Therapies. Mol Cancer Ther. 2022;21(5):751-61. DOI:10.1158/1535-7163.MCT-21-0847
33. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. JAMA Oncol. 2023;9(2):197-205. DOI:10.1001/jamaoncol.2022.5610
34. Stinchcombe T, Monk BJ, Okines AFC, et al. SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations (trial in progress). J Clin Oncol. 2021;39:TPS3151. DOI:10.1200/JCO.2021.381.5_suppl.TPS3151
35. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47-58. DOI:10.1200/JCO.23.02005
36. Willis K, Snead K, Thurman R, et al. Disitamab vedotin, an investigational HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical cancer models. Cancer Research. 2023;83(7):560.
37. Nishikawa T, Hasegawa K, Matsumoto K, et al. Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial. J Clin Oncol. 2023;41(15):2789-179. DOI:10.1200/JCO.22.02558
38. National Library of Medicine (US). A Phase 2 Basket Study of Disitamab Vedotin in Adult Subjects With Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors That Express HER2. Identifier: NCT06003231. August 21, 2023 [Updated July 8, 2025]. Available at: https://clinicaltrials.gov/study/NCT06003231. Accessed: 04.09.2024.
39. Rak tela matki i sarkomy matki. Klinicheskie rekomendatsii Minzdrava Rossii. Available at: https://cr.minzdrav.gov.ru/recomend/460_3. Accessed: 04.09.2024 (in Russian).
40. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Uterine Neoplasms. Version 3.2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed: 04.09.2024.
41. Moukarzel LA, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of meta-plastic breast cancers and uterine carcinosarcomas. Mol Oncol. 2021;15(4):1024-109. DOI:10.1002/1878-0261.12813
42. Crane E, Naumann W, Tait D, et al. Molecular variations in uterine carcinosarcomas identify therapeutic opportunities. Int J Gynecol Cancer. 2020;30(4):480-8. DOI:10.1136/ijgc-2019-000920
43. Rottmann D, Snir OL, Wu X, et al. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Mod Pathol. 2020;33(1):118-27. DOI:10.1038/s41379-019-0358-x
44. Buza N. HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of the ISGyP Companion Society Session at the 2020 USCAP Annual Meeting. Int J Gynecol Pathol. 2021;40(1):17-23. DOI:10.1097/PGP.0000000000000711
45. Bartley AN, Washington MK, Ventura CB, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. DOI:10.5858/arpa.2016-0331-CP
46. Zavalishina LE, Gorban' NA, Vtorushin SV, et al. Rukovodstvo po testirovaniiu HER2-statusa. Zlokachestvennye opukholi. 2024 (in Russian). DOI:10.18027/2224-5057-2024-10e-36
2. Состояние онкологической помощи населению России в 2024 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2025 [Sostoianie onkologicheskoi pomoshchi naseleniiu Rossii v 2024 godu. Pod red. A.D. Kaprina, V.V. Starinskogo, A.O. Shakhzadovoi. Moscow: MNIOI im. P.A. Gertsena – filial FGBU «NMITs radiologii» Minzdrava Rossii, 2025 (in Russian)].
3. Baker-Rand H, Kitson SJ. Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment. Cancers (Basel). 2024;16(5):1028. DOI:10.3390/cancers16051028
4. Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27(1):16-41. DOI:10.1093/annonc/mdv484
5. McGunigal M, Liu J, Kalir T, et al. Survival Differences Among Uterine Papillary Serous, Clear Cell and Grade 3 Endometrioid Adenocarcinoma Endometrial Cancers: A National Cancer Database Analysis. Int J Gynecol Cancer. 2017;27(1):85-92. DOI:10.1097/IGC.0000000000000844
6. Li R, Yue Q. A nomogram for predicting overall survival in patients with endometrial carcinoma: A SEER-based study. Int J Gynaecol Obstet. 2023;161(3):744-50. DOI:10.1002/ijgo.14580
7. Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33):3841-80. DOI:10.1200/JCO.20.01076
8. Matulonis UA, Filiaci VL, Huang HQ, et al. Analysis of patient-reported outcomes (PROs) for GOG-258, a randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel (Cis-RT+CP) vs. carboplatin and paclitaxel (CP) for optimally debulked, locally advanced endometrial carcinoma: A Gynecologic Oncology Group/NRG study. JCO. 2018;36(Suppl. 15):5589-59. DOI:10.1200/jco.2018.36.15_suppl.5589
9. Powell MA, Cibula D, O'Malley DM, et al. Efficacy and safety of dostarlimab in combination with chemotherapy in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer in a phase 3, randomized, placebo-controlled trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). Gynecol Oncol. 2025;192:40-9. DOI:10.1016/j.ygyno.2024.10.022
10. Westin SN, Moore KN, Guy M, et al. Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer: Longitudinal changes in circulating tumor DNA. JCO. 2025;43(16_suppl):5512-52. DOI:10.1200/jco.2025.43.16_suppl.5512
11. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-48. DOI:10.1056/NEJMoa2108330
12. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309. DOI:10.1016/S1470-2045(18)30079-2
13. Vermij L, Horeweg N, Leon-Castillo A, et al. HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes. Cancers (Basel). 2020;13(1):44. DOI:10.3390/cancers13010044
14. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469-87. DOI:10.1038/sj.onc.1210477
15. Talia KL, Banet N, Buza N. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18. DOI:10.1016/j.pathol.2022.11.004
16. Giordano SH, Franzoi MAB, Temin S, et al. Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2022;40(23):2612-65. DOI:10.1200/JCO.22.00519
17. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-97. DOI:10.1016/S0140-6736(10)61121-X
18. Diver EJ, Foster R, Rueda BR, Growdon WB. The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer. Oncologist. 2015;20(9):1058-68. DOI:10.1634/theoncologist.2015-0149
19. Aro K, Loukovaara M, Bützow R, Pasanen A. HER2 amplification and HER2 low expression in endometrial carcinoma: prevalence across molecular, histological and clinicopathological risk groups. BJC Rep. 2025;3(1):8. DOI:10.1038/s44276-025-00125-6
20. Gupta S, Bhati P, Nair I, et al. Study of frequency and prognostic significance of HER2 overexpression by immunohistochemistry in high-risk endometrial cancer: A retrospective cohort study. Cancer Res Stat Treat. 2024;7(3):281-9.
21. Halle MK, Tangen IL, Berg HF, et al. HER2 expression patterns in paired primary and metastatic endometrial cancer lesions. Br J Cancer. 2018;118(3):378-87. DOI:10.1038/bjc.2017.422
22. Erickson BK, Najjar O, Damast S, et al. Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study. Gynecol Oncol. 2020;159(1):17-22. DOI:10.1016/j.ygyno.2020.07.016
23. Maadi H, Soheilifar MH, Choi WS, et al. Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma. Cancers (Basel). 2021;13(14):3540. DOI:10.3390/cancers13143540
24. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117-27. DOI:10.1016/j.ccr.2004.06.022
25. Tsang RY, Sadeghi S, Finn RS. Lapatinib, a Dual-Targeted Small Molecule Inhibitor of EGFR and HER2, in HER2-Amplified Breast Cancer: From Bench to Bedside. Clinical Medicine Insights: Therapeutics. 2011;3. DOI:10.4137/cmt.s3783
26. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol. 2018;36(20):2044-101. DOI:10.1200/JCO.2017.76.5966
27. Fader AN, Roque DM, Siegel E, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res. 2020;26(15):3928-95. DOI:10.1158/1078-0432.CCR-20-0953
28. Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(1):15-20. DOI:10.1016/j.ygyno.2009.09.025
29. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-30. DOI:10.1016/S1470-2045(19)30863-0
30. Kulukian A, Lee P, Taylor J, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020;19(4):976-87. DOI:10.1158/1535-7163.MCT-19-0873
31. Erickson BK, Enserro D, Lankes HA, et al. Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026). JCO. 2024;42(16_suppl):TPS5641-P5641. DOI:10.1200/jco.2024.42.16_suppl.tps5641
32. O'Brien NA, Huang HKT, McDermott MSJ, et al. Tucatinib has Selective Activity in HER2-Positive Cancers and Significant Combined Activity with Approved and Novel Breast Cancer-Targeted Therapies. Mol Cancer Ther. 2022;21(5):751-61. DOI:10.1158/1535-7163.MCT-21-0847
33. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. JAMA Oncol. 2023;9(2):197-205. DOI:10.1001/jamaoncol.2022.5610
34. Stinchcombe T, Monk BJ, Okines AFC, et al. SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations (trial in progress). J Clin Oncol. 2021;39:TPS3151. DOI:10.1200/JCO.2021.381.5_suppl.TPS3151
35. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47-58. DOI:10.1200/JCO.23.02005
36. Willis K, Snead K, Thurman R, et al. Disitamab vedotin, an investigational HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical cancer models. Cancer Research. 2023;83(7):560.
37. Nishikawa T, Hasegawa K, Matsumoto K, et al. Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial. J Clin Oncol. 2023;41(15):2789-179. DOI:10.1200/JCO.22.02558
38. National Library of Medicine (US). A Phase 2 Basket Study of Disitamab Vedotin in Adult Subjects With Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors That Express HER2. Identifier: NCT06003231. August 21, 2023 [Updated July 8, 2025]. Available at: https://clinicaltrials.gov/study/NCT06003231. Accessed: 04.09.2024.
39. Рак тела матки и саркомы матки. Клинические рекомендации Минздрава России. Режим доступа: https://cr.minzdrav.gov.ru/recomend/460_3. Ссылка активна на 04.09.2024 [Rak tela matki i sarkomy matki. Klinicheskie rekomendatsii Minzdrava Rossii. Available at: https://cr.minzdrav.gov.ru/recomend/460_3. Accessed: 04.09.2024 (in Russian)].
40. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Uterine Neoplasms. Version 3.2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed: 04.09.2024.
41. Moukarzel LA, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of meta-plastic breast cancers and uterine carcinosarcomas. Mol Oncol. 2021;15(4):1024-109. DOI:10.1002/1878-0261.12813
42. Crane E, Naumann W, Tait D, et al. Molecular variations in uterine carcinosarcomas identify therapeutic opportunities. Int J Gynecol Cancer. 2020;30(4):480-8. DOI:10.1136/ijgc-2019-000920
43. Rottmann D, Snir OL, Wu X, et al. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Mod Pathol. 2020;33(1):118-27. DOI:10.1038/s41379-019-0358-x
44. Buza N. HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of the ISGyP Companion Society Session at the 2020 USCAP Annual Meeting. Int J Gynecol Pathol. 2021;40(1):17-23. DOI:10.1097/PGP.0000000000000711
45. Bartley AN, Washington MK, Ventura CB, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. DOI:10.5858/arpa.2016-0331-CP
46. Завалишина Л.Э., Горбань Н.А., Вторушин С.В., и др. Руководство по тестированию HER2-статуса. Злокачественные опухоли. 2024 [Zavalishina LE, Gorban' NA, Vtorushin SV, et al. Rukovodstvo po testirovaniiu HER2-statusa. Zlokachestvennye opukholi. 2024 (in Russian)]. DOI:10.18027/2224-5057-2024-10e-36
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Авторы
В.В. Саевец*1,2, Н.К. Кузьмин1, А.Ю. Шаманова1,2
1ГАУЗ «Челябинский областной клинический центр онкологии и ядерной медицины», Челябинск, Россия;
2ФГБОУ ВО «Южно-Уральский государственный медицинский университет» Минздрава России, Челябинск, Россия
*lalili2013@mail.ru
1Chelyabinsk Regional Clinical Centre for Oncology and Nuclear Medicine, Chelyabinsk, Russia;
2South-Ural State Medical University, Chelyabinsk, Russia
*lalili2013@mail.ru
1ГАУЗ «Челябинский областной клинический центр онкологии и ядерной медицины», Челябинск, Россия;
2ФГБОУ ВО «Южно-Уральский государственный медицинский университет» Минздрава России, Челябинск, Россия
*lalili2013@mail.ru
________________________________________________
1Chelyabinsk Regional Clinical Centre for Oncology and Nuclear Medicine, Chelyabinsk, Russia;
2South-Ural State Medical University, Chelyabinsk, Russia
*lalili2013@mail.ru
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